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ESRA19-0271 Intrathecal administration of hyperbaric prilocaine is a source of systemic O-toluidine
Background and aimsHyperbaric 2% prilocaine (HP) is increasingly used for spinal anesthesia. It is the only local anesthetic metabolized to o-toluidine, a human bladder carcinogen. Massive increase of o-toluidine hemoglobin adducts (HAoT), a marker of o-toluidine carcinogenic pathway, was described following subcutaneous injection. In the present study we aimed to assess a single intrathecal dose of HP as a source of HAoT and urinary o-toluidine (UoT).MethodsAfter ethical committee approval and informed written consent, 10 patients undergoing surgery received 50 mg of HP intrathecally. Blood and urine samples were collected before injection and up to 24 hours later.UoT and HAoT were measured by tandem mass-spectrometry after gas-chromatographic separation. Values are expressed as mean ± standard deviation. Pair Students t-test was used for the significance tests.ResultsIntrathecal administration of 50 mg of HP leads to a massive increase of HAoT (0.11±0.02 to 11.59±1.89 ng/g Hb after 24h, p<0.0001, figure 1). Peak of UoT was observed after 8h (0.1±0.1 to 351.6±352.7 µg/L, p<0.001) and declined to 80.0±66.8 µg/L after 24h (figure 2).Abstract ESRA19-0271 Figure 1Abstract ESRA19-0271 Figure 2ConclusionsIntrathecal administration of HP leads to a relevant systemic burden of carcinogenic o-toluidine. Therefore, the carcinogenic risk of HP administration should be the object of ethical considerations and further clinical investigations.
Journal Article
The fluorspar mines of Newfoundland : their history and the epidemic of radiation lung cancer
John Martin tells the history of Newfoundland's fluorspar mines from their founding to the last shipment of fluorspar in 1990 and declaration of bankruptcy a year later. He focuses on the health hazards experienced by the miners, and how the mining companies, workers, governments, and health services came to terms with the unfolding human tragedy. He also covers such matters as the improvement of methods for dust quantification and radiation surveillance in the mines, battles for compensation, and the influence of the St Lawrence case on the development of labour law in the province.
Book
Gut microbiota carcinogen metabolism causes distal tissue tumours
Exposure to environmental pollutants and human microbiome composition are important predisposition factors for tumour development
1
,
2
. Similar to drug molecules, pollutants are typically metabolized in the body, which can change their carcinogenic potential and affect tissue distribution through altered toxicokinetics
3
. Although recent studies demonstrated that human-associated microorganisms can chemically convert a wide range of xenobiotics and influence the profile and tissue exposure of resulting metabolites
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,
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, the effect of microbial biotransformation on chemical-induced tumour development remains unclear. Here we show that the depletion of the gut microbiota affects the toxicokinetics of nitrosamines, which markedly reduces the development and severity of nitrosamine-induced urinary bladder cancer in mice
6
,
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. We causally linked this carcinogen biotransformation to specific gut bacterial isolates in vitro and in vivo using individualized bacterial culture collections and gnotobiotic mouse models, respectively. We tested gut communities from different human donors to demonstrate that microbial carcinogen metabolism varies between individuals and we showed that this metabolic activity applies to structurally related nitrosamine carcinogens. Altogether, these results indicate that gut microbiota carcinogen metabolism may be a contributing factor for chemical-induced carcinogenesis, which could open avenues to target the microbiome for improved predisposition risk assessment and prevention of cancer.
A study links environmental nitrosamines to bladder cancer through their metabolism by specific commensal microorganisms occurring in the gastrointestinal tract of humans and mice.
Journal Article
Tainted Earth
Smelting is an industrial process involving the extraction of metal from ore. During this process, impurities in ore-including arsenic, lead, and cadmium-may be released from smoke stacks, contaminating air, water, and soil with toxic-heavy metals.
The problem of public health harm from smelter emissions received little official attention for much for the twentieth century. Though people living near smelters periodically complained that their health was impaired by both sulfur dioxide and heavy metals, for much of the century there was strong deference to industry claims that smelter operations were a nuisance and not a serious threat to health. It was only when the majority of children living near the El Paso, Texas, smelter were discovered to be lead-exposed in the early 1970s that systematic, independent investigation of exposure to heavy metals in smelting communities began. Following El Paso, an even more serious led poisoning epidemic was discovered around the Bunker Hill smelter in northern Idaho. In Tacoma, Washington, a copper smelter exposed children to arsenic-a carcinogenic threat.
Thoroughly grounded in extensive archival research,Tainted Earthtraces the rise of public health concerns about nonferrous smelting in the western United States, focusing on three major facilities: Tacoma, Washington; El Paso, Texas; and Bunker Hill, Idaho. Marianne Sullivan documents the response from community residents, public health scientists, the industry, and the government to pollution from smelters as well as the long road to protecting public health and the environment. Placing the environmental and public health aspects of smelting in historical context, the book connects local incidents to national stories on the regulation of airborne toxic metals.
The nonferrous smelting industry has left a toxic legacy in the United States and around the world. Unless these toxic metals are cleaned up, they will persist in the environment and may sicken people-children in particular-for generations to come. The twentieth-century struggle to control smelter pollution shares many similarities with public health battles with such industries as tobacco and asbestos where industry supported science created doubt about harm, and reluctant government regulators did not take decisive action to protect the public's health.
eBook
Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract
Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.
Triclosan (TCS), an antimicrobial agent commonly found in consumer products, has been reported to exacerbates colitis in animal models. Here, using in vitro and in vivo approaches, the authors show that gut bacterial enzymes can drive the metabolic activation and gut toxicity of TCS, highlighting an important role of intestinal microbial factors in the complex etiology of colitis.
Journal Article
Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis
A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens.
IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens.
These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply.
We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program.
Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912.
Journal Article
DCAMCP : A deep learning model based on capsule network and attention mechanism for molecular carcinogenicity prediction
The carcinogenicity of drugs can have a serious impact on human health, so carcinogenicity testing of new compounds is very necessary before being put on the market. Currently, many methods have been used to predict the carcinogenicity of compounds. However, most methods have limited predictive power and there is still much room for improvement. In this study, we construct a deep learning model based on capsule network and attention mechanism named DCAMCP to discriminate between carcinogenic and non‐carcinogenic compounds. We train the DCAMCP on a dataset containing 1564 different compounds through their molecular fingerprints and molecular graph features. The trained model is validated by fivefold cross‐validation and external validation. DCAMCP achieves an average accuracy (ACC) of 0.718 ± 0.009, sensitivity (SE) of 0.721 ± 0.006, specificity (SP) of 0.715 ± 0.014 and area under the receiver‐operating characteristic curve (AUC) of 0.793 ± 0.012. Meanwhile, comparable results can be achieved on an external validation dataset containing 100 compounds, with an ACC of 0.750, SE of 0.778, SP of 0.727 and AUC of 0.811, which demonstrate the reliability of DCAMCP. The results indicate that our model has made progress in cancer risk assessment and could be used as an efficient tool in drug design.
Journal Article