Occupational exposure to potentially toxic elements alters gene expression profiles in formal and informal Brazilian workers.

Chemical elements, such as toxic metals, have previously demonstrated their ability to alter gene expression in humans and other species. In this study, microarray analysis was used to compare the gene expression profiles of different occupational exposure populations: a) informal workers who perform soldering of jewelry inside their houses (n = 22) in São Paulo (SP) State; and b) formal workers from a steel company (n = 10) in Rio de Janeiro (RJ) state, Brazil. Control participants were recruited from the same neighborhoods without occupational chemical exposure (n = 19 in SP and n = 8 in RJ). A total of 68 blood samples were collected and RNA was extracted and hybridized using an Agilent microarray platform. Data pre-processing, statistical and pathway analysis were performed using GeneSpring software. Different expression was detected by fold-change analysis resulting in 16 up- and 33 down-regulated genes in informal workers compared to the control group. Pathway analysis revealed genes enriched in MAPK, Toll-like receptor, and NF-kappa B signaling pathways, involved in inflammatory and immune responses. In formal workers, 20 up- and 50 down-regulated genes were found related to antimicrobial peptides, defensins, neutrophil degranulation, Fc-gamma receptor-dependent phagocytosis, and pathways associated with atherosclerosis development, which is one of the main factors involved in the progression of cardiovascular diseases. The gene IFI27 was the only one commonly differentially expressed between informal and formal workers and is known to be associated with various types of cancer. In conclusion, differences in gene expression related to occupational exposure are mainly associated with inflammation and immune response. Previous research has identified a link between inflammation and immune responses and the development of chronic diseases, suggesting that prolonged occupational exposures to potentially toxic elements in Brazilian metal workers could lead to negative health outcomes. Further analysis should be carried out to investigate its direct effects and to validate causal associations.

Assessing personal exposure using Agent Based Modelling informed by sensors technology.

Technology innovations create possibilities to capture exposure-related data at a great depth and breadth. Considering, though, the substantial hurdles involved in collecting individual data for whole populations, this study introduces a first approach of simulating human movement and interaction behaviour, using Agent Based Modelling (ABM). A city scale ABM was developed for urban Thessaloniki, Greece that feeds into population-based exposure assessment without imposing prior bias, basing its estimations onto emerging properties of the behaviour of the computerised autonomous decision makers (agents) that compose the city-system. Population statistics, road and buildings networks data were transformed into human, road and building agents, respectively. Survey outputs with time-use patterns were associated with human agent rules, aiming to model representative to real-world behaviours. Moreover, time-geography of exposure data, derived from a local sensors campaign, was used to inform and enhance the model. As a prevalence of an agent-specific decision-making, virtual individuals of different sociodemographic backgrounds express different spatiotemporal behaviours and their trajectories are coupled with spatially resolved pollution levels. Personal exposure was evaluated by assigning PM concentrations to human agents based on coordinates, type of location and intensity of encountered activities. Study results indicated that PM2.5 inhalation adjusted exposure between housemates can differ by 56.5% whereas exposure between two neighbours can vary by as much as 87%, due to the prevalence of different behaviours. This study provides details of a new methodology that permits the cost-effective construction of refined time-activity diaries and daily exposure profiles, taking into account different microenvironments and sociodemographic characteristics. The proposed method leads to a refined exposure assessment model, addressing effectively vulnerable subgroups of population. It can be used for evaluating the probable impacts of different public health policies prior to implementation reducing, therefore, the time and expense required to identify efficient measures.

Cardioprotective effects of hesperidin on carbon monoxide poisoned in rats.

Carbon monoxide (CO) poisoning causes cardiotoxicity and so far, no definite antidote has been proposed to overcome CO-induced adverse outcomes. Hesperidin, a citrus flavonoid, has shown cardio-protective effects in cardiac ischemia/reperfusion models. This study investigated the protective effects of hesperidin against CO-induced cardiac injury. To induce CO poisoning, rats were exposed to CO at 3000 ppm for 60 min. On the exposure day and the four following days, hesperidin (at three different doses of 25, 50, and 100 mg/kg/day) was administered intraperitoneally. A group of animals received normal saline and served as the control group. The electrocardiogram (ECG) was recorded and evaluated with special focus on S-T segment changes (depression or elevation), T-wave alterations, AV block and ventricular and supraventricular arrhythmias. On day 6 (i.e., the day after the last injection day), the animals were sacrificed and the hearts were harvested and evaluated for necrosis using hematoxylin and eosin staining. In addition, Akt protein expression levels and BAX/BCL2 ratio were determined by western blotting. Our results showed that hesperidin decreased cardiac necrosis. In animals treated with hesperidin 100 mg/kg, Akt protein expression was increased, while the BAX/BCL2 ratio was significantly decreased. ECG changes were reversed in all groups 2 h following CO exposure, regardless of hesperidin administration. Overall, hesperidin decreased the deleterious cardiac effects of CO poisoning in rats.

Urinary bisphenol A in children, mothers and fathers from Slovenia: Overall results and determinants of exposure.

In the present study, urinary bisphenol A (BPA) levels were reported for the first time in the Slovenian general population and were evaluated with regard to dietary and non-dietary exposure sources, and compared according to age, gender and area of residence. First morning urine was collected from children (6-11 years), their mothers (30-52 years) and fathers (30-53 years), living in urban and rural areas of Slovenia. Besides basic questionnaire data on general population characteristics, socio-economic status and dietary habits, BPA-specific data was also collected, including consumption of food and beverages from plastic and canned containers, presence of white dental fillings, the use of specific consumer products and hormonal treatments. Urine samples were analysed for both free and conjugated BPA using GC-MS/MS. The urinary levels of total BPA in children, mothers and fathers were low, with geometric means of 1.51, 0.79, and 0.20 µg/g creatinine, respectively. The levels were comparable with the levels reported for other European countries and were all below the current health-based guidance values. In line with large-scale surveys, the data revealed age-dependant BPA urinary levels, with the highest levels in the youngest age group. In mothers, urinary levels of BPA were determined by hormonal interactions more than dietary sources, while a positive association between urinary BPA and diet was apparent in children (canned food/drink and food from plastic material) and fathers (canned food/drink). The study clearly shows that physiological and behavioural differences account for differences in levels of urinary BPA among study groups, a finding that sets the priorities for future research.

Risk characterization of bisphenol-A in the Slovenian population starting from human biomonitoring data.

The current study aims to characterize exposure and risk associated to bisphenol-A (BPA) exposure in Slovenia, starting from biomonitoring data. Based on the urinary data, daily intake for the individuals was back-calculated using a physiology based biokinetic (PBBK) model properly parameterized for BPA, coupled with an exposure reconstruction algorithm. Re-running the PBBK model in forward mode allowed the estimation of biologically effective dose (free plasma BPA) and the respective daily area under the curve (AUC). Finally, risk characterization ratio was derived using both external and internal dose metrics. The urinary BPA levels were found low, with GM of 0.79, 1.51 and 0.20 µg/g creatinine for mothers, children and fathers respectively, similar to the levels of other European countries. Based on the above and accounting for the dynamics of exposure and biokinetics, daily intake was estimated, median exposure levels have been estimated equal to 0.019, 0.035 and 0.005 µg/kg_bw/d for mothers, fathers and children respectively. The highest estimated intake level was found in a child, equal to 0.87 µg/kg_bw/d, while the maximum intake for mothers and fathers were 0.7 and 0.8 µg/kg_bw/d respectively. The respective RCR levels using the EFSA t-TDI of 4 µg/kg_bw/d were 2 magnitudes of order lower below 1, independently of the selected method. It has to be noted that had daily intake been estimated solely based on the urinary concentrations mass balance, the estimated intake would be lower, as a result of the oversimplification on exposure and elimination time dynamics. This highlights the importance for using PBBK modelling based exposure reconstruction schemes for rapidly metabolized and excreted compounds such as BPA, as well as the study design of efficient sampling for rapidly metabolized compounds.

A dual mixture of persistent organic pollutants modifies carbohydrate metabolism in the human hepatic cell line HepaRG.

Individuals as well as entire ecosystems are exposed to mixtures of Persistent Organic Pollutants (POPs). Previously, we showed, by a non-targeted approach, that the expression of several genes involved in carbohydrate metabolism was almost completely inhibited in the human hepatic cell line HepaRG following exposure to a mixture of the organochlorine insecticide alpha-endosulfan and 2,3,7,8 tetrachlorodibenzo-p-dioxin. In this European HEALS project, which studies the effects of the exposome on human health, we used a Physiologically Based BioKinetic model to compare the concentrations previously used in vitro with in vivo exposures for humans. We investigated the effects of these POPs on the levels of proteins, on glycogen content, glucose production and the oxidation of glucose into CO2 and correlated them to the expression of genes involved in carbohydrate metabolism as measured by RT-qPCR. Exposure to individual POPs and the mixture decreased the expression of the proteins investigated as well as glucose output (up to 82%), glucose oxidation (up to 29%) and glycogen content (up to 48%). siRNAs that specifically inhibit the expression of several xenobiotic receptors were used to assess receptor involvement in the effects of the POPs. In the HepaRG model, we demonstrate that the effects are mediated by the aryl hydrocarbon receptor and the estrogen receptor alpha, but not the pregnane X receptor or the constitutive androstane receptor. These results provide evidence that exposure to combinations of POPs, acting through different signaling pathways, may affect, more profoundly than single pollutants alone, metabolic pathways such as carbohydrate/energy metabolism and play a potential role in pollutant associated metabolic disorders.

Physiology-based toxicokinetic modelling in the frame of the European Human Biomonitoring Initiative.

Given the opportunities provided by internal dosimetry modelling in the interpretation of human biomonitoring (HBM) data, the assessment of the links between exposure to chemicals and observed HBM data can be effectively supported by PBTK modelling. This paper gives a comprehensive review of available human PBTK models for compounds selected as a priority by the European Human Biomonitoring Initiative (HBM4EU). We highlight their advantages and deficiencies and suggest steps for advanced internal dose modelling. The review of the available PBTK models highlighted the conceptual differences between older models compared to the ones developed recently, reflecting commensurate differences in research questions. Due to the lack of coordinated strategies for deriving useful biomonitoring data for toxicokinetic properties, significant problems in model parameterisation still remain; these are further increased by the lack of human toxicokinetic data due to ethics issues. Finally, questions arise as well as to the extent they are really representative of interindividual variability. QSARs for toxicokinetic properties is a complementary approach for PBTK model parameterisation, especially for data poor chemicals. This approach could be expanded to model chemico-biological interactions such as intestinal absorption and renal clearance; this could serve the development of more complex generic PBTK models that could be applied to newly derived chemicals. Another gap identified is the framework for mixture interaction terms among compounds that could eventually interact in metabolism. From the review it was concluded that efforts should be shifted toward the development of generic multi-compartmental and multi-route models, supported by targeted biomonitoring coupled with parameterisation by both QSAR approach and experimental (in-vivo and in-vitro) data for newly developed and data poor compounds.

Biomarkers of exposure in environment-wide association studies - Opportunities to decode the exposome using human biomonitoring data.

BACKGROUND: The European Union's 7th Framework Programme (EU's FP7) project HEALS - Health and Environment-wide Associations based on Large Population Surveys - aims a refinement of the methodology to elucidate the human exposome. Human biomonitoring (HBM) provides a valuable tool for understanding the magnitude of human exposure from all pathways and sources. However, availability of specific biomarkers of exposure (BoE) is limited. OBJECTIVES: The objective was to summarize the availability of BoEs for a broad range of environmental stressors and exposure determinants and corresponding reference and exposure limit values and biomonitoring equivalents useful for unraveling the exposome using the framework of environment-wide association studies (EWAS). METHODS: In a face-to-face group discussion, scope, content, and structure of the HEALS deliverable "Guidelines for appropriate BoE selection for EWAS studies" were determined. An expert-driven, distributed, narrative review process involving around 30 individuals of the HEALS consortium made it possible to include extensive information targeted towards the specific characteristics of various environmental stressors and exposure determinants. From the resulting 265 page report, targeted information about BoE, corresponding reference values (e.g., 95th percentile or measures of central tendency), exposure limit values (e.g., the German HBM I and II values) and biomonitoring equivalents (BEs) were summarized and updated. RESULTS: 64 individual biological, chemical, physical, psychological and social environmental stressors or exposure determinants were included to fulfil the requirements of EWAS. The list of available BoEs is extensive with a number of 135; however, 12 of the stressors and exposure determinants considered do not leave any measurable specific substance in accessible body specimens. Opportunities to estimate the internal exposure stressors not (yet) detectable in human specimens were discussed. CONCLUSIONS: Data about internal exposures are useful to decode the exposome. The paper provides extensive information for EWAS. Information included serves as a guideline - snapshot in time without any claim to comprehensiveness - to interpret HBM data and offers opportunities to collect information about the internal exposure of stressors if no specific BoE is available.

Addressing complexity of health impact assessment in industrially contaminated sites via the exposome paradigm.

BACKGROUND: this paper is based upon work from COST Action ICSHNet. Assessment of the health impacts related to industrially contaminated sites (ICSs) is a major scientific challenge with multiple societal implications. Most studies related to associations between ICSs and public health do not provide established mechanistic links between environmental exposure and disease burden, potentially resulting in suboptimal risk management measures. OBJECTIVES: to assess the potential of the exposome paradigm to overhaul ICS risk assessment and management leading to precision prevention and targeted interventions. METHODS: we selected the second largest waste landfill in Europe and the data collected in the frame of the HERACLES study on the exposome and health and analysed them together with clinical evidence of neurodevelopmental perturbations following the exposome-wide association study paradigm using the exposome analysis tools; briefly, these pertain to refined exposure assessment, internal dosimetry, and human biomonitoring, multi-omics/toxicity pathway analysis and advanced statistical tools for environment-wide association studies. Waste streams and the related contamination of environmental media are not viewed in isolation, but rather as components of the expotype, the vector of exposures an individual is exposed to over time. Thus, a multi-route and multi-pathway exposure estimation can be performed setting a realistic basis for integrated health risk and impact assessment. The study was located in the area around the landfill of Fili, outside Athens (Greece). Since 2012, 325 children were recruited and have been followed using a combination of human biomonitoring, advanced-omics analysis on biosamples, environmental monitoring for metals and organic contaminants, and dietary pattern information. The children were clinically tested for neurodevelopmental perturbations during different developmental stages and the results were analysed according to the exposome-wide association study methodology in conjunction with environmental exposure, but also socioeconomic, dietary, and metabolic determinants of internal exposure and health risk. RESULTS: using the exposome analysis tools, we confirmed that proximity to a landfill and the consequent soil contamination with metals are critical for children neurodevelopment. However, it was found that additional parameters such as parental education level, socioeconomic status, and nutrition contribute either positively or negatively on child neurodevelopment. CONCLUSIONS: the exposome concept comes to overhaul the nature vs. nurture paradigm and embraces a world of dynamic interactions between environmental exposures, endogenous exposures, and genetic expression in humans. In this context, the exposome paradigm provides a novel tool for holistic ICS health risk management. The effectiveness of the exposome approach is demonstrated in the case of Athens, the capital of Greece, where health effects associated to long term exposure to a major waste management facility (landfill) are presented.

A review of exposure assessment methods for epidemiological studies of health effects related to industrially contaminated sites.

BACKGROUND: this paper is based upon work from COST Action ICSHNet. Health risks related to living close to industrially contaminated sites (ICSs) are a public concern. Toxicology-based risk assessment of single contaminants is the main approach to assess health risks, but epidemiological studies which investigate the relationships between exposure and health directly in the affected population have contributed important evidence. Limitations in exposure assessment have substantially contributed to uncertainty about associations found in epidemiological studies. OBJECTIVES: to examine exposure assessment methods that have been used in epidemiological studies on ICSs and to provide recommendations for improved exposure assessment in epidemiological studies by comparing exposure assessment methods in epidemiological studies and risk assessments. METHODS: after defining the multi-media framework of exposure related to ICSs, we discussed selected multi-media models applied in Europe. We provided an overview of exposure assessment in 54 epidemiological studies from a systematic review of hazardous waste sites; a systematic review of 41 epidemiological studies on incinerators and 52 additional studies on ICSs and health identified for this review. RESULTS: we identified 10 multi-media models used in Europe primarily for risk assessment. Recent models incorporated estimation of internal biomarker levels. Predictions of the models differ particularly for the routes 'indoor air inhalation' and 'vegetable consumption'. Virtually all of the 54 hazardous waste studies used proximity indicators of exposure, based on municipality or zip code of residence (28 studies) or distance to a contaminated site (25 studies). One study used human biomonitoring. In virtually all epidemiological studies, actual land use was ignored. In the 52 additional studies on contaminated sites, proximity indicators were applied in 39 studies, air pollution dispersion modelling in 6 studies, and human biomonitoring in 9 studies. Exposure assessment in epidemiological studies on incinerators included indicators (presence of source in municipality and distance to the incinerator) and air dispersion modelling. Environmental multi-media modelling methods were not applied in any of the three groups of studies. CONCLUSIONS: recommendations for refined exposure assessment in epidemiological studies included the use of more sophisticated exposure metrics instead of simple proximity indicators where feasible, as distance from a source results in misclassification of exposure as it ignores key determinants of environmental fate and transport, source characteristics, land use, and human consumption behaviour. More validation studies using personal exposure or human biomonitoring are needed to assess misclassification of exposure. Exposure assessment should take more advantage of the detailed multi-media exposure assessment procedures developed for risk assessment. The use of indicators can be substantially improved by linking definition of zones of exposure to existing knowledge of extent of dispersion. Studies should incorporate more often land use and individual behaviour.

Comprehensive mapping of the AOP-Wiki database: identifying biological and disease gaps.

Introduction: The Adverse Outcome Pathway (AOP) concept facilitates rapid hazard assessment for human health risks. AOPs are constantly evolving, their number is growing, and they are referenced in the AOP-Wiki database, which is supported by the OECD. Here, we present a study that aims at identifying well-defined biological areas, as well as gaps within the AOP-Wiki for future research needs. It does not intend to provide a systematic and comprehensive summary of the available literature on AOPs but summarizes and maps biological knowledge and diseases represented by the already developed AOPs (with OECD endorsed status or under validation). Methods: Knowledge from the AOP-Wiki database were extracted and prepared for analysis using a multi-step procedure. An automatic mapping of the existing information on AOPs (i.e., genes/proteins and diseases) was performed using bioinformatics tools (i.e., overrepresentation analysis using Gene Ontology and DisGeNET), allowing both the classification of AOPs and the development of AOP networks (AOPN). Results: AOPs related to diseases of the genitourinary system, neoplasms and developmental anomalies are the most frequently investigated on the AOP-Wiki. An evaluation of the three priority cases (i.e., immunotoxicity and non-genotoxic carcinogenesis, endocrine and metabolic disruption, and developmental and adult neurotoxicity) of the EU-funded PARC project (Partnership for the Risk Assessment of Chemicals) are presented. These were used to highlight under- and over-represented adverse outcomes and to identify and prioritize gaps for further research. Discussion: These results contribute to a more comprehensive understanding of the adverse effects associated with the molecular events in AOPs, and aid in refining risk assessment for stressors and mitigation strategies. Moreover, the FAIRness (i.e., data which meets principles of findability, accessibility, interoperability, and reusability (FAIR)) of the AOPs appears to be an important consideration for further development.

Time-trends in human urinary concentrations of phthalates and substitutes DEHT and DINCH in Asian and North American countries (2009-2019).

BACKGROUND: Many phthalates are environmental pollutants and toxic to humans. Following phthalate regulations, human exposure to phthalates has globally decreased with time in European countries, the US and Korea. Conversely, exposure to their substitutes DEHT and/or DINCH has increased. In other countries, including China, little is known on the time-trends in human exposure to these plasticizers. OBJECTIVE: We aimed to estimate time-trends in the urinary concentrations of phthalates, DEHT, and DINCH metabolites, in general population from non-European countries, in the last decade. METHODS: We compiled human biomonitoring (HBM) data from 123 studies worldwide in a database termed "PhthaLit". We analyzed time-trends in the urinary concentrations of the excreted metabolites of various phthalates as well as DEHT and DINCH per metabolite, age group, and country/region, in 2009-2019. Additionally, we compared urinary metabolites levels between continents. RESULTS: We found solid time-trends in adults and/or children from the US, Canada, China and Taiwan. DEHP metabolites decreased in the US and Canada. Conversely in Asia, 5oxo- and 5OH-MEHP (DEHP metabolites) increased in Chinese children. For low-weight phthalates, the trends showed a mixed picture between metabolites and countries. Notably, MnBP (a DnBP metabolite) increased in China. The phthalate substitutes DEHT and DINCH markedly increased in the US. SIGNIFICANCE: We addressed the major question of time-trends in human exposure to phthalates and their substitutes and compared the results in different countries worldwide. IMPACT: Phthalates account for more than 50% of the plasticizer world market. Because of their toxicity, some phthalates have been regulated. In turn, the consumption of non-phthalate substitutes, such as DEHT and DINCH, is growing. Currently, phthalates and their substitutes show high detection percentages in human urine. Concerning time-trends, several studies, mainly in Europe, show a global decrease in phthalate exposure, and an increase in the exposure to phthalate substitutes in the last decade. In this study, we address the important question of time-trends in human exposure to phthalates and their substitutes and compare the results in different countries worldwide.

Exposure to flame retardants in European children - Results from the HBM4EU aligned studies.

Many legacy and emerging flame retardants (FRs) have adverse human and environmental health effects. This study reports legacy and emerging FRs in children from nine European countries from the HBM4EU aligned studies. Studies from Belgium, Czech Republic, Germany, Denmark, France, Greece, Slovenia, Slovakia, and Norway conducted between 2014 and 2021 provided data on FRs in blood and urine from 2136 children. All samples were collected and analyzed in alignment with the HBM4EU protocols. Ten halogenated FRs were quantified in blood, and four organophosphate flame retardants (OPFR) metabolites quantified in urine. Hexabromocyclododecane (HBCDD) and decabromodiphenyl ethane (DBDPE) were infrequently detected (<16% of samples). BDE-47 was quantified in blood from Greece, France, and Norway, with France (0.36 ng/g lipid) having the highest concentrations. BDE-153 and -209 were detected in <40% of samples. Dechlorane Plus (DP) was quantified in blood from four countries, with notably high median concentrations of 16 ng/g lipid in Slovenian children. OPFR metabolites had a higher detection frequency than other halogenated FRs. Diphenyl phosphate (DPHP) was quantified in 99% of samples across 8 countries at levels ∼5 times higher than other OPFR metabolites (highest median in Slovenia of 2.43 ng/g lipid). FR concentrations were associated with lifestyle factors such as cleaning frequency, employment status of the father of the household, and renovation status of the house, among others. The concentrations of BDE-47 in children from this study were similar to or lower than FRs found in adult matrices in previous studies, suggesting lower recent exposure and effectiveness of PBDE restrictions.

FAIR environmental and health registry (FAIREHR)- supporting the science to policy interface and life science research, development and innovation.

The environmental impact on health is an inevitable by-product of human activity. Environmental health sciences is a multidisciplinary field addressing complex issues on how people are exposed to hazardous chemicals that can potentially affect adversely the health of present and future generations. Exposure sciences and environmental epidemiology are becoming increasingly data-driven and their efficiency and effectiveness can significantly improve by implementing the FAIR (findable, accessible, interoperable, reusable) principles for scientific data management and stewardship. This will enable data integration, interoperability and (re)use while also facilitating the use of new and powerful analytical tools such as artificial intelligence and machine learning in the benefit of public health policy, and research, development and innovation (RDI). Early research planning is critical to ensuring data is FAIR at the outset. This entails a well-informed and planned strategy concerning the identification of appropriate data and metadata to be gathered, along with established procedures for their collection, documentation, and management. Furthermore, suitable approaches must be implemented to evaluate and ensure the quality of the data. Therefore, the 'Europe Regional Chapter of the International Society of Exposure Science' (ISES Europe) human biomonitoring working group (ISES Europe HBM WG) proposes the development of a FAIR Environment and health registry (FAIREHR) (hereafter FAIREHR). FAIR Environment and health registry offers preregistration of studies on exposure sciences and environmental epidemiology using HBM (as a starting point) across all areas of environmental and occupational health globally. The registry is proposed to receive a dedicated web-based interface, to be electronically searchable and to be available to all relevant data providers, users and stakeholders. Planned Human biomonitoring studies would ideally be registered before formal recruitment of study participants. The resulting FAIREHR would contain public records of metadata such as study design, data management, an audit trail of major changes to planned methods, details of when the study will be completed, and links to resulting publications and data repositories when provided by the authors. The FAIREHR would function as an integrated platform designed to cater to the needs of scientists, companies, publishers, and policymakers by providing user-friendly features. The implementation of FAIREHR is expected to yield significant benefits in terms of enabling more effective utilization of human biomonitoring (HBM) data.

Health Risk Assessment of Ortho-Toluidine Utilising Human Biomonitoring Data of Workers and the General Population.

The aim of this work was to demonstrate how human biomonitoring (HBM) data can be used to assess cancer risks for workers and the general population. Ortho-toluidine, OT (CAS 95-53-4) is an aniline derivative which is an animal and human carcinogen and may cause methemoglobinemia. OT is used as a curing agent in epoxy resins and as intermediate in producing herbicides, dyes, and rubber chemicals. A risk assessment was performed for OT by using existing HBM studies. The urinary mass-balance methodology and generic exposure reconstruction PBPK modelling were both used for the estimation of the external intake levels corresponding to observed urinary levels. The external exposures were subsequently compared to cancer risk levels obtained from the evaluation by the Scientific Committee on Occupational Exposure Limits (SCOEL). It was estimated that workers exposed to OT have a cancer risk of 60 to 90:106 in the worst-case scenario (0.9 mg/L in urine). The exposure levels and cancer risk of OT in the general population were orders of magnitude lower when compared to workers. The difference between the output of urinary mass-balance method and the general PBPK model was approximately 30%. The external exposure levels calculated based on HBM data were below the binding occupational exposure level (0.5 mg/m3) set under the EU Carcinogens and Mutagens Directive.

An exposome connectivity paradigm for the mechanistic assessment of the effects of prenatal and early life exposure to metals on neurodevelopment.

The exposome paradigm through an integrated approach to investigating the impact of perinatal exposure to metals on child neurodevelopment in two cohorts carried out in Slovenia (PHIME cohort) and Greece (HERACLES cohort) respectively, is presented herein. Heavy metals are well-known neurotoxicants with well-established links to impaired neurodevelopment. The links between in utero and early-life exposure to metals, metabolic pathway dysregulation, and neurodevelopmental disorders were drawn through urinary and plasma untargeted metabolomics analysis, followed by the combined application of in silico and biostatistical methods. Heavy metal prenatal and postnatal exposure was evaluated, including parameters indirectly related to exposure and health adversities, such as sociodemographic and anthropometric parameters and dietary factors. The primary outcome of the study was that the identified perturbations related to the TCA cycle are mainly associated with impaired mitochondrial respiration, which is detrimental to cellular homeostasis and functionality; this is further potentiated by the capacity of heavy metals to induce oxidative stress. Insufficient production of energy from the mitochondria during the perinatal period is associated with developmental disorders in children. The HERACLES cohort included more detailed data regarding diet and sociodemographic status of the studied population, allowing the identification of a broader spectrum of effect modifiers, such as the beneficial role of a diet rich in antioxidants such as lycopene and ω-3 fatty acids, the negative effect the consumption of food items such as pork and chicken meat has or the multiple impacts of fish consumption. Beyond diet, several other factors have been proven influential for child neurodevelopment, such as the proximity to pollution sources (e.g., waste treatment site) and the broader living environment, including socioeconomic and demographic characteristics. Overall, our results demonstrate the utility of exposome-wide association studies (EWAS) toward understanding the relationships among the multiple factors that determine human exposure and the underlying biology, reflected as omics markers of effect on neurodevelopment during childhood.

User-Centred Design of a Final Results Report for Participants in Multi-Sensor Personal Air Pollution Exposure Monitoring Campaigns.

Using low-cost portable air quality (AQ) monitoring devices is a growing trend in personal exposure studies, enabling a higher spatio-temporal resolution and identifying acute exposure to high concentrations. Comprehension of the results by participants is not guaranteed in exposure studies. However, information on personal exposure is multiplex, which calls for participant involvement in information design to maximise communication output and comprehension. This study describes and proposes a model of a user-centred design (UCD) approach for preparing a final report for participants involved in a multi-sensor personal exposure monitoring study performed in seven cities within the EU Horizon 2020 ICARUS project. Using a combination of human-centred design (HCD), human-information interaction (HII) and design thinking approaches, we iteratively included participants in the framing and design of the final report. User needs were mapped using a survey (n = 82), and feedback on the draft report was obtained from a focus group (n = 5). User requirements were assessed and validated using a post-campaign survey (n = 31). The UCD research was conducted amongst participants in Ljubljana, Slovenia, and the results report was distributed among the participating cities across Europe. The feedback made it clear that the final report was well-received and helped participants better understand the influence of individual behaviours on personal exposure to air pollution.

Unraveling the blood transcriptome after real-life exposure of Wistar-rats to PM2.5, PM1 and water-soluble metals in the ambient air.

Exposure to particulate matter (PM) is one of the most important environmental issues in Europe with major health impact. Various sizes of PM are suspended in the atmosphere and contributes to ambient air pollution. The current study aimed to explore the differential gene expression in blood, and the effect on the respective biological signaling pathways in Wistar rats, after exposure to PM2.5 and PM1 ambient air particles for an eight-week period. A control group was included with animals breathing non-filtered atmospheric air. In parallel, filtered PM2.5 and PM1 was collected in separate samplers. The results after whole genome microarray analysis showed 23 differentially expressed genes (DEGs) between control and PM2.5 group. In addition, pairwise comparison between control and PM1 group displayed 5635 DEGs linked to 69 biological pathways involved in inflammatory response, cell cycle and carcinogenicity. The smaller the size of the inhaled particles, the more gene alterations are triggered compared to non-filtered air group. More specifically, in inflammation signaling procedures differentially regulated gene expression was shown for interleukin-4 (IL-4), IL-7, IL-1, IL-5, IL-9, IL-6 and IL-2. We have identified that RASGFR1, TRIM65, TRIM33, PLEKHB1, CAR4, S100A8, S100A9, ALPL, NP4 and the PROK2 genes are potential targets for the development of adverse outcome pathways (AOPs) due to "real-life" exposure of Wistar rats. Particle measurements during the exposure period showed elevated concentrations of Fe, Mn and Zn in both PM1 and PM2.5 filter fractions, and of Cu in PM2.5. In addition, water-soluble concentration of metals showed significant differences between PM1 and PM2.5 fractions for V, Zn, As, Pb and Mn. In summary, in this study specific gene biomarkers of exposure to ambient air have been identified and heavy metals that are possibly linked to their altered regulation have been found. The results of this research will pave the way for the development of novel AOPs concerning the health effects of the environmental pollution.

Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases.

Multiple medical, lifestyle, and environmental conditions, including smoking and particulate pollution, have been considered as risk factors for COronaVIrus Disease 2019 (COVID-19) susceptibility and severity. Taking into account the high level of toxic metals in both particulate matter (PM2.5) and tobacco smoke, the objective of this review is to discuss recent data on the role of heavy metal exposure in development of respiratory dysfunction, immunotoxicity, and severity of viral diseases in epidemiological and experimental studies, as to demonstrate the potential crossroads between heavy metal exposure and COVID-19 severity risk. The existing data demonstrate that As, Cd, Hg, and Pb exposure is associated with respiratory dysfunction and respiratory diseases (COPD, bronchitis). These observations corroborate laboratory findings on the role of heavy metal exposure in impaired mucociliary clearance, reduced barrier function, airway inflammation, oxidative stress, and apoptosis. The association between heavy metal exposure and severity of viral diseases, including influenza and respiratory syncytial virus has been also demonstrated. The latter may be considered a consequence of adverse effects of metal exposure on adaptive immunity. Therefore, reduction of toxic metal exposure may be considered as a potential tool for reducing susceptibility and severity of viral diseases affecting the respiratory system, including COVID-19.

The toxic influence and biodegradation of carbon nanofibers in freshwater invertebrates of the families Gammaridae, Ephemerellidae, and Chironomidae.

Carbon nanofibers (CNFs) are widely used in consumer products today. In this study, we assessed the effects of CNFs on the digestive system of three freshwater invertebrate species (Gammaridae, Ephemerellidae, and Chironomidae). The aquatic insects Diamesa sp., Drunella cryptomeria, and Gammarus suifunensis were incubated with the CNFs at the concentration of 100 mg/L during the 7-days period. Histological examination of the whole specimens and the longitudinal sections revealed no toxic effects of CNFs. However, a noticeable change in the structure of the CNFs accumulated in the intestines of the aquatic insects was found by Raman spectroscopy. The registered decrease in the relative proportion of amorphous carbon included in the CNF sample was found in the intestines of Diamesa sp. and D. cryptomeria. The registered effect can indicate a biodegradation of amorphous carbon in the digestive tract of these two insect species. In contrast, the decrease of highly structured carbons and the decrease of G-bonds intensity were registered in the digestive tract of G. suifunensis. This observation demonstrates the partial biodegradation of CNFs in the digestive tract of G. suifunensis.