TY - JOUR
AU1 - Reith, Alastair J M
AU2 - Spence, Charles
AB - Abstract Of all the oral sensations that are experienced, “metallic” is one that is rarely reported in healthy participants. So why, then, do chemotherapy patients so frequently report that “metallic” sensations overpower and interfere with their enjoyment of food and drink? This side-effect of chemotherapy—often referred to (e.g., by patients) as “metal mouth”—can adversely affect their appetite, resulting in weight loss, which potentially endangers (or at the very least slows) their recovery. The etiology of “metal mouth” is poorly understood, and current management strategies are largely unevidenced. As a result, patients continue to suffer as a result of this poorly understood phenomenon. Here, we provide our perspective on the issue, outlining the evidence for a range of possible etiologies, and highlighting key research questions. We explore the evidence for “metallic” as a putative taste, and whether “metal mouth” might therefore be a form of phantageusia, perhaps similar to already-described “release-of-inhibition” phenomena. We comment on the possibility that “metal mouth” may simply be a direct effect of chemotherapy drugs. We present the novel theory that “metal mouth” may be linked to chemotherapy-induced sensitization of TRPV1. Finally, we discuss the evidence for retronasal olfaction of lipid oxidation products in the etiology of “metal mouth.” This article seeks principally to guide much-needed future research which will hopefully one day provide a basis for the development of novel supportive therapies for future generations of patients undergoing chemotherapy. chemesthesis, metallic, phantom, retronasal, taste, TRPV1 Introduction A subset of chemotherapy patients report alterations to oral sensation as a side-effect during treatment, including a loss of sensation, distortions, and phantom sensations. Patients commonly report unpleasant, unexplained, persistent “metallic” sensations in the mouth (Rhodes et al. 1994; McDaniel and Rhodes 1998; Newell et al. 1998; Wickham et al. 1999; Bernhardson et al. 2008; Jensen et al. 2008; Rehwaldt et al. 2009; Boltong et al. 2012; Coa et al. 2015; IJpma et al. 2015; IJpma et al. 2017; Amézaga et al. 2018) which are probably more qualitatively similar to “metallic” sensations reported with metals such as iron or copper, as opposed to other metals such as calcium (which is more bitter) or sodium (which is more salty) (Richter and MacLean 1939; Tordoff 1996; Lawless et al. 2003; Yang and Lawless 2005; Lim and Lawless 2005a; Omur-Ozbek and Dietrich 2011). This “metal mouth” phenomenon affects patients on multiple different treatment regimens, and there is no clear association with the platinum content of the drugs (e.g., IJpma et al. 2017; Amézaga et al. 2018). Estimates of the prevalence of “metal mouth” among chemotherapy patients vary (see Table 1), often depending on the study design. The lowest estimate of prevalence (9.7%) was reported by Bernhardson et al. (2008). Here, the chemosensory descriptor “metallic” was seemingly not listed on the questionnaire sheet; patients had to provide the word themselves and list it under “other” (cf. Lawless et al. 2005, Experiment 3). Perhaps unsurprisingly, studies where the prompt word “metallic” is given to patients in advance have documented a higher prevalence range (≥15.7%). Studies also differ markedly in other aspects of their methodology, and the cancer types, drug regimens, and patient groups included (see Table 1). For example, one study only included patients with a history of chemotherapy-induced chemosensory disturbance (Rehwaldt et al. 2009), and unsurprisingly reported the highest prevalence estimate, 78.4%. Sometimes “metallic” was the only descriptor that patients were able to select (e.g., Newell et al. 1998), but sometimes alternative chemosensory descriptors, for example, “blood taste,” “bad taste,” and “chemical taste,” were provided as options alongside “metallic taste” (e.g., Coa et al. 2015; IJpma et al. 2017; Amézaga et al. 2018). Table 1. Studies reporting the prevalence of “metal mouth” sensations in chemotherapy patients, in chronological order. Study . Patient population . No. of patients, n . Method of data collection . Data obtained . Reported prevalence of “metallic taste” (%) . McDaniel and Rhodes (1998) Exclusively breast cancer patients receiving their first round of chemotherapy: cyclophosphamide, doxorubicin, and 5-FU 25 Telephone questionnaire Descriptors about taste change provided (80.0%); taste was: metallic (40.0%), nauseating (40.0%) 10/25 (40.0%) Newell et al. (1998) Variety of cancers and chemotherapy regimes 121 Questionnaire Metallic taste (32.2%); no alternative taste options presented 39/121 (32.2%) Wickham et al. (1999) Variety of cancers and chemotherapy regimes 284 Questionnaire Any change in taste (68.0%); loss of taste (35.9%); presence of a: metallic taste (31.3%), bitter taste (9.5%), salty taste (7.4%), sweet taste (6.7%), or sour taste (3.9%) 89/284 (31.3%) Bernhardson et al. (2008) Variety of cancers and chemotherapy regimes 518 Questionnaire Any change in taste (67.0%); change in: salt taste (27.4%), sweet taste (23.9%), bitter taste (16.2%), sour taste (14.3%), or “other.” Here, patients specified metallic (9.7%), taste loss (6.9%), “indescribable” taste change (5.8%), or other changes (9.7%) 50/518 (9.7%) Jensen et al.(2008) Exclusively breast cancer patients, typically receiving cyclophosphamide, epirubicin, and 5-FU 45 Patient interview Any change in taste (84.4%), presence of “dysgeusia that is a metallic or drug taste” (33.3%), loss of taste (22.2%), other taste changes (11.1%) 15/45 (33.3%) Rehwaldt et al. (2009) Predominantly breast cancer patients having completed at least 2 rounds of chemotherapy and reporting associated “taste changes” 37 Questionnaire Change in: metallic (78.4%), bitter (56.8%); loss of taste (67.6%); dry mouth (83.8%); which has affected ability to eat (75.6%) 29/37 (78.4%) Coa et al. (2015) Variety of cancers, chemotherapy regimes, and other treatments 1199 Questionnaire Any change in taste (67.2%); increased sensitivity to: metallic (18.6%), salt (14.5%), sweet (13.4%), bitter (9.3%), sour (7.4%); decreased sensitivity to: sweet (9.3%), salt (8.6%), sour (4.8%), bitter (4.7%) 223/1199 (18.6%) IJpma et al. (2017) Variety of cancers and chemotherapy, hormonal therapy, and targeted therapy regimes 127 Questionnaire Any change in taste (62.2%), any persistent taste in the past week (45.7%), from the options “blood, bitter, something chemical, something musty, drugs, metallic, sweet, salty, sour, other” 15.7% identified the presence of a persistent metallic taste in the past week 20/127 (15.7%) Amézaga et al. (2018) Variety of cancers and chemotherapy regimes 151 Questionnaire Any change in taste (77.5%); loss of taste (43.0%); abnormal sensitivity to: salt (44.4%), sweet (35.1%), bitter (29.1%), sour (25.8%), hot food (20.5%), cold food (35.8%); presence of a metallic taste (39.1%), presence of a persistent bad taste (45.0%), presence of other strange tastes (23.8%), foods taste different than before (50.3%), dry mouth (63.6%), sores in the mouth (34.4%) 59/151 (39.1%) Study . Patient population . No. of patients, n . Method of data collection . Data obtained . Reported prevalence of “metallic taste” (%) . McDaniel and Rhodes (1998) Exclusively breast cancer patients receiving their first round of chemotherapy: cyclophosphamide, doxorubicin, and 5-FU 25 Telephone questionnaire Descriptors about taste change provided (80.0%); taste was: metallic (40.0%), nauseating (40.0%) 10/25 (40.0%) Newell et al. (1998) Variety of cancers and chemotherapy regimes 121 Questionnaire Metallic taste (32.2%); no alternative taste options presented 39/121 (32.2%) Wickham et al. (1999) Variety of cancers and chemotherapy regimes 284 Questionnaire Any change in taste (68.0%); loss of taste (35.9%); presence of a: metallic taste (31.3%), bitter taste (9.5%), salty taste (7.4%), sweet taste (6.7%), or sour taste (3.9%) 89/284 (31.3%) Bernhardson et al. (2008) Variety of cancers and chemotherapy regimes 518 Questionnaire Any change in taste (67.0%); change in: salt taste (27.4%), sweet taste (23.9%), bitter taste (16.2%), sour taste (14.3%), or “other.” Here, patients specified metallic (9.7%), taste loss (6.9%), “indescribable” taste change (5.8%), or other changes (9.7%) 50/518 (9.7%) Jensen et al.(2008) Exclusively breast cancer patients, typically receiving cyclophosphamide, epirubicin, and 5-FU 45 Patient interview Any change in taste (84.4%), presence of “dysgeusia that is a metallic or drug taste” (33.3%), loss of taste (22.2%), other taste changes (11.1%) 15/45 (33.3%) Rehwaldt et al. (2009) Predominantly breast cancer patients having completed at least 2 rounds of chemotherapy and reporting associated “taste changes” 37 Questionnaire Change in: metallic (78.4%), bitter (56.8%); loss of taste (67.6%); dry mouth (83.8%); which has affected ability to eat (75.6%) 29/37 (78.4%) Coa et al. (2015) Variety of cancers, chemotherapy regimes, and other treatments 1199 Questionnaire Any change in taste (67.2%); increased sensitivity to: metallic (18.6%), salt (14.5%), sweet (13.4%), bitter (9.3%), sour (7.4%); decreased sensitivity to: sweet (9.3%), salt (8.6%), sour (4.8%), bitter (4.7%) 223/1199 (18.6%) IJpma et al. (2017) Variety of cancers and chemotherapy, hormonal therapy, and targeted therapy regimes 127 Questionnaire Any change in taste (62.2%), any persistent taste in the past week (45.7%), from the options “blood, bitter, something chemical, something musty, drugs, metallic, sweet, salty, sour, other” 15.7% identified the presence of a persistent metallic taste in the past week 20/127 (15.7%) Amézaga et al. (2018) Variety of cancers and chemotherapy regimes 151 Questionnaire Any change in taste (77.5%); loss of taste (43.0%); abnormal sensitivity to: salt (44.4%), sweet (35.1%), bitter (29.1%), sour (25.8%), hot food (20.5%), cold food (35.8%); presence of a metallic taste (39.1%), presence of a persistent bad taste (45.0%), presence of other strange tastes (23.8%), foods taste different than before (50.3%), dry mouth (63.6%), sores in the mouth (34.4%) 59/151 (39.1%) Updated from the list of studies up to 2014 provided by IJpma et al. (2015). Open in new tab Table 1. Studies reporting the prevalence of “metal mouth” sensations in chemotherapy patients, in chronological order. Study . Patient population . No. of patients, n . Method of data collection . Data obtained . Reported prevalence of “metallic taste” (%) . McDaniel and Rhodes (1998) Exclusively breast cancer patients receiving their first round of chemotherapy: cyclophosphamide, doxorubicin, and 5-FU 25 Telephone questionnaire Descriptors about taste change provided (80.0%); taste was: metallic (40.0%), nauseating (40.0%) 10/25 (40.0%) Newell et al. (1998) Variety of cancers and chemotherapy regimes 121 Questionnaire Metallic taste (32.2%); no alternative taste options presented 39/121 (32.2%) Wickham et al. (1999) Variety of cancers and chemotherapy regimes 284 Questionnaire Any change in taste (68.0%); loss of taste (35.9%); presence of a: metallic taste (31.3%), bitter taste (9.5%), salty taste (7.4%), sweet taste (6.7%), or sour taste (3.9%) 89/284 (31.3%) Bernhardson et al. (2008) Variety of cancers and chemotherapy regimes 518 Questionnaire Any change in taste (67.0%); change in: salt taste (27.4%), sweet taste (23.9%), bitter taste (16.2%), sour taste (14.3%), or “other.” Here, patients specified metallic (9.7%), taste loss (6.9%), “indescribable” taste change (5.8%), or other changes (9.7%) 50/518 (9.7%) Jensen et al.(2008) Exclusively breast cancer patients, typically receiving cyclophosphamide, epirubicin, and 5-FU 45 Patient interview Any change in taste (84.4%), presence of “dysgeusia that is a metallic or drug taste” (33.3%), loss of taste (22.2%), other taste changes (11.1%) 15/45 (33.3%) Rehwaldt et al. (2009) Predominantly breast cancer patients having completed at least 2 rounds of chemotherapy and reporting associated “taste changes” 37 Questionnaire Change in: metallic (78.4%), bitter (56.8%); loss of taste (67.6%); dry mouth (83.8%); which has affected ability to eat (75.6%) 29/37 (78.4%) Coa et al. (2015) Variety of cancers, chemotherapy regimes, and other treatments 1199 Questionnaire Any change in taste (67.2%); increased sensitivity to: metallic (18.6%), salt (14.5%), sweet (13.4%), bitter (9.3%), sour (7.4%); decreased sensitivity to: sweet (9.3%), salt (8.6%), sour (4.8%), bitter (4.7%) 223/1199 (18.6%) IJpma et al. (2017) Variety of cancers and chemotherapy, hormonal therapy, and targeted therapy regimes 127 Questionnaire Any change in taste (62.2%), any persistent taste in the past week (45.7%), from the options “blood, bitter, something chemical, something musty, drugs, metallic, sweet, salty, sour, other” 15.7% identified the presence of a persistent metallic taste in the past week 20/127 (15.7%) Amézaga et al. (2018) Variety of cancers and chemotherapy regimes 151 Questionnaire Any change in taste (77.5%); loss of taste (43.0%); abnormal sensitivity to: salt (44.4%), sweet (35.1%), bitter (29.1%), sour (25.8%), hot food (20.5%), cold food (35.8%); presence of a metallic taste (39.1%), presence of a persistent bad taste (45.0%), presence of other strange tastes (23.8%), foods taste different than before (50.3%), dry mouth (63.6%), sores in the mouth (34.4%) 59/151 (39.1%) Study . Patient population . No. of patients, n . Method of data collection . Data obtained . Reported prevalence of “metallic taste” (%) . McDaniel and Rhodes (1998) Exclusively breast cancer patients receiving their first round of chemotherapy: cyclophosphamide, doxorubicin, and 5-FU 25 Telephone questionnaire Descriptors about taste change provided (80.0%); taste was: metallic (40.0%), nauseating (40.0%) 10/25 (40.0%) Newell et al. (1998) Variety of cancers and chemotherapy regimes 121 Questionnaire Metallic taste (32.2%); no alternative taste options presented 39/121 (32.2%) Wickham et al. (1999) Variety of cancers and chemotherapy regimes 284 Questionnaire Any change in taste (68.0%); loss of taste (35.9%); presence of a: metallic taste (31.3%), bitter taste (9.5%), salty taste (7.4%), sweet taste (6.7%), or sour taste (3.9%) 89/284 (31.3%) Bernhardson et al. (2008) Variety of cancers and chemotherapy regimes 518 Questionnaire Any change in taste (67.0%); change in: salt taste (27.4%), sweet taste (23.9%), bitter taste (16.2%), sour taste (14.3%), or “other.” Here, patients specified metallic (9.7%), taste loss (6.9%), “indescribable” taste change (5.8%), or other changes (9.7%) 50/518 (9.7%) Jensen et al.(2008) Exclusively breast cancer patients, typically receiving cyclophosphamide, epirubicin, and 5-FU 45 Patient interview Any change in taste (84.4%), presence of “dysgeusia that is a metallic or drug taste” (33.3%), loss of taste (22.2%), other taste changes (11.1%) 15/45 (33.3%) Rehwaldt et al. (2009) Predominantly breast cancer patients having completed at least 2 rounds of chemotherapy and reporting associated “taste changes” 37 Questionnaire Change in: metallic (78.4%), bitter (56.8%); loss of taste (67.6%); dry mouth (83.8%); which has affected ability to eat (75.6%) 29/37 (78.4%) Coa et al. (2015) Variety of cancers, chemotherapy regimes, and other treatments 1199 Questionnaire Any change in taste (67.2%); increased sensitivity to: metallic (18.6%), salt (14.5%), sweet (13.4%), bitter (9.3%), sour (7.4%); decreased sensitivity to: sweet (9.3%), salt (8.6%), sour (4.8%), bitter (4.7%) 223/1199 (18.6%) IJpma et al. (2017) Variety of cancers and chemotherapy, hormonal therapy, and targeted therapy regimes 127 Questionnaire Any change in taste (62.2%), any persistent taste in the past week (45.7%), from the options “blood, bitter, something chemical, something musty, drugs, metallic, sweet, salty, sour, other” 15.7% identified the presence of a persistent metallic taste in the past week 20/127 (15.7%) Amézaga et al. (2018) Variety of cancers and chemotherapy regimes 151 Questionnaire Any change in taste (77.5%); loss of taste (43.0%); abnormal sensitivity to: salt (44.4%), sweet (35.1%), bitter (29.1%), sour (25.8%), hot food (20.5%), cold food (35.8%); presence of a metallic taste (39.1%), presence of a persistent bad taste (45.0%), presence of other strange tastes (23.8%), foods taste different than before (50.3%), dry mouth (63.6%), sores in the mouth (34.4%) 59/151 (39.1%) Updated from the list of studies up to 2014 provided by IJpma et al. (2015). Open in new tab There is perhaps also a broader concern: namely, because “metallic taste” is often discussed among the chemotherapy patient community, there might be an element of suggestibility—where patients begin to interpret their sensory experience (which may be unfamiliar and hence difficult to label) as whatever “taste” is preselected for them (e.g., see Nitschke et al. 2006). This can be inadvertent: phrases such as “metallic taste” can simply slip into the vernacular (as discussed by Lawless et al. 2005). Patients suffering from a host of different individual sensory distortions may well already have been lumped together in the “metallic taste” category, thus potentially giving rise to an over-reporting bias. It may be instructive to investigate how patients who had been trained in the food industry describe the taste changes they experience during chemotherapy (as they are likely to have a broader vocabulary to label what is a new and unfamiliar sensory experience). Although other taste changes in chemotherapy patients are probably linked to the death of taste cell progenitors in the affected modality (e.g., see Mukherjee and Delay, 2011; Jewkes et al. 2018) the etiology of “metal mouth” is particularly curious because “metallic” is not a widely recognized modality of taste. There is no accepted “metallic” taste receptor (but see Nelson et al. 2001; Riera et al. 2007; Riera et al. 2009a); although people do ascribe the descriptor “metallic” to a particular kind of oral sensation (e.g., Lawless et al. 2005, Experiment 2; but see Lawless et al. 2005, Experiment 3). In experimental situations, neurologically healthy human participants can detect the presence of iron, copper, zinc, and other metals on the tongue (Zacarias et al. 2001; Lawless et al. 2004; 2005; Lim and Lawless 2005b; Laughlin et al. 2011), and detect the differences between different metals on a sensory basis (Laughlin et al. 2011; Omur-Ozbek and Dietrich 2011; Piqueras-Fiszman et al. 2012). Although the phrase “metallic taste” is commonly used, how these well-known metallic sensations are actually transduced remains unclear. In summary, “metallic” sensations in chemotherapy are commonly reported; they can severely distort patients’ experiences of food (and linger after eating and drinking); and they are also entirely unexplained. Maintaining proper nutrition is undoubtedly vital in helping cancer patients withstand a punishing chemotherapy regime (see also Spence 2017, on the importance of proper nutrition in the hospital setting). Distorted, lingering, unpleasant mouth sensations are linked to a loss of appetite and weight loss (Coa et al. 2015; Nolden et al. 2019a, 2019b) and could potentially predispose patients to cachexia—the irreversible muscle wasting condition which accounts for an estimated 20% of cancer-associated deaths (Blackburn 2009; Hong et al. 2009). Here, we will provide our perspective on the poorly understood “metal mouth” side-effect of chemotherapy, discussing some possible causes of the metallic sensation and highlighting selected areas of the field for further investigation. Background: chemotherapy is toxic and causes oral sensory loss The “metal mouth” sensation in chemotherapy occurs either at the same time as, or because of, other changes affecting the chemosensory system. Principally, self-reported “taste loss” is a common finding among chemotherapy patients (e.g., Wickham et al. 1999; Berteretche et al. 2004; Rehwaldt et al. 2009; Gamper et al. 2012; IJpma et al. 2015; Amézaga et al. 2018). Taste loss in chemotherapy may occur because cytotoxic drugs can injure multiple cell types in the oral cavity, with gustatory neurons, taste receptor cells, and salivary glands potentially all at risk. Given that much of reported “flavor” derives from retronasal olfaction (e.g., Murphy and Cain 1980; Rozin 1982; and see Spence 2015, for a review), olfactory toxicity may also be a significant factor in the reported “taste” changes in chemotherapy (e.g., see Bernhardson et al. 2009) (and see Figure 1). This is the background upon which the “metal mouth” phenomenon somehow develops. Figure 1. Open in new tabDownload slide Simplified illustration of the contribution of taste to flavor. Key elements are emphasized: namely, the cross-talk between the chorda tympani and the glossopharyngeal nerve, which may involve reciprocal inhibition; the presence of broadly discrete clusters of taste buds on the tongue, which have separate innervation; and the integration of olfactory inputs into flavor perception. Note that several of these flavor-forming structures are affected by the action of cytotoxic drugs. Figure 1. Open in new tabDownload slide Simplified illustration of the contribution of taste to flavor. Key elements are emphasized: namely, the cross-talk between the chorda tympani and the glossopharyngeal nerve, which may involve reciprocal inhibition; the presence of broadly discrete clusters of taste buds on the tongue, which have separate innervation; and the integration of olfactory inputs into flavor perception. Note that several of these flavor-forming structures are affected by the action of cytotoxic drugs. First, chemotherapy causes a widespread peripheral sensory neuropathy, leading to numbness and sensory loss in a “stocking and glove” distribution in the extremities. Platinates (e.g., cisplatin and oxaliplatin) form platinum–DNA adducts, leading to the apoptosis of sensory neurons (Fischer et al. 2001; Ta et al. 2006). Platinates, taxanes (e.g., paclitaxel and docetaxel), and vinca alkaloids (e.g., vinblastine and vincristine) impair microtubule homeostasis, suppressing axonal transport, for example, of neuronal growth factors (Owellen et al. 1976; Topp et al. 2000; Peters et al. 2007; Velasco and Bruna 2015). If chemotherapy is also significantly toxic to gustatory neurons, this may help to explain why chemotherapy patients are prone to suffering from a loss of oral sensation, including a loss of taste (e.g., Berteretche et al. 2004; Gamper et al. 2012; IJpma et al. 2015). Second, it has been reported that chemotherapy is toxic to taste receptor cell progenitors (Mukherjee et al. 2013; Mukherjee et al. 2017; Jewkes et al. 2018; Delay et al. 2019). Following bolus administration of the chemotherapeutic agent cyclophosphamide, mice lose the ability to discriminate between tastants (see Figure 2). This is thought to be attributable to altered turnover: mature taste cells are less likely to be replaced if there are fewer progenitors to replace them. Histological examination following cyclophosphamide administration revealed fewer taste papillae, and more disordered papillar structure, including a lack of taste pores (Mukherjee and Delay 2011; Mukherjee et al. 2013). Additionally, loss of innervation to the tongue has independently been found to induce taste bud degeneration (Vintschgau and Hönigschmied 1877; Huang and Lu 1996; Huang and Lu 2001; Guagliardo and Hill 2007). Figure 2. Open in new tabDownload slide An example of loss of taste function in chemotherapy. CYP = cyclophosphamide group (injected with bolus on day 0), saline = control. Mice were tested on their ability to discriminate (% successful detection) between umami taste substances monosodium glutamate and IMP, which control mice can discriminate ~90% of the time. The relative failure of mice in the CYP group to discriminate (50% = chance) could be linked to the direct effect of losing taste receptor cells in the umami modality (i.e., a loss of sensitivity); to concomitant nerve damage; or to abnormal modulation of taste receptor cell activity, for example, by cytokines. This loss of umami taste discrimination following a cyclophosphamide bolus appears to be biphasic, probably because of the different life expectancies of taste receptor cell populations in the tongue. SP = punisher for failure to discriminate. ***P < 0.001. [Figure reproduced from Mukherjee and Delay 2011, with permission from Elsevier.] Figure 2. Open in new tabDownload slide An example of loss of taste function in chemotherapy. CYP = cyclophosphamide group (injected with bolus on day 0), saline = control. Mice were tested on their ability to discriminate (% successful detection) between umami taste substances monosodium glutamate and IMP, which control mice can discriminate ~90% of the time. The relative failure of mice in the CYP group to discriminate (50% = chance) could be linked to the direct effect of losing taste receptor cells in the umami modality (i.e., a loss of sensitivity); to concomitant nerve damage; or to abnormal modulation of taste receptor cell activity, for example, by cytokines. This loss of umami taste discrimination following a cyclophosphamide bolus appears to be biphasic, probably because of the different life expectancies of taste receptor cell populations in the tongue. SP = punisher for failure to discriminate. ***P < 0.001. [Figure reproduced from Mukherjee and Delay 2011, with permission from Elsevier.] Third, chemotherapy may be toxic to salivary glands, as patients commonly suffer from oral dryness (Wickham et al. 1999; Jensen et al. 2003; Cheng 2007; Rehwaldt et al. 2009). Damage to the salivary glands reduces saliva production, meaning less solvent is present in the oral cavity (see Spence 2011, for a review). Solutes include taste substances which need to access and bind with their receptors on the tongue (as discussed in Doty and Bromley 2004); loss of saliva can therefore lead to a loss of taste. Loss of saliva might also cause some background perception similar to astringency—which is described as a feeling of puckering, roughing, or dryness in the mouth (e.g., Lee and Lawless 1991; but see Fleming et al. 2016). Astringency is commonly perceived alongside tastes/flavors such as bitter and metallic, for example in metals such as iron and copper (Lawless et al. 2004; Lim and Lawless 2005a, 2005b; Stevens et al. 2008; Omur-Ozbek and Dietrich 2011), as well as in strong tea, coffee, and oaked wine (e.g., Guinard et al. 1986). Taste-modifying proteins such as carbonic anhydrase 6 (CA6) are also present in saliva; and, among other alterations to the salivary proteome, reduced levels of CA6 have been found in chemotherapy patients (Wang et al. 2018a) and in patients with postcoryzal oral sensory loss (Henkin et al. 1999). On a related note, anecdotal evidence suggests that adding novel taste-modifying substances to saliva (e.g., bromelain or miraculin) may be helpful in terms of diminishing metallic flavor percepts in chemotherapy (Wilken and Satiroff 2012; Harding 2017). The off-target toxicities of chemotherapy described above may be compounded by damage to the flavor-forming tissues of the olfactory system (e.g., Bernhardson et al. 2009). Surrounding this injury are the reactive oxygen species generated by chemotherapy, which are known to be cytotoxic (see Yang et al. 2018, for a review); and an altered oral inflammatory state, which there is evidence to suggest may be linked to taste changes. Briefly, TUNEL and cleaved caspase-3 assays indicate that cyclophosphamide-induced taste cell death in mice is necrotic (Mukherjee and Delay 2011). Inflammation would also incur neuronal death (e.g., Ye et al. 2013); and, in an LPS (lipopolysaccharide) based model of inflammation, destruction of proliferating cells aggravated taste cell loss (Cohn et al. 2010) just like in chemotherapy. This may be linked to the upregulation of interferons—harbingers of taste cell death (Wang et al. 2007). Other inflammatory cytokines such as TNF (tumor necrosis factor) may also distort taste sensations; for example, TNF−/− mice are less sensitive to the bitter taste substance quinine (Feng et al. 2015). Finally, and importantly, there is immense variability in chemotherapy patients’ symptom reports: whereas some report barely any change in taste, others experience debilitating taste loss and/or metallic sensations. To the best of our knowledge, no association with any particular chemotherapy regime has yet been identified (Amézaga et al. 2018), although the addition of anti-emetics has been found to increase the likelihood of any self-reported taste change (Nolden et al. 2019a). Variability in symptom reports also seems likely to be influenced by interpersonal variance in human taste capacity. Whether PROP “supertasters” (Bartoshuk 2000) or other chemosensory variants in the population (e.g., Green and Hayes 2003; Green and George 2004; Xu et al. 2007; Allen et al. 2014) report taste alterations more often, and whether taste bud density is correlated with the degree of taste change, are interesting research questions for the future. To summarise, chemotherapy is toxic to a range of sensory structures, and somehow in a subset of individuals the aversive “metallic” percept arises. We will now present the evidence for a series of theoretical explanations for this that warrant future research attention. The “tinnitus of taste?” It is currently uncertain whether “metallic” is a modality of taste. Metals in the mouth may form a miniature Voltaic pile, generating electric current and often a “metallic” sensation (Sulzer 1762, p. 82). Modern-day batteries can achieve a similar effect (Lawless et al. 2005; McClure and Lawless 2007; Stevens et al. 2008) which could be partly due to metal ions traversing the epithelium of the tongue by ionophoresis. Indeed, the strength of reported “metallic” sensation evoked by solid metal spoons correlates moderately (R2 = 0.33) with the anodicity of the metal (Laughlin et al. 2011). Taste receptors on the tongue such as T1R3 might bind the metal ions. Broadly speaking, three populations of T1R-expressing taste receptor cells exist on the murine tongue: T1R1/T1R3-expressing (umami) taste receptor cells; T1R2/T1R3-expressing (sweet) taste receptor cells; and a hitherto-unexplained population of taste receptor cells expressing T1R3 alone (Nelson et al. 2001). In T1R3−/− mice, hedonic responses to metallic (e.g., iron and zinc) solutions are muted (see Figure 3). Wild-type mice will drink these metal solutions copiously (Riera et al. 2009a), suggesting that T1R3 agonism might produce a pleasurable metallic sensation in mice, although which taste receptor cell population(s) are responsible for this is not clear. T1R3 has also been characterized separately in the more aversive sensation induced by calcium salts (Tordoff et al. 2012). Finally, metal ions have also been found to ligate the bitter taste receptor T2R7 (Wang et al. 2019). Figure 3. Open in new tabDownload slide T1R3−/− mice exhibit no significant preference for concentrations of metal sulfate solutions which wild-type mice find hedonically appealing (when compared with water). Preference ratios from two-bottle tests where metal sulfate solution was presented in the cage alongside water. Preference ratio = volume of metal sulfate solution consumed ÷ (total volume of metal sulfate solution + volume of water consumed). Top: iron sulfate solution; bottom: zinc sulfate solution. *P < 0.05, TRPM5 vs. WT; +P < 0.05, T1R3 vs. WT. Please refer to the online version of the article to follow the colour code. [Reproduced from Riera et al. 2009a, with permission from the Society for Neuroscience via Copyright Clearance Center.] Figure 3. Open in new tabDownload slide T1R3−/− mice exhibit no significant preference for concentrations of metal sulfate solutions which wild-type mice find hedonically appealing (when compared with water). Preference ratios from two-bottle tests where metal sulfate solution was presented in the cage alongside water. Preference ratio = volume of metal sulfate solution consumed ÷ (total volume of metal sulfate solution + volume of water consumed). Top: iron sulfate solution; bottom: zinc sulfate solution. *P < 0.05, TRPM5 vs. WT; +P < 0.05, T1R3 vs. WT. Please refer to the online version of the article to follow the colour code. [Reproduced from Riera et al. 2009a, with permission from the Society for Neuroscience via Copyright Clearance Center.] “Metallic” sensations have also been reported in human participants when several different taste modalities are stimulated synchronously; for example, during direct electrical stimulation of the chorda tympani (Frenckner and Preber 1954), and following generalized damage to the chorda tympani, for example following ear surgery (Rice 1963; Bull 1965; Mahendran et al. 2005; Galindo et al. 2009). Following nerve damage in the auditory system, there may be no reduction in auditory cortex activity, suggesting that compensatory amplification has occurred (as reviewed by Roberts 2018). Both noise-evoked and spontaneous activity can be amplified. Amplification of spontaneous activity in the auditory nerve may be experienced by patients as tinnitus (phantom sound). Tinnitus (Miaskowski et al. 2018) and other phantoms and distortions (e.g., paraesthesias) have also been reported as side-effects of chemotherapy. Speculatively, chemotherapy-induced nerve damage in the gustatory system might lead to global, synchronous amplification in the chorda tympani experienced as a “metallic” sensation. One outstanding research question here concerns whether chemotherapy patients experiencing “metal mouth” exhibit altered gustatory cortex activity (e.g., on functional MRI, cf. Henkin et al. 2000) compared to those with no reported oral sensory change. However, a normal representation of metallic on “taste maps” in the gustatory cortex (e.g., Chen et al. 2011; Chikazoe et al. 2019) has not been established. There is limited evidence from studies on human participants undergoing chorda tympani anesthesia. Here, despite profound local sensory loss, “sip and spit” testing has revealed little or no loss of whole-mouth taste intensity (see Figure 4) (Ostrom et al. 1985; Catalanotto et al. 1993; Lehman et al. 1995; Yanagisawa et al. 1998), suggesting that oral sensory loss can sometimes elicit a compensatory amplification that is somewhat similar to tinnitus. Furthermore, some human participants in these experiments reported experiencing phantom sensations, including “metallic” phantoms (Yanagisawa et al. 1998), although other taste phantoms (e.g., sweet phantoms) were also reported. Notably, in contrast to chemotherapy, phantoms under chorda tympani anesthesia are frequently positively valenced, indicating that chorda tympani anesthesia is an imperfect model of taste change in chemotherapy. In summary, although something akin to a “tinnitus of taste” model of “metal mouth” is theoretically conceivable, it is unclear precisely how it would work in practice and, to the best of our knowledge, it has never been investigated. Figure 4. Open in new tabDownload slide In unilateral chorda tympani anesthesia, despite local sensory loss on the ipsilateral side of the tongue (Front of the Tongue, Right), there is no loss of reported whole-mouth taste intensity of the tastants sodium chloride (NaCl, salty), sucrose (Suc, sweet), and citric acid (CA, sour); and there is an increase in reported whole-mouth taste intensity of quinine hydrochloride (QHCl, bitter). *P < 0.05. [Reproduced from Lehman et al. 1995, with permission from Elsevier.] Figure 4. Open in new tabDownload slide In unilateral chorda tympani anesthesia, despite local sensory loss on the ipsilateral side of the tongue (Front of the Tongue, Right), there is no loss of reported whole-mouth taste intensity of the tastants sodium chloride (NaCl, salty), sucrose (Suc, sweet), and citric acid (CA, sour); and there is an increase in reported whole-mouth taste intensity of quinine hydrochloride (QHCl, bitter). *P < 0.05. [Reproduced from Lehman et al. 1995, with permission from Elsevier.] Sparing the posterior tongue It is unclear whether the length-dependence of chemotherapy-induced neurotoxicity in the somatosensory system applies to the chorda tympani, with its tortuous length through the petrous part of the temporal bone; but there is evidence that the pattern of gustotoxicity on the tongue roughly follows the distribution of the chorda tympani, with taste receptor cells on the anterior portion of the tongue potentially worst-affected by cyclophosphamide. After cyclophosphamide is injected into mice, anterior (fungiform) papillae are diminished faster, such that type II (phospholipase Cβ2-positive) taste cells tend to die sooner after cyclophosphamide injection if situated more anteriorly on the tongue (see Figure 5) (Mukherjee and Delay 2011; Mukherjee et al. 2013; Mukherjee et al. 2017). Because the posterior part of the tongue is disproportionately dedicated to bitter taste (e.g., Adler et al. 2000; Matsunami et al. 2000; Voigt et al. 2012; Feeney and Hayes 2014), this suggests that bitter taste faculties might be preferentially preserved under chemotherapy. Not only is hypersensitivity to bitter frequently reported by chemotherapy patients, it is well-correlated with the presence of metal mouth as well (IJpma et al. 2017). Recently, solutions of metal salts—including zinc and copper—have been found to ligate the bitter taste receptor T2R7 when expressed in transiently transfected human embryonic kidney (HEK) cells (Wang et al. 2019). This suggests that part of the T2R repertoire is responsive to metals, which may explain some of the overlap between bitter taste and the metallic sensation, which are commonly reported together (e.g., Bromberger and Percival 2007, p. 139). Another bitter taste receptor, T2R5, is thought to be slightly upregulated in chemotherapy patients, especially in those who report phantom sensations (see Figure 6) (Tsutsumi et al. 2016), but to the best of our knowledge, whether T2R7 is upregulated/sensitized in chemotherapy has never been tested in this way. This is worthy of further investigation. Figure 5. Open in new tabDownload slide Phospholipase Cβ2-positive (PLCβ2+) type II taste receptor cells in fungiform papillae on the anterior tongue (left) are diminished faster following administration of cyclophosphamide bolus (on day 0) than PLCβ2+ (type II) taste receptor cells in circumvallate papillae on the posterior tongue (right). CYP = cyclophosphamide group; AMF/CYP = cyclophosphamide group treated with cytoprotectant, amifostine. ***P < 0.001, **P < 0.01, *P < 0.05. Please refer to the online version of the article to follow the colour code. [Reproduced from Mukherjee et al. 2013, under CC-BY license.] Figure 5. Open in new tabDownload slide Phospholipase Cβ2-positive (PLCβ2+) type II taste receptor cells in fungiform papillae on the anterior tongue (left) are diminished faster following administration of cyclophosphamide bolus (on day 0) than PLCβ2+ (type II) taste receptor cells in circumvallate papillae on the posterior tongue (right). CYP = cyclophosphamide group; AMF/CYP = cyclophosphamide group treated with cytoprotectant, amifostine. ***P < 0.001, **P < 0.01, *P < 0.05. Please refer to the online version of the article to follow the colour code. [Reproduced from Mukherjee et al. 2013, under CC-BY license.] Figure 6. Open in new tabDownload slide (A) Zinc sulfate solution activates the bitter taste receptor T2R7 in transiently transfected HEK cells. RFU = relative fluorescence units, fluo-4 Ca2+ indicator used. Black trace: HEK cell transfected with T2R7; green-gray trace: mock-transfected HEK cell. [Figure reproduced from Wang et al. 2019, under CC-BY license.] (B) Upregulation of another bitter taste receptor, T2R5, in the lingual epithelia of chemotherapy patients only occurs to a significant extent if phantom sensations are also present. *P < 0.05. [Reproduced from Tsutsumi et al. 2016, with permission from John Wiley & Sons via Copyright Clearance Center.] Figure 6. Open in new tabDownload slide (A) Zinc sulfate solution activates the bitter taste receptor T2R7 in transiently transfected HEK cells. RFU = relative fluorescence units, fluo-4 Ca2+ indicator used. Black trace: HEK cell transfected with T2R7; green-gray trace: mock-transfected HEK cell. [Figure reproduced from Wang et al. 2019, under CC-BY license.] (B) Upregulation of another bitter taste receptor, T2R5, in the lingual epithelia of chemotherapy patients only occurs to a significant extent if phantom sensations are also present. *P < 0.05. [Reproduced from Tsutsumi et al. 2016, with permission from John Wiley & Sons via Copyright Clearance Center.] From studies of chorda tympani anesthesia, participants also reported mildly increased sensitivity to bitter (Lehman et al. 1995; Yanagisawa et al. 1998). “Cross-talk” between the chorda tympani and glossopharyngeal nerves (see Figure 1) (reviewed in Bartoshuk et al. 2005; Snyder and Bartoshuk 2016) is one suggested mechanism: attenuated signals in the chorda tympani produce a compensatory overamplification of signals in the glossopharyngeal nerve (a so-called “release-of-inhibition”). The same “release-of-inhibition” might apply to pain signals in the trigeminal nerve (Tie et al. 1999). Multidimensional scaling analyses suggest that bitterness and trigeminality are associated with the metallic sensation, being in themselves corollaries of electrical stimulation of the tongue (see Stevens et al. 2008; and also McClure and Lawless 2007). If cytotoxicity preferentially affects the anterior tongue, “release-of-inhibition” of the posterior tongue may contribute to bitter sensitivity and metal mouth. An outstanding research question is whether there might be any benefit from some form of posterior tongue anesthesia. Further investigation is required. A direct effect of the drug? Many drugs taste foul or bitter (cf. Wan et al. 2015). Pill formulations are designed to mask this at first-pass, but some compounds evoke “tastes” when given intravenously (i.v.)—a phenomenon known as “intravascular taste.” For example, orally ingested saccharin tastes sweet; and human participants seem to experience a similar sweet taste in the oral cavity when saccharin is injected i.v. (Fishberg et al. 1933). This may be for a number of reasons: for example, saccharin could permeate into saliva; it could pass between tight junctions in taste epithelium; or it could interact with taste receptor cells via the basolateral surface (Schiffman 2015). This “intravascular taste” effect with saccharin was recently re-examined, over 80 years after the original experiment, using molecular kinetic analysis (Choi et al. 2015). By calculating time delays, the authors elegantly concluded that i.v. saccharin probably traverses the tight junctions to enter the oral cavity, eventually eliciting its “intravascular taste” by the same mechanism (e.g., T1R2-T1R3 agonism) as this taste sensation is elicited following oral administration. However, for other taste substances, a different mechanism of “intravascular taste” may apply. L-Arginine—bitter when taken orally (Schiffman et al. 1981)—reportedly elicits a metallic sensation in the oral cavity when injected i.v. (Veldhuis et al. 2006; Schiffman 2015), for reasons which remain unclear. For drugs such as amiodarone which elicit metallic sensations, and perhaps for some chemotherapy agents, unknown taste mechanisms which permit intravascular taste may be at play. TRPV1 and metals Nerve endings in skin, and trigeminal nerve endings in the oral mucosa, including on the epithelial surface of the tongue, express the transient receptor potential (TRP) cation channel TRPV1. TRPV1 is polymodal, responding to pain, temperature, acid, alcohol, and various compounds found in spices, for example, capsaicin, piperine, and eugenol (see Boonen et al. 2017, for a review). When humans perceive “metallic” in the mouth, reports occasionally include words like “burning,” “tingling,” “sharp,” or “not a taste” (Lawless et al. 2004; Lim and Lawless, 2005a; Lubran et al. 2005). Indeed, there is evidence to suggest metallic transduction could be partly chemesthetic. Artificial sweeteners (e.g., saccharin and acesulfame-K) can be aversive at high concentrations, with bitter and metallic among other sensory qualities reported (Helgren et al. 1955; Schiffman et al. 1995). The bitterness seems to be due to ligation of T2Rs (Kuhn et al. 2004), but other aversive components, such as metallic, could be encoded separately. Transiently transfected HEK cells were used to evaluate bitter taste substances, metallic compounds, and artificial sweeteners and investigate whether they could signal via the polymodal receptor TRPV1. Metallic compounds and artificial sweeteners both activated TRPV1, whereas bitter taste substances did not (Riera et al. 2007). This potentially isolates the metallic sensory elements of artificial sweeteners. In behavioral studies, TRPV1 knockout mice were also less averse to artificial sweeteners (Riera et al. 2008) and metallic compounds (Riera et al. 2009a)—although the effect sizes were small. If metallic compounds are true chemesthetic ligands, there is probably more to the metallic sensation than the “burn” of TRPV1. Chemesthetic compounds often ligate a profile of different receptors; for example, hydroxy-α-sanshool (from Sichuan peppers) ligates TRPV1, TRPA1, and chemesthetic K+ channels, which creates a “tingling” sensation (Bautista et al. 2008; Riera et al. 2009b; Cometto-Muñiz and Simons 2015; and see Boonen et al. 2017). Importantly, there is evidence to suggest TRPV1 may be sensitized in chemotherapy. Not only does oxidative stress sensitize TRPV1 (Chuang and Lin 2009), but at least three chemotherapy drugs—oxaliplatin, paclitaxel, and vincristine—have been found to sensitize TRPV1, markedly heightening capsaicin responses in dorsal root ganglia (see Figure 7) (Anand et al. 2010; Li et al. 2015; Wang et al. 2018b). There may be a link to inflammatory activation via interplay with Toll-like receptor (TLR4) (Li et al. 2015) and the cytokine TNF-α (Wang et al. 2018b). Researchers have not—to the best of our knowledge—investigated whether TRPV1 sensitization also occurs in the oral cavity during chemotherapy. Chemotherapy patients may report burning oral pain, which is often ascribed to hyposalivation or Candida (e.g., Grushka et al. 2002; Harding 2017). However, this could also conceivably be a symptom of chemotherapy-induced sensory neuropathy involving TRPV1. Outside the context of chemotherapy, burning oral pain caused by nerve damage (Bartoshuk et al. 1999; Lauria et al. 2005; Nasri-Heir et al. 2011; Jääskeläinen 2018) is associated with TRPV1 overexpression and bitter-metallic orosensory experiences (Yilmaz et al. 2007; Borsani et al. 2014). If sensitization of TRPV1 and/or other chemesthetic receptors is mechanistically important in metal mouth, the design and approval of suitable antagonists could be a possible future supportive therapy for further investigation. Figure 7. Open in new tabDownload slide Upregulation of TRPV1 shown by western blot (left), and sensitization of TRPV1 shown by patch-clamp (right), in dorsal root ganglia from rats treated with vincristine. Similar data exist for oxaliplatin and paclitaxel. ***P < 0.001, **P < 0.01. CAP = capsaicin. [Reproduced from Wang et al. 2018b, with permission from Spandidos Publications.] Figure 7. Open in new tabDownload slide Upregulation of TRPV1 shown by western blot (left), and sensitization of TRPV1 shown by patch-clamp (right), in dorsal root ganglia from rats treated with vincristine. Similar data exist for oxaliplatin and paclitaxel. ***P < 0.001, **P < 0.01. CAP = capsaicin. [Reproduced from Wang et al. 2018b, with permission from Spandidos Publications.] A role for retronasal perception? Retronasal olfaction (see Figure 8a) occurs when volatiles in the oral cavity pass through the nasopharynx to interact with the olfactory epithelium on the roof of the nasal cavity. This sensory experience is commonly misattributed to the mouth and experienced as “taste” (Murphy and Cain 1980; Rozin 1982; Spence 2015). Nose-clamping experiments with human participants aim to separate retronasal olfactory elements of the flavor experience from taste. According to the logic of this kind of study, in the “nose unclamped” condition, oral and retronasal elements are both experienced; whereas, with nose clamped, only oral elements are experienced. Figure 8. Open in new tabDownload slide (A) Simplified illustration of the difference between orthonasal and retronasal olfaction. [Reproduced from Dietrich, 2009, with permission from IWA Publishing.] We can only retronasally experience olfactory stimuli that are already present in the oral cavity—and they can only be mislocalized as “tastes” if a congruent sensory stimulus is also present in the oral cavity (see Spence, 2016, for a review). (B) Skeletal formulae of some “metallic” volatiles. From top: 1-octen-3-one, 1-nonen-3-one, (Z)-1,5-octadien-3-one. Humans are exquisitely sensitive to 1-octen-3-one, which remains odorous at a concentration of 7 ng/L—although the character of this odour changes from “metallic” to “mushroom” at low concentrations. [Structures drawn with PubChem Sketcher.] (C) Formation of 1-octen-3-one on GC-MS when metal is placed on human skin. Despite being a small peak, because it is detectable at such low concentrations, 1-octen-3-one is the most significant contributor to the “metallic” odour out of all of the volatiles identified. [Reproduced from Glindemann et al. 2006, with permission from John Wiley & Sons via Copyright Clearance Center.] Figure 8. Open in new tabDownload slide (A) Simplified illustration of the difference between orthonasal and retronasal olfaction. [Reproduced from Dietrich, 2009, with permission from IWA Publishing.] We can only retronasally experience olfactory stimuli that are already present in the oral cavity—and they can only be mislocalized as “tastes” if a congruent sensory stimulus is also present in the oral cavity (see Spence, 2016, for a review). (B) Skeletal formulae of some “metallic” volatiles. From top: 1-octen-3-one, 1-nonen-3-one, (Z)-1,5-octadien-3-one. Humans are exquisitely sensitive to 1-octen-3-one, which remains odorous at a concentration of 7 ng/L—although the character of this odour changes from “metallic” to “mushroom” at low concentrations. [Structures drawn with PubChem Sketcher.] (C) Formation of 1-octen-3-one on GC-MS when metal is placed on human skin. Despite being a small peak, because it is detectable at such low concentrations, 1-octen-3-one is the most significant contributor to the “metallic” odour out of all of the volatiles identified. [Reproduced from Glindemann et al. 2006, with permission from John Wiley & Sons via Copyright Clearance Center.] Importantly, metals reported as “metallic” with the nose unclamped can still be sensed in the mouth with the nose clamped (Zacarias et al. 2001; Lawless et al. 2004, 2005; Lim and Lawless 2005b; Epke et al. 2009; Laughlin et al. 2011; Skinner et al. 2017) strongly suggesting an important oral component to metallic perception. However, especially at low concentrations, retronasal involvement can be particularly crucial: with the nose unclamped, so that retronasal volatiles can enter, participants are often markedly more sensitive at detecting “metallic” metals (Hettinger et al. 1990; Lawless et al. 2004, 2005; Lim and Lawless 2005a; Epke et al. 2009; Omur-Ozbek and Dietrich 2011; Skinner et al. 2017). Metal ions themselves are thought to be insufficiently volatile to travel up the nasopharynx (but see Lubran et al. 2005; Skinner et al. 2017). So how is the “metallic” sensation conveyed to the olfactory epithelium? In the dairy industry, “metallic” volatiles such as 1-octen-3-one (see Figure 8b; at top) were first identified as lipid oxidation products isolated from oxidized butterfat (Stark and Forss 1962). 1-Octen-3-one was later found to be produced from the oxidation of cell membrane lipids such as linoleic acid (Tressl et al. 1982; Ullrich and Grosch 1987). Interestingly, 1-octen-3-one has also been identified as a putative lipid oxidation product from scallops bathed in Fe2+-containing red wine (Tamura et al. 2009; discussed in Spence et al. 2017), and as a major contributing volatile to the reported “metallic” flavor in chopped liver (Im et al. 2004). 1-Octen-3-one is also formed when metals (iron and copper) are placed on human skin (Glindemann et al. 2006) (see Figure 8c), presumably as a product of the metal-catalyzed oxidation of lipids on the skin. Intriguingly, the effect could not be immediately replicated on the same skin patches, suggesting a finite pool of oxidizable lipid on the skin (Glindemann et al. 2006). Lipid oxidation has also been observed when metals are placed in the oral cavity (Mirlohi et al. 2011; Omur-Ozbek et al. 2012). However, the thiobarbituric acid reactive substances (TBARS) test used could not specifically identify 1-octen-3-one as a metal-catalyzed lipid oxidation product here. Theoretically, chemotherapy-induced oxidative stress (Yang et al. 2018) could lead to increased intra-oral lipid oxidation, although, again, it is not clear how this profile of lipid oxidation products might be sensorially perceived. It also turns out that the degree of salivary lipid oxidation in cancer patients is a poor predictor of oral sensory change (Mirlohi et al. 2015); and again, the TBARS method used cannot discern specific changes in the production of “metallic” volatiles. In summary, it therefore currently remains unclear whether any significant overproduction of 1-octen-3-one and/or other “metallic” volatiles can occur in chemotherapy. Independently of increased oxidative stress, it is conceivable that “metallic” volatiles might be produced in chemotherapy patients due to increased traces of blood in the oral cavity in the context of mucositis, with the iron in hemoglobin able to catalyze lipid oxidation (Glindemann et al. 2006; and see Im et al. 2004). Alternatively, due to a combination of hyposalivation and immunosuppression, commensals such as Candida can overgrow in the oral cavity during chemotherapy (Lalla et al. 2010), and might in theory produce “metallic” volatiles. 1-Octen-3-one can be detected at concentrations as low as 7 ng/L. At these very low concentrations, 1-octen-3-one is not described as “metallic”; instead it is “earthy” or “mushroomy” (Stark and Forss 1962; Pyysalo 1976). Indeed, 1-octen-3-one has been identified as a metabolite in various species of mushrooms (Pyysalo 1976; Tressl et al. 1982; Cho et al. 2007; Xu et al. 2019) and fungal infections (Darriet et al. 2002; la Guerche et al. 2006). However, no Candida volatile screen has to the best of our knowledge positively identified 1-octen-3-one (negative results include Hertel et al. 2016). Further investigation into supportive therapies for metal mouth could focus on repairing the oral mucosa, treating commensal overgrowth, or reducing local oxidative stress. Finally, and importantly, chemotherapy patients report “metal mouth,” not “metal nose.” Retronasal olfactory stimuli tend to be perceived as local to the nose unless there is also a congruent stimulus present in the oral cavity which can be integrated into a flavor percept (Lim and Johnson 2011, 2012; Spence 2016). For example, trace levels of iron and copper in water produce bitterness and astringency in participants with the nose clamped. However, with the nose unclamped, retronasally experienced odors do seem to provide congruence, and iron and copper are experienced as “metallic” (Dietrich 2009; Omur-Ozbek and Dietrich 2011). Conclusions In conclusion, the purpose of this article has been to provide a much-needed perspective on the origin of the mysterious and under-researched phenomenon of “metal mouth” as a side-effect of cancer chemotherapy. Although we are necessarily limited in the strength of the conclusions that we can draw due to the lack of research that has been conducted in this area, there remain some compelling theories which we would commend to readers’ attention for further investigation in the future. Although a role for retronasal olfaction in metallic perception is well-established (e.g., Lawless et al. 2005; Omur-Ozbek and Dietrich 2011; Skinner et al. 2017), metals can also be independently perceived in the oral cavity (e.g., Zacarias et al. 2001; Lawless et al. 2005; Laughlin et al. 2011; Skinner et al. 2017) perhaps as a result of the activation of taste receptor cells or trigeminal nerve endings. There is evidence to suggest metallic compounds can activate T1R3, T2R7, and TRPV1 (Riera et al. 2007; Riera et al. 2009a; Wang et al. 2019). Metal mouth is one among many sensory distortions and phantoms that are associated with cytotoxic chemotherapy drugs (e.g., Bernhardson et al. 2009; Miaskowski et al. 2018) which are toxic to nerves (e.g., Peters et al. 2007), salivary glands (e.g., Rehwaldt et al. 2009), and taste epithelium (e.g., Mukherjee and Delay 2011). Selective toxicity to the anterior tongue (e.g., Mukherjee et al. 2013) could lead to “release-of-inhibition” (see Snyder and Bartoshuk 2016); and, perhaps coupled with overactivation of T2Rs (Tsutsumi et al. 2016; Wang et al. 2019), this could help to explain phantoms and hypersensitivity to bitter taste associated with metal mouth (IJpma et al. 2017; but see Yanagisawa et al. 1998). Chemotherapy-induced peripheral sensory neuropathy is linked to the sensitization of TRPV1 (e.g., Wang et al. 2018b) and TRPV1 is also overexpressed following nerve damage in the oral cavity (e.g., Yilmaz et al. 2007). Finally, it has been suggested that metal mouth can be explained by the retronasal activation of olfactory epithelium (e.g., Omur-Ozbek et al. 2012), perhaps due to an intra-oral overproduction of metallic volatiles, although a source for these metallic volatiles in chemotherapy has yet to be identified (e.g., Mirlohi et al. 2015), and it is not clear which congruent stimulus (Lim and Johnson 2011, 2012) would localize this metallic percept to the mouth. Further investigation is required, both into the etiology of metal mouth and into possible supportive therapies. Conflict of interest The authors have no conflicts of interest to declare. Acknowledgements The authors have no particular funding sources or grants to acknowledge. 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Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
TI - The Mystery of “Metal Mouth” in Chemotherapy
JF - Chemical Senses
DO - 10.1093/chemse/bjz076
DA - 2020-03-25
UR - https://www.deepdyve.com/lp/oxford-university-press/the-mystery-of-metal-mouth-in-chemotherapy-f1pXczr1JV
SP - 73
EP - 84
VL - 45
IS - 2
DP - DeepDyve
ER -