Metabolism and interactions of pesticides in human and animal <em>in vitro</em> hepatic models

Abstract Risk assessment of chemicals needs reliable scientific information and one source of information is the characterization of the metabolic fate and toxicokinetics of a chemical. Metabolism is often the most important factor contributing to toxicokinetics. Cytochrome P450 (CYP) enzymes are a superfamily of microsomal proteins playing a pivotal role in xenobiotic metabolism. In the present study, pesticides were used as representative xenobiotics since exposure to pesticides is a global challenge to risk assessment. Human and animal in vitro hepatic models were applied with the advantage of novel analytical techniques (LC/TOF-MS and LC/MS-MS) to elucidate the in vitro metabolism and interaction of selected pesticides. The results of these studies demonstrate that CYP enzymes catalyze the bioactivation of profenofos, diuron and carbosulfan into their more toxic metabolites desthiopropylprofenofos, N-demethyldiuron and carbofuran, respectively. The suspected carcinogenic metabolite of metalaxyl, 2,6-dimethylaniline, was not detected. CYP3A4 and CYP2C19 activities may be important in determining the toxicity arising from exposure to profenofos and carbosulfan. Individuals with high CYP1A2 and CYP2C19 activities might be more susceptible to diuron toxicity. Qualitative results of in vitro metabolism were generally in agreement with the results obtained from the published in vivo data, at least for the active chemical moiety and major metabolites. Considerable differences in the quantities of the metabolites produced within the species, as well as in the ratios of the metabolites among the species, were observed. These findings illustrate that in vitro screening of qualitative and quantitative differences are needed to provide a firm basis for interspecies and in vitro-in vivo extrapolations. Based on our findings, in vitro-in vivo extrapolation based on the elucidation of the in vitro metabolic pattern of pesticides in human and animal hepatic models could be a good model for understanding and extending the results of pesticides metabolism studies to human health risk assessment

Chloro-s-triazines-toxicokinetic, toxicodynamic, human exposure, and regulatory considerations

Abstract Chloro-s-triazines-atrazine, cyanazine, propazine, simazine, and terbuthylazine-are structurally similar herbicides, differing only in specific s-triazine4-and 6-N alkyl substituents. It is generally regarded that their toxicokinetics, such as, metabolic pathways, biological effects and toxicities, also share more similar features than the differences. Consequently, it is useful to compare their characteristics to potentially find useful structure-activity relationships or other similarities or differences regarding different active compounds, their metabolites, and biological effects including toxic outcomes. The ultimate goal of these exercises is to apply the summarized knowledge-as far as it is possible regarding a patchy and often inadequate database-to cross the in vitro-in vivo and animal-human borders and integrate the available data to enhance toxicological risk assessment for the benefit of humans and ecosystems

Temporal trends of contaminants in Arctic human populations

Abstract The first Arctic Monitoring and Assessment Programme (AMAP) report was published in 1998 and followed by three assessment reports of human health (AMAP 2003, 2009 and 2015). The focus area of the AMAP reports was to monitor levels of environmental contaminants in the Arctic and to assess the health effects connected with detected levels in Arctic countries. This review gives an overview of temporal trends of contaminants and their health effects in humans of the Arctic based on data published by AMAP, as well as Russian scientific literature. Several time series of 31 contaminants in humans of the Arctic from different cohorts are reported. The lengths of time series and periods covered differ from each other. International restrictions have decreased the levels of most persistent organic pollutants in humans and food webs. Percentage changes for contaminants in human biological matrices (blood samples from children, mothers and males and breast milk samples) for the period of sampling showed declining trends in most of the monitored Arctic locations, with the exception of oxychlordane, hexachlorobenzene (HCB), 2,2′,4,4′,5,5′-hexabromodiphenyl ether (PBDE153) and perfluorinated compounds (PFCs)

Human infectious diseases and the changing climate in the Arctic

Abstract Climatic factors, especially temperature, precipitation, and humidity play an important role in disease transmission. As the Arctic changes at an unprecedented rate due to climate change, understanding how climatic factors and climate change affect infectious disease rates is important for minimizing human and economic costs. The purpose of this systematic review was to compile recent studies in the field and compare the results to a previously published review. English language searches were conducted in PubMed, ScienceDirect, Scopus, and PLOS One. Russian language searches were conducted in the Scientific Electronic Library “eLibrary.ru”. This systematic review yielded 22 articles (51%) published in English and 21 articles (49%) published in Russian since 2012. Articles about zoonotic and vector-borne diseases accounted for 67% (n = 29) of the review. Tick-borne diseases, tularemia, anthrax, and vibriosis were the most researched diseases likely to be impacted by climatic factors in the Arctic. Increased temperature and precipitation are predicted to have the greatest impact on infectious diseases in the Arctic

Metabolic profiling and in vitro-in vivo extrapolation of furathiocarb in mammalian hepatic microsomes

Abstract Furathiocarb is a carbamate insecticide found in marine ecosystems as well as river water and sediments. The aim of this study was to characterize species differences in the in vitro metabolism of furathiocarb in seven mammalian species (human, monkey, minipig, rat, mouse, dog, rabbit) analyzed by LC-TOF-MS/MS, in order to provide qualitative and quantitative chemical-specific data to enhance toxicological risk assessment. Furathiocarb was mainly biotransformed to carbofuran metabolic pathway via (N-S) bond-cleavage. Two hydroxylated and sulfoxidated metabolites of furathiocarb were also detected (oxidation pathway). No unique human metabolites were detected. The carbofuran metabolic pathway was more predominant than the furathiocarb oxidation pathway in all species studied; differences based on hepatic clearance rates (CLH), were up to 9.4-fold in monkey and 7-fold in rats, while it was 4.3-fold in human. Animal to human differences in the carbofuran pathway are within the default toxicokinetic uncertainty factor, except for mouse (3.9-fold). Our findings on metabolic profiling and in vitro-in vivo extrapolations are helpful for the interpretation of toxicological findings and chemical risk assessment of furathiocarb

Human biomonitoring of environmental contaminants in Gulf Countries:current status and future directions

Abstract Background: This systematic review aimed to evaluate the status of Human Biomonitoring (HBM) in the Gulf Cooperation Council (GCC) region and provide recommendations for future research, considering the increased environmental contaminants that pose a threat to human health in this rapidly industrializing area. Methods: A thorough search was performed in PubMed and Web of Science databases up to February 2023 to identify biomonitoring studies on human exposure and levels in the GCC region. Two independent reviewers assessed study eligibility, conducted data extraction and risk of bias assessment. The NIH Quality Assessment Tools and PRISMA guidelines were utilized for quality evaluation and reporting of results. Results: A total of 38 eligible articles were included in this systematic review out of 662 articles screened. The majority of the publications were from Saudi Arabia (n = 24) and Kuwait (n = 10), while limited representation was found from Qatar (n = 3) and the UAE (n = 1). No articles were identified from Oman and Bahrain. The studies focused on metals, organohalogen compounds, pesticides, polycyclic aromatic hydrocarbons, and phthalates. The findings revealed elevated levels of metals and established correlations between metal exposure and adverse health effects, including infant neurodevelopmental issues, vitamin D deficiency, and oxidative stress. The presence of organohalogen compounds and pesticides was prevalent in the GCC region, with significant associations between exposure to these compounds and negative health outcomes. Notably, high levels of perchlorate were observed in the Kuwaiti population, and a study from Saudi Arabia found an association between per- and polyfluorinated substances and increased odds of osteoporosis. Conclusions: This review emphasizes the need to address environmental health challenges in the GCC region through improved HBM research methods and strategies. Implementing biomonitoring programs, conducting cohort studies, investing in tools and expertise, promoting collaboration, and engaging the community are crucial for reliable HBM data in the GCC

Characterization of furathiocarb metabolism in in-vitro human liver microsomes and recombinant cytochrome P450 enzymes

Abstract Furathiocarb is a carbamate insecticide detected in ecosystems. Its main metabolite carbofuran has been alluded to affect birth outcomes and disturb hormone levels in humans. The metabolism of furathiocarb in humans has not been characterized. The metabolism studies were performed using hepatic microsomes from ten donors and fifteen human cDNA-expressed CYPs. The initial screening and identification of the metabolites were performed by LC-TOF. Quantifications and fragmentations were performed by LC/MS-MS. Furathiocarb was metabolized to eight phase I metabolites via two general pathways, carbofuran metabolic pathway and furathiocarb oxidation pathway. Six metabolites in the carbofuran metabolic pathway (carbofuran, 3-hydroxycarbofuran, 3-ketocarbofuran, 3-keto-7-phenolcarbofuran, 3-hydroxy-7-phenolcarbofuran, and 7-phenolcarbofuran) were identified with the help of authentic standards. The two unidentified metabolites in the furathiocarb oxidation pathway are probably hydroxylated and sulfoxidated derivatives of furathiocarb. The carbofuran metabolic pathway was more predominant than the furathiocarb oxidation pathway, ratios ranged from 24- to 115-fold in a 10-donor panel of hepatic microsomes. On the basis of recombinant CYP studies, the carbofuran pathway was dominated by CYP3A4 (95.9%); contributions by CYP1A2 (1.3%) and CYP2B6 (2.0%) were minor. The minor furathiocarb oxidation pathway was catalyzed by CYP2C19 and CYP2D6 (hydroxylated/sulfoxidated metabolite A) and by CYP3A5, CYP3A4 and CYP2A6 (metabolite B). High and significant correlation between carbofuran metabolic pathway and CYP3A4 marker activities (midazolam-1’-hydroxylation and omeprazole-sulfoxidation) were observed. Ketoconazole, a CYP3A4-inhibitor, inhibited the carbofuran pathway by 32–86% and hydroxylated/sulfoxidated metabolite-B formations by 41–62%. The data suggest that in humans, the carbofuran metabolic pathway is dominant, and CYP3A4 is the major enzyme involved. These results provide useful scientific information for furathiocarb risk assessment in humans

Research on selected wildlife infections in the circumpolar arctic:a bibliometric review

Abstract One Health, a multidisciplinary approach to public health, which integrates human, animal, and environmental studies, is prudent for circumpolar Arctic health research. The objective of our bibliometric review was to identify and compare research in select infectious diseases in Arctic wildlife species with importance to human health indexed in English language databases (PubMed, Scopus) and the Russian database eLibrary.ru. Included articles (in English and Russian languages) needed to meet the following criteria: (1) data comes from the Arctic, (2) articles report original research or surveillance reports, (3) articles were published between 1990 and 2018, and (4) research relates to naturally occurring infections. Of the included articles (total n = 352), most were from Russia (n = 131, 37%), Norway (n = 58, 16%), Canada (n = 39, 11%), and Alaska (n = 39, 11%). Frequently reported infectious agents among selected mammals were Trichinella spp. (n = 39), Brucella spp. (n = 25), rabies virus (n = 11), Echinococcus spp. (n = 10), and Francisella tularensis (n = 9). There were 25 articles on anthrax in eLibrary.ru, while there were none in the other two databases. We identified future directions where opportunities for further research, collaboration, systematic reviews, or monitoring programs are possible and needed

The association between blood copper concentration and biomarkers related to cardiovascular disease risk:analysis of 206 individuals in the Northern Finland Birth Cohort 1966

Abstract Background: Copper is an abundant trace element in humans where alterations in the circulating concentration could inform on chronic disease aetiology. To date, data are lacking to study how copper may associate with cardiovascular disease (CVD) risk factors in young and healthy population. Molecular evidence suggests an important role of copper in liver metabolism, an essential organ in maintaining cardiovascular health and inflammation, therefore supporting copper as an associated biomarker of the risk. Objective: We performed a cross-sectional analysis to examine the possible associations between blood copper levels and risk factors for CVD and pre-inflammatory process. Design: The data has been collected from a sub-sample set of the Northern Finland Birth Cohort 1966 (NFBC1966) at 31 years. Participants: The study included 206 individuals, 116 men and 90 women. To reduce environmental individual variations affecting both copper and the metabolic profile in the study sample, the participants were selected as: i) being born in Finnish Lapland and ii) living in their birth place for the last five years preceding blood sampling. Main outcome measures: Fasting blood copper concentration was measured by inductively coupled plasma mass spectrometer. The CVD risk factors included 6 metabolic clusters (30 cardiovascular and pro-inflammatory factors) assessed by nuclear magnetic resonance. Multivariate linear regression analysis was performed to test the linear association between blood copper and 6 metabolic clusters for CVD risk. Associations were assessed under correction for multiple testing. Results: Copper (Cu) levels were comparable in men and women, with no difference between sexes (p-value  &lt;0.60). In multiple regression models, sex adjusted, copper was associated with 9 metabolites from 4 metabolic clusters. After adjustment with BMI, copper was associated with 4 metabolites from 3 metabolic clusters: glutamine, beta-hydroxybutyrate, alpha-1-acid glycoprotein (AGP) and high-sensitive C-reactive protein (hs-CRP). After correction for multiple testing, Cu was found positively associated with only 2 biomarkers of inflammation including AGP [p = 0.04] and hs-CRP [p  = 0.0001]. Conclusions: Considering the strength and limitation of the study design, the present study does not support evidence for an independent role of copper on biomarkers for CVD risk. Nevertheless, we are reporting a robust association of copper with the inflammatory load that is important to consider in light with the inflammatory component of chronic health. In addition, the association of copper with metabolites may be attributable to BMI or environmental factors associated to it, and warrants further research in large population samples

Non-occupational exposure to pesticides and health markers in general population in Northern Finland:differences between sexes

Abstract Background: Occupational exposure to pesticides has been reported among general population worldwide. However, little is known about the associations between non-occupational exposure to pesticides, and biological markers of health and their response by sex. Objectives: We aimed to assess the associations between non-occupational overall pesticide exposure, length of exposure and specific pesticides reported with 35 biological markers of health representing cardiometabolic, haematological, lung function, sex hormones, liver and kidney function profiles, and vitamin D in Finnish cohort. Methods: 31-year cross-sectional examination of the Northern Finland Birth Cohort 1966 provided blood samples for biomarker measurements in 1997–1998. Number of subjects varied between 2361 and 5037 for given exposures and certain outcome associations. Multivariable regression analyses were performed to examine associations between overall pesticide exposure (OPE), length of pesticide exposure in months (PEM), in years (PEY), and specific pesticides use (PEU) or not with cardiometabolic [SBP, DBP, TC, LDL, HDL, triglycerides, fasting glucose, insulin, HOMA-IR, HOMA-B, HOMA-S, hs-CRP], hematological [WBC, RBC, Hb, HCT, MCV, MCH, MCHC, platelets], lung function (FVC, FEV1), sex hormones [luteinizing hormone (LH), testosterone (TT), sex-hormone binding globulin (SHBG)], liver and kidney function profiles [total protein, albumin, globulin, ALP, ALT, GGT, urea, creatinine], and vitamin D adjusting for sex, BMI, socioeconomic position (SEP) and season of pesticide use. Results: This cohort study on up to 5037 adults with non-occupational OPE, PEM, PEY and PEU differed by sex and SEP. In regression analyses, all the exposures were positively associated with total cholesterol and low-density lipoprotein cholesterol, and PEU was negatively associated with high-density lipoprotein cholesterol in females. OPE and PEM were positively associated with haematocrit in females and PEU with platelets in males. PEU was negatively associated with mean corpuscular haemoglobin. OPE and PEM were positively associated with LH in males. OPE was negatively associated with total protein and albumin in males. Conclusions: In Finnish young adults, non-occupational overall pesticide exposure, length of exposure and specific pesticides were associated with multiple biological markers of health. The biological markers seem to be indicative of adverse effects of pesticides and warrant for further studies to replicate the findings and determine the underlying mechanisms