A weight of evidence assessment of the genotoxicity of 2,6-xylidine based on existing and new data, with relevance to safety of lidocaine exposure

Kirkland, David; Sheil, Meredith; Streicker, Michael; Johnson, George E.

doi:10.1016/j.yrtph.2020.104838

Cited by 10 publications

(5 citation statements)

References 110 publications

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“…This reflects the considerable constraints necessarily imposed by safe food security systems [ 9 ] that can readily lead to market failure if products continue to struggle to progress in complex regulatory approval processes, have insufficient clinical impact to be well regarded by and purchased by producers or misinformation on product risks is allowed to remain unaddressed. An example is the ongoing concerns expressed with lidocaine, with its metabolite, 2,6-xylidine, identified as a rat carcinogen [ 46 ]. This criticism persists despite lidocaine not having been associated with cancer in humans or livestock during the eight decades of therapeutic use.…”

Section: Discussionmentioning

confidence: 99%

“…This criticism persists despite lidocaine not having been associated with cancer in humans or livestock during the eight decades of therapeutic use. A recent review identified that 2,6-xylidine is a non-direct-acting (metabolic threshold-dependent) genotoxin and is not genotoxic in vivo in rats in the absence of the acute systemic toxic effects that occur at levels 35× beyond lidocaine-related exposure in humans and livestock [ 46 ]. Such challenges will likely continue to confound both the assessment of pain and evaluation of new analgesia products, particularly in commercial settings, where different measurements of pain and new drugs and strategies likely to continue to be investigated and available evidence rightly questioned.…”

Section: Discussionmentioning

confidence: 99%

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Role of Topical Anaesthesia in Pain Management of Farm Animals, a Changing Paradigm

Windsor

2022

Animals

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Field evidence indicates that livestock producers are motivated by access to products that readily deliver pain management during husbandry interventions and, more recently, viral epidermal infectious diseases, including FMD. There has been impressive adoption in Australia of a farmer-applied spray-on topical anaesthetic wound formulation (TAF; Tri-Solfen®, Medical Ethics, Australia), initially for managing pain of the breech modification ‘mulesing’ procedure that reduces susceptibility of sheep to flystrike. Over 120 million lambs have now received pain relief and cattle producers have commenced using the TAF for a range of husbandry procedures. This product has demonstrated efficacy for surgical castration and tail docking of lambs, surgical castration and dehorning of calves, surgical castration of piglets, debridement of lesions of the hoof for lame cattle and, importantly, treatment of clinical FMD lesions, including decubitus ulcerations occurring from prolonged recumbency. Multimodal use of an NSAID for improved pain management is advocated, particularly meloxicam, available by prescription from veterinarians for injection and as an oral formulation (Ilium Buccalgesic®, Troy Laboratories, Australia), with current work assessing the potential for prolonged delivery in molasses blocks. Increased use of TAF with NSAIDs significantly reduces pain and suffering in livestock, with enhanced healing of FMD lesions, reduced viral loads from Orf infections in lambs and diminished necessity of ‘antibiotic cover’, assisting antimicrobial-resistance (AMR) stewardship.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of Topical Anaesthesia in Pain Management of Farm Animals, a Changing Paradigm

Windsor

2022

Animals

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“…As a local anesthetic that also activates T2R14, the potential effects of lidocaine as a chemotherapeutic bitter agonist for HNSCCs has not been explored [54]. With high solubility, documented safety data, and the use of it in the HNSCC surgery setting, lidocaine has the potential to be an easily translatable treatment for these cancers [119, 120].…”

Section: Discussionmentioning

confidence: 99%

Lidocaine Induces Apoptosis in Head and Neck Squamous Cell Carcinoma Through Activation of Bitter Taste Receptor T2R14

Miller

Mueller

Holivert

et al. 2022

Preprint

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Head and Neck Squamous Cell Carcinomas (HNSCCs) have high mortality due to late stage diagnosis, high metastasis rates, and poor treatment options. Current therapies are invasive and aggressive, leading to a severe decline in patient quality of life (QoL). It is vital to create new therapies that are both potent and localized and/or targeted to prolong survival while maintaining QoL. Lidocaine is a local anesthetic used in HNSCC surgery settings. Lidocaine also activates bitter taste (taste family 2) receptor 14 (T2R14). T2Rs are G-protein coupled receptors (GPCRs) that increase intracellular Ca2+ when activated. T2Rs are expressed in mucosal epithelia, including internal regions of the head and neck, and are accessible drug targets. Here, we show that lidocaine increases intracellular Ca2+ and decreases cAMP in several HNSCC cell lines. Ca2+ release from the ER results in Ca2+ uptake into the mitochondria. Ca2+ mobilization is blocked with GPCR inhibitors and T2R14 antagonist, 6-methoxyflavanone. Lidocaine activation of T2R14 depolarizes the mitochondrial membrane, inhibits cell proliferation, and induces apoptosis. Lidocaine activates caspase-3 and -7 cleavage and also increases total caspase protein levels despite no changes in mRNA production. Both total and cleaved caspase products were upregulated even in the presence of cycloheximide, an inhibitor of protein synthesis. This suggests inhibition of the ubiquitin-proteasome system. It is vital to understand Lidocaine-induced apoptosis in HSNCCs to utilize its chemotherapeutic effects as a treatment option. In addition, future studies on T2R14 expression in HNSCC patients could provide insight for implementing lidocaine as a targeted topical therapy.

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“…Current evidence-based literature also reveals this precipitate to show certain degree of cytotoxicity, genotoxicity, metabolic overload and acute systemic toxicity of the liver. [ 24 25 ] However, quantity of the precipitate formed in the canal system is negligible when compared to actual levels required to show any significant systemic effects in humans.…”

Section: Discussionmentioning

confidence: 99%

Efficient removal of 2,6-xylidine precipitate using different agitation protocols: An in vitro field emission scanning electron microscopic study

Shetty¹,

Sripada²,

Bhandary³

et al. 2021

J Conserv Dent

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Background: Any solution of chemical nature when combined will result in the formation of a precipitate, which in the root canal system will interfere with the hermetic seal. In clinical practice presence of any precipitate, especially carcinogenic in nature, should be eliminated. Aim: To evaluate whether final irrigation with different agitation protocols will remove the precipitate formed following lidocaine hydrochloride and sodium hypochlorite combination at the coronal, middle, and apical-root thirds. Materials and Methods: Forty-four uniradicular teeth were standardized at 17 mm. All specimens were injected with 2% lidocaine hydrochloride and 2.5% sodium hypochlorite, followed by mechanical instrumentation using rotary files. Further, specimens were arbitrarily divided into four groups ( n = 11) based on the final irrigation protocol: Group 1: No irrigation; Group 2: Manual irrigation; Group 3: Mechanical irrigation; Group 4: Ultrasonic irrigation. Samples were sectioned and Field Field Emission Scanning Electron Microscopic (FESEM) analysis of the canal wall was done at coronal, middle, and apical thirds. Results: FESEM images revealed occluded dentinal tubules with the presence of precipitate seen in all-thirds of each specimen. Conclusion: No irrigation protocol was successful in removing the precipitate formed; but when compared ultrasonic irrigation had the least precipitate seen at-coronal,-middle and apical thirds.

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A weight of evidence assessment of the genotoxicity of 2,6-xylidine based on existing and new data, with relevance to safety of lidocaine exposure

Cited by 10 publications

References 110 publications

Role of Topical Anaesthesia in Pain Management of Farm Animals, a Changing Paradigm

Role of Topical Anaesthesia in Pain Management of Farm Animals, a Changing Paradigm

Lidocaine Induces Apoptosis in Head and Neck Squamous Cell Carcinoma Through Activation of Bitter Taste Receptor T2R14

Efficient removal of 2,6-xylidine precipitate using different agitation protocols: An in vitro field emission scanning electron microscopic study

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