A review of the flavor profile of metal salts: understanding the complexity of metallic sensation
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Chemical Senses, 2021, Vol 46, 1–8
https://doi.org/10.1093/chemse/bjab043
Review Article
Advance Access publication 8 September 2021
Review Article
A review of the flavor profile of metal salts:
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understanding the complexity of metallic
sensation
Michelle J. Y. Ecarma and Alissa A. Nolden
Department of Food Science, University of Massachusetts Amherst, Amherst, MA 01003, USA
Corresponding author: Alissa A. Nolden, Department of Food Science, University of Massachusetts Amherst, 240 Chenoweth
Labs, 102 Holdsworth Way, Amherst, MA 01003, USA. e-mail: anolden@umass.edu
Editorial Decision 6 September 2021.
Abstract
The oral sensation of metallic is a complex experience. Much of our current understanding of me-
tallic sensation is from the investigation of metal salts, which elicit diverse sensations, including
taste, smell, and chemesthetic sensations, and therefore meet the definition of a flavor rather than
a taste. Due to the involvement of multiple chemosensory systems, it can be challenging to define
and characterize metallic sensation. Here, we provide a comprehensive review of the psychophys-
ical studies quantifying and characterizing metallic sensation, focusing on metal salts. We examine
the factors that impact perception, including anion complex, concentration, nasal occlusion, and
pH. In addition, we summarize the receptors thought to be involved in the perception of metallic
sensation (i.e., TRPV1, T1R3, TRPA1, and T2R7) either as a result of in vitro assays or from studies in
knock-out mice. By enhancing our scientific understanding of metallic sensation and its transduc-
tion pathways, it has the potential to improve food and pharmaceuticals, help identify suppression
or masking strategies, and improve the ability to characterize individual differences in metallic
sensation. It also has the potential to translate to clinical populations by addressing the disparities
in knowledge and treatment options for individuals suffering from metallic taste disorder (i.e.,
phantom taste or “metal mouth”). Future psychophysical studies investigating the sensory per-
ception of metal salts should include a range of compounds and diverse food matrices, coupled
with modern sensory methods, which will help to provide a more comprehensive understanding
of metallic sensation.
Key words: sensory evaluation, taste, olfaction, metal mouth, metallic taste
Introduction can be detected in a variety of foods and beverages (e.g., apple juice,
chocolate, fish products, dairy, meat, nuts, oils, cereals, and beer)
The sensation of metallic is undesirable when encountered in foods
from the production of volatile compounds due to microbial activity
and beverages and can indicate unsafe or low-quality food. Metallic
(Calkins and Hodgen 2007; Amrein et al. 2010; Borthwick and
is a common complaint in fortified foods, notably with added min-
Da Costa 2017) and lipid oxidation (Venkateshwarlu et al. 2004;
erals such as calcium, magnesium, iron, and zinc (Hurrell 2002;
Glindemann et al. 2006; Hashizume et al. 2007) as well as in cases
Lawless et al. 2003, 2004; Kiskini et al. 2012; Wang et al. 2016) or
of flavor scalping, where the packaging imparts a taste onto the food
contains non-nutritive sweeteners (NNS) (Riera et al. 2008; Carniel
(Borocz-Szabo 1980; Lawless et al. 2004). The perception of metallic
Beltrami et al. 2018). (For a summary of the compounds that evoke
is also a hurdle for the pharmaceutical industry, with approximately
metallic sensation, see Pirkwieser et al. 2021.) Additionally, metallic
1
Published by Oxford University Press on behalf of US Government 2021.2 Chemical Senses, 2021, Vol. 46
59% of the top 200 drugs in the U.S. known to evoke bitter or me- without nasal occlusion). The psychophysical methods employed
tallic sensations (Doty et al. 2008; Schiffman 2015). As a result of across studies vary, which include detection threshold (Tordoff
these unpleasant sensations, consumers report decreased enthu- 1996; Cuppett et al. 2006; Epke et al. 2007), discrimination testing
siasm for these products and may result in poor compliance (Walsh (Zacarias et al. 2001; Lawless et al. 2004; Lim and Lawless 2005a),
et al. 2014; Schiffman 2015). Characterizing metallic sensation and suprathreshold intensity (Tordoff 1996; Keast 2003; Lawless et al.
uncovering its transduction pathway is vital for identifying effective 2004; Hong 2011), time-intensity scaling (Yang and Lawless 2006;
strategies for reducing metallic sensation such as mixture suppres- Hong et al. 2010a), descriptive analysis (Yang and Lawless 2005;
sion or blocking ligand sites for known receptors, which has been a Epke et al. 2009; Hong 2011; Hong and Kim 2011), and multidi-
successful approach for reducing bitter perception (Sohi et al. 2004; mensional scaling (Lim and Lawless 2005b). Each method provides
Gittings et al. 2014; Mennella et al. 2015). Reducing or blocking me- a different perspective that facilitates an in-depth examination of
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tallic sensation will help to increase liking, intake, and compliance the evidence. Twelve original research studies evaluated the sensory
of these foods, beverages, dietary supplements, and pharmaceutical psychophysical response from one or more metal salts. In summar-
products. izing these studies, there was a total of 6 metal ions (i.e., calcium,
Unlike the sensations from prototypical taste stimuli (e.g., the copper, iron, magnesium, and zinc), with varying anion complex
sweetness of sucrose, the saltiness of sodium chloride), evidence (i.e., chloride, gluconate, glycerophosphate, hydroxide, iodide, lac-
suggests metallic sensation occurs via multiple chemosensory path- tate, sulfate, and phosphate), resulting in 18 different metal salts.
ways—specifically gustatory, olfactory, and trigeminal (Lawless See Table 1 for a complete list of metal salts that have undergone
et al. 2004). Therefore, metallic sensation more accurately de- psychophysical assessment.
scribes a flavor rather than a taste (Lawless et al. 2004; Stevens et al.
2006). Although diverse compounds evoke metallic sensation (see Flavor profile of metal salts
(Pirkwieser et al. 2021), much of our understanding of the sensory The perception of metallic sensation integrates multiple sensory
characteristics is through the investigation of divalent metal salts modalities, including gustatory, olfactory, and trigeminal pathways.
(also known as metal salts). These compounds have a neutral charge Here, we have organized the review by metal salt, describing the sen-
and consist of a metal ion (e.g., iron) and either an acid (e.g., sulfuric sory profile for each. We describe measures of taste (i.e., sweet, sour,
acid) or a nonmetal (e.g., chloride). Examples of metal salts include bitter, salty, and umami), chemesthesis (i.e., astringency, irritation,
iron sulfate, copper chloride, and calcium lactate. However, not all spicy, tingle), and olfaction when available, as not all studies meas-
metal salts evoke metallic sensation (e.g., potassium iodide), not all ured responses to all sensations. For example, some studies predated
are suitable for psychophysical study (i.e., toxicity, availability, and the recognition of umami as a taste sensation (Lim and Lawless
cost), or not all are considered safe for consumption (e.g., lead). 2005b). See Table 2 for a complete list of sensations reported from
Many of these multivalent cations are biologically relevant and are the psychophysical evaluation of metal salts. Of the 12 studies, 10
essential to structure and function throughout the body, such as nu- investigated taste and/or trigeminal sensations and 10 assessed ol-
cleic acid development and other vital processes (Wacker and Vallee factory input.
1959; Festa and Thiele 2011).
The objective of the current review is to summarize the current
Calcium
knowledge of the sensations elicited by metal salts, with a specific
Taste sensations reported from calcium are predominantly bitter,
focus on metallic sensation. We provide a detailed summary of the
with sweet, salt, and sour reports, along with metallic and astrin-
psychophysical assessments of metal salts, including diverse sensory
gent sensations (Lawless et al. 2003; Lim and Lawless 2005b). The
methods, which inherently provide different information regarding
the sensory profile. When available, we examine the influence of ol-
Table 1. List of metal salts evaluated using psychophysical
faction (ortho- and retronasal olfaction) on the sensory profile of
methods
metal salts by comparing psychophysical response across nasal con-
ditions (i.e., nose open vs. nose closed) (e.g., Epke et al. 2009). These Metal ion Anionic complex Compound
findings have helped to understand the integration of chemosensory abbreviation
pathways. We highlight several areas that need further examination
Calcium Chloride CaCl2
regarding metallic sensation, such as establishing knowledge on indi-
Gluconate Glycerophosphate C3H7CaO6P
vidual differences, identifying strategies for reducing metallic sensa- Hydroxide Ca(OH)2
tion, and the potential to extend to clinical populations, specifically Lactate C6H10CaO6
improving the ability to diagnose and treat metallic taste disorder. Phosphate Ca3(PO4)2
As part of the review, we summarize the current evidence for recep- Sulfate CaSO4
tors thought to be involved in the transduction of metal salts. The Copper Chloride CuCl2
culmination of this work demonstrates the complexity of metallic Lactate Cu(C3H5O3)2
sensation and the involvement of multiple sensory pathways. Sulfate CuSO4
Iron Chloride FeCl2
Gluconate FeC12H22O14
Sulfate FeSO4
Psychophysical studies in healthy human Magnesium Chloride MgCl2
subjects Sulfate MgSO4
This review summarizes the literature that quantifies or describes Zinc Acetate Zn(CH3CO2)2
Bromide ZnBr2
taste, smell, and chemesthetic attributes of metal salts using psycho-
Chloride ZnCl2
physical evaluation methods. Within the current literature, several
Iodide ZnI2
different methodologies evaluated metal salts, which in some cases Sulfate ZnSO4
focus on the involvement of the olfactory system (i.e., with andChemical Senses, 2021, Vol. 46 3
Table 2. List of sensations reported for metal salts alum (Peleg et al. 1998; Hong et al. 2006). These studies demon-
strate the relationship between the perceived metallic sensation and
Taste Chemesthesis Flavor/aroma
the solubility of the metal, which is dependent on the ionic strength,
Bitter Irritation Metallic and thus, modified by the pH and the specific anion complex.
Salty Burning/spicy Zinc penny Concerning olfaction, nasal occlusion does not influence the sen-
Sour Astringent/drying Blood sory profile of copper, suggesting sensation is dependent on gusta-
Sweet Electric sensation Rusty nail tory mechanisms with little to no input from olfaction, especially
Umami/savory Tingle Copper coin when compared with ferrous salts (Lawless et al. 2004; Epke and
Rancid Lawless 2007; Epke et al. 2009). In one study, olfactory input did
Caramel
not modulate the perception of copper sulfate, which was reportedly
Burnt
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predominantly bitter and astringent properties (Lawless et al. 2004).
Smokey
Another study compared nose-open to nose-closed conditions for
0.001 M copper sulfate and reported no difference in ratings for
intensity of these sensations varied by anion complex, especially for intensity (i.e., metallic, astringent, bitter, sour) between the 2 condi-
bitterness intensity. Calcium chloride elicited more intense ratings tions, except for metallic aftertaste (Epke et al. 2009). Skinner et al.
than calcium lactate, gluconate, or glycerophosphate (Tordoff 1996; (2017) found copper sulfate to induce tingling during nose-open,
Yang and Lawless 2005; Lim and Lawless 2005b). but not under nose-closed conditions, suggesting olfactory or som-
Tordoff (1996) reported the ability of humans to perceive cal- atosensory systems are involved in the perception of copper. The
cium via detection threshold and suprathreshold testing of calcium: temporal sensory profile of copper revealed that concentration influ-
phosphate, hydroxide, chloride, lactate, and gluconate. There was enced the perception of metallic and bitterness, whereas pH signifi-
no noticeable difference in detection thresholds for calcium salts. cantly affected astringency aftertaste. A lower pH led to prolonged
Suprathreshold concentrations of calcium chloride and lactate evoke and more intense sensations of astringency, suggesting that higher
predominantly bitter sensations, followed by sour and sweet, which amounts of free copper ions are available to bind with saliva pro-
varied as a function of concentration. Regarding orthonasal olfac- teins (Hong et al. 2010b).
tory detection, Tordoff (1996) compared the ability to discriminate
metal salts (calcium chloride and calcium lactate) from water by Iron
smelling the samples. Participants sampled 2 different concentra- In comparison with other metal compounds, some describe iron as
tions, low (1 mM) and high (100 mM). For both compounds, parti- the “most flavorful” and a “true metallic taste,” and when compared
cipants did not perform better than the chance for either compound with other prototypical tastants and mixtures, iron sulfate had a dis-
when presented at 1 mM but did discriminate both from water when tinct sensory profile (Stevens et al. 2006). In addition to metallic
presented at 100 mM. When comparing sensitivity at 100 mM, par- sensation, iron compounds are bitter, sour, and astringent or drying,
ticipants were significantly better at discriminating calcium lactate which varies by concentration and anionic pairing (Lawless et al.
than calcium chloride. This suggests that olfaction is important in 2004, 2005; Yang and Lawless 2006; Epke and Lawless 2007; Epke
the sensory profile of calcium lactate and calcium chloride, but odor et al. 2009; Hong 2011; Ömür-Özbek et al. 2012). Other descriptors
profiles may differ across compounds and concentrations. Skinner include “rusty nail flavor,” “electric sensation,” “penny-like,” and
et al. (2017) evaluated a single concentration (0.015 M) of calcium “rancid” (Lim and Lawless 2005a), with specific descriptors differing
chloride using discrimination and intensity methods. Participants across iron compounds. Participants described ferrous chloride as
were not able to discriminate based on smelling the headspace of “caramel,” “burnt,” or “smokey,” whereas ferrous gluconate was
calcium chloride. For intensity ratings, bitterness was the most in- sweeter and less bitter, which may be a result of complexing with the
tense sensation with no difference between nasal conditions. Other gluconate anion (Lim and Lawless 2005a, 2006).
sensations include astringent, metallic, and salty. From this study, The metallic sensation perceived from ferrous salts are charac-
there was little evidence that the olfactory system is involved in the terized by, and highly dependent on, retronasal olfaction (Lawless
perception of calcium chloride (Skinner et al. 2017). et al. 2004; Lim and Lawless 2005a; Lubran et al. 2005; Yang and
Lawless 2005; Epke et al. 2009). For olfactory input, participants
Copper described ferrous chloride as “bland” or having “no flavor” when
Copper evokes both bitter and astringent sensations, increasing in- wearing nose plugs (Lim and Lawless 2005a). During nasal occlu-
tensity across concentrations (Zacarías et al. 2001; Lawless et al. sion, participants described ferrous sulfate as tasting like a “rusty
2004; Lim and Lawless 2005b; Cuppett et al. 2006; Epke et al. 2009; nail” and evoke “electric sensations.” During the nose-open condi-
Hong 2011; Hong and Kim 2011). Other sensations reported from tions, participants reported a decrease in bitterness. When asked to
sampling copper include sour, salty, and metallic; with prominent sniff the headspace of ferrous solutions, participants often reported
bitter and astringent aftertastes (Zacarías et al. 2001; Lawless et al. no orthonasal aroma, suggesting that olfactory input is occurring
2004; Cuppett et al. 2006). Studies reporting descriptive attributes through retronasal detection (Lim and Lawless 2005; Yang and
related to sensations evoked by copper include “bloody,” “copper Lawless 2006; Epke and Lawless 2007).
coin,” “rusty nail/metal,” “rancid,” and “electric sensation” (Lim
and Lawless 2005b; Hong and Kim 2011). Copper sulfate elicits Magnesium
more intense bitterness than ferrous and calcium sulfate compounds Magnesium is primarily bitter and salty, which can vary across con-
(Lawless et al. 2004). Hong et al. (2010a) evaluated the influence of centrations, and bitterness intensity varies across anionic complex
pH on intensity perceptions of copper and reported that astringency (Lawless et al. 2004; Lim and Lawless 2005b; Yang and Lawless
ratings increased in proportion with increases in acidity. A possible 2006; Whelton et al. 2007; Dietrich and Burlingame 2015). Lawless
explanation for this finding is that copper forms insoluble particu- et al. (2003) also note astringent, metallic, sour, and sweet sensa-
late complexes with saliva as the pH decreases, as is the case with tions, whereas Green and Hayes (2003) report an “irritative, burning4 Chemical Senses, 2021, Vol. 46
component” from magnesium chloride. Although previously used as Several studies acknowledge the involvement of retronasal ol-
a reference for bitter taste, magnesium sulfate can also evoke salty faction on the perception of metal salts, with a specific emphasis
and sour taste sensations, along with lower intensities for metallic, on metallic sensation. Retronasal perception is potentially a re-
astringent, and irritative sensations (Lawless et al. 2003). Participants sult of lipid oxidation that occurs during mastication thought to
report astringent sensations from sampling magnesium salts, with be a result of metal salts interacting with salivary components
lower astringency for magnesium sulfate, further demonstrating the producing oxidation compounds in the oral cavity (Lawless et al.
influence of the anionic complex on the sensory profile of metal salts 2004; Lubran et al. 2005; Epke and Lawless 2007; Dietrich 2009;
(Whelton et al. 2007). Of the studies identified, there was no com- Epke et al. 2009; Ömür-Özbek et al. 2012; Skinner et al. 2017).
parison between nose-open and nose-closed conditions; therefore, Metallic-smelling odorants, 1-octene-3-one and 1-nonene-3-
it remains unknown whether retronasal olfaction is involved in the one, present in ferrous sulfate solutions, were found to induce a
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perception of magnesium. “tingling irritation” during orthonasal evaluation (Lubran et al.
2005). For ferrous sulfate, oxidation must occur to perceive
Zinc retronasal odor, which can occur via contact with skin or saliva.
Zinc evokes diverse sensations, including umami (or glutamate-like There was no perception of metallic sensation when sniffing (i.e.,
taste, savory, meaty), pungency/spiciness, and astringency (Keast orthonasal olfaction) ferrous sulfate (Lawless et al. 2004; Lim
2003; Lim and Lawless 2005b; Yang and Lawless 2006). Perception and Lawless 2006; Epke and Lawless 2007). These studies pro-
of astringency varies by anionic complex, with reduced astringency vide strong evidence that olfaction is involved in the perception
for zinc iodide compared with zinc acetate, sulfate, and bromide of metal salts.
(Keast 2003). Zinc readily forms complexes with thiol and hydroxyl The current work is not without its challenges. The studies re-
groups, which are common on salivary constituents (e.g., proteins, viewed here have used a variety of techniques, which have helped lay
peptides, and amino acids), providing a likely explanation for the the groundwork toward understanding this sensation. Nevertheless,
predominate astringency sensation from zinc (Keast et al. 2004). the data cannot provide strong conclusions regarding the sensory
There were no psychophysical studies specifically designed to profile of metal salts due to the differences in stimuli selected for each
evaluate the influence of retronasal olfaction in the perception of study and the variability in the attributes measured. Additionally, as
zinc. However, one study reported zinc chloride and sulfate clustered noted by some studies, there are concerns with the lack of partici-
with different groups in different nasal conditions (i.e., nose open vs. pants’ familiarity with metallic sensation, which is often confused
nose closed). In the nose-open condition, zinc compounds grouped with other sensations such as bitter and sour (Lim and Lawless
with alum, whereas in the nose-closed condition, grouped with alum, 2005a, b). Further sensory evaluation is warranted, with a specific
ferrous gluconate, and ferrous sulfate (Lim and Lawless 2005b). need to develop a complete sensory profile inclusive of taste, olfac-
Although this study provides a first look at the sensory characteris- tion, and chemesthesis qualities.
tics of zinc compared with other metal salts, additional research will
expand our understanding of its sensory profile and diverse flavor Individual differences in perception
components. Individual differences exist in the perception of gustatory, olfac-
tory, and trigeminal stimuli; yet, there is a poor understanding of
Summary of psychophysical response to metal salts the variability in the perception of metallic sensation across indi-
The literature reviewed here is consistent in their findings in that viduals. There continues to be growing evidence that genetic var-
they all report differences in the sensations across metal salts and iations in taste and trigeminal receptor genes can correspond to
demonstrate that perception is a result of evoking multiple trans- individual differences in psychophysical response to chemical
duction pathways. stimuli and impact food choice, intake, and human health (Hayes
Although trigeminal sensations may be the least investigated et al. 2013; Chamoun et al. 2018; Nolden and Feeney 2020). One
sensory attribute associated with metal salts, 3 studies reported on study provides evidence that there could be a genetic component,
the perception of irritating sensations (Lubran et al. 2005; Riera as metallic intensity ratings were associated with intensity ratings
et al. 2007; Hu et al. 2009). Often, irritation occurs alongside un- of propylthiouracil (PROP) (i.e., “taster status”). Individuals rating
pleasant sensations (e.g., bitterness), a phenomenon referred to as PROP as more bitter (classified as “supertasters”) reported iron sul-
a halo effect (Lawless et al. 2003; Lim and Lawless 2005b; Yang fate to have a significantly higher intensity compared to medium
and Lawless 2005). However, given that both trigeminal and bitter and non-tasters of PROP (Bajec and Pickering 2008). However, an-
taste receptors are reportedly involved in the transduction of metal other study failed to find a relationship when comparing detection
salts (see Section Identified receptors involved in metallic sensa- thresholds of PROP and the mean detection threshold of five cal-
tion), both sensations may be involved. Astringency is a common cium salts (Tordoff 1996). Although PROP bitterness is associated
attribute reported from sampling metal salts and can include other with genetic polymorphisms in TAS2R38, further studies are neces-
related descriptors, such as oral roughness, dryness, and puckering sary to confirm whether the TAS2R38 diplotype is associated with
(Peleg et al. 1998; Cuppett et al. 2006; Hong et al. 2010b). This metallic perception, as not all compounds associated with PROP
sensation occurs following delubrication of the mouth following bitterness are related to the TAS2R38 diplotype (Nolden et al.
the formation of precipitative complexes with salivary proline- 2020). Individual differences in salivary proteins may be associated
rich proteins (PRPs) (Gibbins and Carpenter 2013; Delius et al. with metallic sensation, as metal salts complex with salivary pro-
2017; Braud and Boucher 2020). More research in this area will teins (Hong et al. 2009, 2010b; Carpenter 2013; Running 2018).
help understand the trigeminal sensations associated with each Therefore, variations in the salivary proteome may result in differ-
metal ion and the factors that influence its perception, such as the ences in perceived sensory profile (Crawford and Running 2020).
complexing anion, concentration, and pH, along with individual Future studies can examine the variability in the perception of me-
differences in salivary composition (e.g., Crawford and Running tallic sensation, which is likely to be associated with multiple demo-
2020). graphic and biological factors.Chemical Senses, 2021, Vol. 46 5
Metallic taste disorder receptor 1 type 3) (Tordoff et al. 2008), TRPA1 (transient receptor
In the absence of stimuli, some individuals report perceiving a me- potential cation channel subfamily A member 1) (Gu and Lin 2010),
tallic sensation, often described as “metal mouth” (Reith and Spence and T2R7 (bitter taste 2 receptor member 7) (Behrens et al. 2019;
2020). Individuals experiencing an oral sensation without stimula- Wang et al. 2019) to be involved in metallic transduction pathway.
tion are one type of chemosensory disorder known as phantogeusia Transduction pathways for taste and tactile sensations are often first
(i.e., phantom taste). Metal mouth is a common symptom reported identified through observing behavioral and physiological responses
by chemotherapy patients and individuals with xerostomia/dry to in vitro and in vivo stimulation, as is the case for metal salts. There
mouth and damage to the chorda tympani nerve. Reports of altered is evidence that these receptors have the potential to contribute to
taste sensation are associated with inadequate nutrition, reduced metallic sensation (Table 3).
appetite, and overall lower quality of life (Reith and Spence 2020;
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Cohen et al. 2016). TRPV1
Despite acknowledging metal mouth and supporting studies The first chemosensory receptor found to respond to metal salts
documenting its detrimental effects (Rehwaldt et al. 2009; Ijpma was TRPV1 (Ahern et al. 2005). This receptor, the transient re-
et al. 2017; Reith and Spence 2020), there are inadequate tools ceptor potential cation channel subfamily V member 1, also known
available for diagnosing metal mouth and in need of effective treat- as the capsaicin receptor, is well known for its involvement in the
ments. Developing a universal description of metallic sensation will transduction of chemesthetic stimuli (e.g., capsaicin, ethanol, and
allow patients to communicate their experiences more effectively. By piperine). Studies have demonstrated TRPV1 responds to metal salts
collecting measures of patient experiences (e.g., severity, occurrence, in vitro (Ahern et al. 2005; Riera et al. 2007). Metal salts—specif-
frequency), it can potentially uncover underlying connections with ically, copper, zinc, magnesium, and iron sulfide—activate TRPV1
other symptoms and clinical characteristics (e.g., chemotherapeutic, in a dose-dependent manner (Riera et al. 2007). Using a behavioral
gastrointestinal symptoms) (see (Nolden et al. 2019; Joseph et al. mouse model, removal of Trpv1 resulted in altered response copper
2020)). Additionally, a standardized method of evaluating metallic sulfide, but not iron or magnesium sulfide (Riera et al. 2009).
phantom taste will be necessary for identifying clinically effective
treatments. Although it is not known whether metallic sensation and T1R3
metallic taste disorder share similar transduction pathways, a better Taste receptor type 1 member 3 (T1R3), a receptor involved in the
understanding of metallic perception is imperative to enable innova- transduction of sweet and umami taste sensations, may be involved
tive clinical research to develop diagnostic tools and therapies. in the transduction of metallic sensation (Tordoff et al. 2008; Riera
et al. 2008, 2009). There have been reports of the importance of T1r3
in preferences for magnesium chloride (Tordoff et al. 2008), iron,
Identified receptors involved in metallic
and zinc sulfide (Riera et al. 2009) when presented with a 2-bottle
sensation preference test in mice. For these studies, researchers estimate prefer-
Evidence of taste and trigeminal receptors ence by comparing intake of solutions prepared with metal salts be-
Given the multifaceted sensory responses from metal salts, tween mice with and without functioning T1r3 receptors. Mice with
identifying the transduction pathways involved will allow for a functioning T1r3 receptors avoid these solutions, whereas knock-out
better understanding of metallic sensation. Integrating both bio- (KO; mice lacking functional receptors) are indifferent to metal salt
logical and psychophysical studies will allow for the most compre- solutions. Tordoff et al. (2008) demonstrated that these differences
hensive understanding of metallic sensation to date. Traditionally, might be associated with genetic variability (specifically, amino acid
past work suggests gustatory and chemesthetic compounds only ac- substitutions I60T and V689A in Tas1r3). Although this work does
tivated taste and trigeminal receptors; however, several studies have not provide information on perception or activation, it demonstrates
discovered that chemesthetic compounds evoke taste sensations that T1r3 is involved with the development of aversion among mice.
(e.g., bitterness in capsaicin) (Green and Hayes 2003; Nolden and This relationship has yet to be confirmed in humans but provides
Hayes 2017), with variability in perception corresponding to gen- evidence that compounds known to evoke metallic sensations may
etic differences in bitter taste receptors (Nolden et al. 2016). This involve the gustatory pathway.
appears to be the case with metal salts, with activation observed for
taste and trigeminal receptors. Between 2005 and 2019, researchers TRPA1
in chronological order identified TRPV1 (transient receptor poten- A second receptor from the TRP family thought to be involved in
tial cation channel subfamily V member 1) (Riera 2007), T1r3 (taste metallic sensation is the transient potential receptor A1 (TRPA1).
Table 3. List of receptors thought to be involved in the transduction of metal salts
Receptor Responding stimuli Model Source
T1r3 CaCl2 KO mice Riera et al. (2008)
FeSO4, ZnSO4, Mg2+, and Ca3+ KO mice Riera et al. (2009)
CaCl2, CaLa, MgCl2 KO mice Tordoff et al. (2008)
T2R7 MgSO4, MgCl2, MnCl2, FeSO4 Heterologous expression Behrens et al. (2019)
Al2(SO4)3, CuSO4, ZnSO4, MgCl2, CaCl2, MnCl2 Heterologous expression Wang et al. (2019)
TRPV1 CuSO4, ZnSO4, FeSO4 Heterologous expression Riera et al. (2007)
FeSO4, CuSO4 Heterologous expression Riera et al. (2009)
Trpa1 ZnCl2, Ca2+, Cu2+, Cd2+ KO mice; pulmonary sensory neurons Gu and Lin (2010)
KO, knock-out.6 Chemical Senses, 2021, Vol. 46
TRPA1 is involved in the perception of heat and cold temperat- involvement of taste, olfaction, and trigeminal pathways. Building
ures and irritative compounds, such as allyl isothiocyanate and a scientific framework for metallic sensation will help establish ap-
cinnamaldehyde (Laursen et al. 2014). Interestingly, TRPA1 recep- propriate methods (for both training and sensory methods) that will
tors localize to a subpopulation of nociceptive neurons that express improve the ability to quantify metallic sensation for both com-
TRPV1 (Bessac and Jordt 2008). Even though these receptors are pounds in isolation and complex matrices (e.g., foods, beverages,
co-expressed, zinc chloride stimulates Trpa1 in vitro (Hu et al. 2009) and pharmaceuticals).
and results in a physiological response in mice when exposed to zinc, This review focused on the metallic sensation perceived from metal
cadmium, and copper (Gu and Lin 2010). These 2 studies concluded salts; yet, metallic sensation extends beyond these compounds. For
that Trpa1 might be involved in protecting the airways when ex- example, Stark and Hofmann (2005) analyzed flavor compounds in
posed to heavy metals. No studies have described this receptor in roasted cocoa nibs, identifying the cyclic dipeptide 2,5-diketopiperazine
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terms of involvement in the chemosensory pathway for the percep- to evoke significant, bitter taste, along with astringent and metallic
tion of metal salts or other compounds that evoke metallic sensation. sensations during sensory evaluation. In addition to chocolate, these
compounds exist in other foods and beverages (see Borthwick and
T2R7 Da Costa 2017). Many NNS evoke metallic sensation, including
The taste receptor T2R7, a member of the bitter taste receptor family acesulfame-K, saccharin, stevia, aspartame, steviol glycosides, and cyc-
(T2Rs), is likely involved with the physiological processes involved lamate, with increasing metallic sensation as concentration increases
in the transduction of metallic sensation (Behrens et al. 2019; Wang and can have a lingering aftertaste (Schiffman 2000; Riera et al. 2009;
et al. 2019). Wang et al. (2019) identified T2R7 to respond to various Wang et al. 2016; Parker et al. 2018). Understanding the implications
di- and trivalent salts in vitro. In order of highest to lowest sensitivity, of this aversive sensation on consumption can support future strides
the receptor responded to aluminum sulfate, copper sulfate, zinc sul- for improvement in the food industry.
fate, magnesium chloride, calcium chloride, and manganese chloride. These studies have provided evidence that metallic sensation is
Meanwhile, there was a lack of response to potassium chloride (a complex and more accurately fits the definition of flavor rather than a
monovalent salt), which suggested specificity to multivalent cations taste. Diverse stimuli evoke metallic sensations, but rarely if ever, is the
(Wang et al. 2019). Behrens et al. (2019) supported these findings phenomenon experienced in isolation. Other sensations often perceived
and found that magnesium chloride, manganese chloride, and iron alongside metallic include a combination of taste and chemesthetic
sulfate activate T2R7 as well, whereas potassium chloride—noted sensations, and evidence suggests that olfactory input impacts flavor
for its bitterness—did not have a pronounced response (Behrens perception for some compounds. Currently, there is a knowledge gap
et al. 2019). Together, these studies suggest that T2R7 is involved in regarding the psychophysical perception of metallic sensation, in-
transduction of metal salts may explain variability in their sensory cluding normal variation, relationship with chemosensory gene vari-
profile. ants, and identify strategies that block or reduce metallic sensation.
Olfaction Author contributions
For olfactory transduction, individual receptors have yet to be iden-
The authors confirm contribution to the paper as follows: conception and
tified. However, several studies suggest the involvement of retronasal
design: M.E. and A.N.; identification of papers, interpretation, and draft
olfaction due to the production of aromatic compounds from metal
manuscript preparation: M.E.; supervision and substantial contributions
salts undergoing lipid oxidation in the oral cavity (Lawless et al. to manuscript: A.N. All authors reviewed the paper and approved the final
2004; Lubran et al. 2005; Epke et al. 2009; Ömür-Özbek et al. version.
2012). More work will identify and assess the involvement of the ol-
factory system in the perception of metal salts, along with identifying
the olfactory receptors involved. Funding
The authors received no financial support for this article’s research, author-
Summary of receptors ship, or publication.
Identifying the mechanisms involved with metallic perception will
help provide a new understanding of the variability in perception Conflict of interest
across compounds and the factors that modify perception (e.g., con-
The authors declare that there is no conflict of interest.
centration, anion). Future studies may uncover additional receptors,
including olfactory receptors, involved in the transduction of metal
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