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      Altered toxicological endpoints in humans from common quaternary ammonium compound disinfectant exposure

      research-article
      a , b , * , c , c , d , d , e , e , a , a , a , a , a
      Toxicology Reports
      Elsevier
      ADBAC, alkyldimethylbenzyl ammonium chloride, ANOVA, analysis of variance, BAC, benzalkonium chloride, CRP, C-reactive protein, DDAC, didecyldimethyl ammonium chloride, FCCP, trifluoromethoxy carbonylcyanide phenylhydrazone, IL-6, interleukin 6, IL-10, interleukin 10, IL-12, interleukin 12, IRB, Institutional Review Board, LC, liquid chromatography, LOD, level of detection, LOQ, level of quantification, LPS, lipopolysaccharide, NF-κB, nuclear factor kappa beta, NOEL, no effect level, OCR, oxygen consumption rate, OEL, occupational exposure limit, QAC, quaternary ammonium compounds, TNFα, tumor necrosis factor alpha, 7-DHC, 7-Dehydrocholesterol, 8-DHC, 8-Dehydrocholesterol, 7-DHD, 7-Dehydrodesmosterol, Quaternary ammonium compounds, Environmental toxicology, Inflammation, Mitochondrial function, Lipid metabolism

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          Abstract

          Humans are frequently exposed to Quaternary Ammonium Compounds (QACs). QACs are ubiquitously used in medical settings, restaurants, and homes as cleaners and disinfectants. Despite their prevalence, nothing is known about the health effects associated with chronic low-level exposure. Chronic QAC toxicity, only recently identified in mice, resulted in developmental, reproductive, and immune dysfunction. Cell based studies indicate increased inflammation, decreased mitochondrial function, and disruption of cholesterol synthesis. If these findings translate to human toxicity, multiple physiological processes could be affected. This study tested whether QAC concentrations could be detected in the blood of 43 human volunteers, and whether QAC concentrations influenced markers of inflammation, mitochondrial function, and cholesterol synthesis. QAC concentrations were detected in 80 % of study participants. Blood QACs were associated with increase in inflammatory cytokines, decreased mitochondrial function, and disruption of cholesterol homeostasis in a dose dependent manner. This is the first study to measure QACs in human blood, and also the first to demonstrate statistically significant relationships between blood QAC and meaningful health related biomarkers. Additionally, the results are timely in light of the increased QAC disinfectant exposure occurring due to the SARS-CoV-2 pandemic.

          Main Findings

          This study found that 80 % of study participants contained QACs in their blood; and that markers of inflammation, mitochondrial function, and sterol homeostasis varied with blood QAC concentration.

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          Most cited references50

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          Quaternary ammonium disinfectants: microbial adaptation, degradation and ecology.

          Disinfectants play an important role in maintaining acceptable health standards by significantly reducing microbial loads as well as reducing, if not eliminating, pathogens. This review focuses on quaternary ammonium compounds (QACs), a widely used class of organic disinfectants. Specifically, it reviews the occurrence, microbial adaptation, and degradation of QACs, focusing on recent reports on the ecology of QAC-degraders, the pathways and mechanisms of microbial adaptation which lead to resistance to QACs, as well as to antibiotics. With the help of culture-dependent and nonculture-dependent tools, as well as advanced analytical techniques, a better understanding of the fate and effect of QACs and their biotransformation products is emerging. Understanding the underlying mechanisms and conditions that result in QAC resistance and biodegradation will be instrumental in the prudent use of existing QAC formulations and foster the development of safer disinfectants. Development and implementation of (bio)technologies for the elimination of QACs from treated wastewater effluents will lessen adverse impacts to both humans and the environment.
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            Increased Use of Quaternary Ammonium Compounds during the SARS-CoV-2 Pandemic and Beyond: Consideration of Environmental Implications

            Quaternary ammonium compounds (QACs) are active ingredients in over 200 disinfectants currently recommended by the U.S. EPA for use to inactivate the SARS-CoV-2 (COVID-19) virus. The amounts of these compounds used in household, workplace, and industry settings has very likely increased, and usage will continue to be elevated given the scope of the pandemic. QACs have been previously detected in wastewater, surface waters, and sediments, and effects on antibiotic resistance have been explored. Thus, it is important to assess potential environmental and engineering impacts of elevated QAC usage, which may include disruption of wastewater treatment unit operations, proliferation of antibiotic resistance, formation of nitrosamine disinfection byproducts, and impacts on biota in surface waters. The threat caused by COVID-19 is clear, and a reasonable response is elevated use of QACs to mitigate spread of infection. Exploration of potential effects, environmental fate, and technologies to minimize environmental releases of QACs, however, is warranted.
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              Paradigm lost, paradigm found: the re-emergence of hormesis as a fundamental dose response model in the toxicological sciences.

              This paper provides an assessment of the toxicological basis of the hormetic dose-response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose-response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose-response model (hormesis), but also the model that was more common and fundamental than those that the field accepted.
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                Author and article information

                Contributors
                Journal
                Toxicol Rep
                Toxicol Rep
                Toxicology Reports
                Elsevier
                2214-7500
                09 March 2021
                2021
                09 March 2021
                : 8
                : 646-656
                Affiliations
                [a ]Department of Biomedical Science, E. Via College of Osteopathic Medicine – Virginia, Blacksburg, VA, 24060, USA
                [b ]Department of Biomedical Science and Pathobiology, VA-MD College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA
                [c ]Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, 98195, USA
                [d ]Department of Molecular Biosciences, School of Veterinary Medicine, University of California – Davis, Davis, CA, 95618, USA
                [e ]Center for Biostatistics and Health Data Science, Department of Statistics, College of Science, Virginia Tech, Riverside Circle, Roanoke, VA, 24016, USA
                Author notes
                [* ]Corresponding author at: Department of Biomedical Science, E. Via College of Osteopathic Medicine – Virginia, 2265 Kraft Drive, Blacksburg, VA, 24060, USA. thrubec@ 123456vt.vcom.edu
                Article
                S2214-7500(21)00047-0
                10.1016/j.toxrep.2021.03.006
                8041661
                33868951
                35bb93b9-52c8-409f-b766-a22b582fcb73
                © 2021 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 2 November 2020
                : 4 February 2021
                : 6 March 2021
                Categories
                Regular Article

                adbac, alkyldimethylbenzyl ammonium chloride,anova, analysis of variance,bac, benzalkonium chloride,crp, c-reactive protein,ddac, didecyldimethyl ammonium chloride,fccp, trifluoromethoxy carbonylcyanide phenylhydrazone,il-6, interleukin 6,il-10, interleukin 10,il-12, interleukin 12,irb, institutional review board,lc, liquid chromatography,lod, level of detection,loq, level of quantification,lps, lipopolysaccharide,nf-κb, nuclear factor kappa beta,noel, no effect level,ocr, oxygen consumption rate,oel, occupational exposure limit,qac, quaternary ammonium compounds,tnfα, tumor necrosis factor alpha,7-dhc, 7-dehydrocholesterol,8-dhc, 8-dehydrocholesterol,7-dhd, 7-dehydrodesmosterol,quaternary ammonium compounds,environmental toxicology,inflammation,mitochondrial function,lipid metabolism

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