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Is Lithium biologically an important or toxic element to living organisms? An

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Environ Sci Pollut Res
DOI 10.1007/s11356-016-7898-0

REVIEW ARTICLE

Is lithium biologically an important or toxic element to living

organisms? An overview
Babar Shahzad 1 & Mudassar Niaz Mughal 2 & Mohsin Tanveer 3 & Dorin Gupta 4 &
Ghazanfar Abbas 5

Received: 8 February 2016 / Accepted: 11 October 2016

# Springer-Verlag Berlin Heidelberg 2016

Abstract Industrialized world is exposing living organisms
to different chemicals and metals such as lithium (Li). Due to
their use in common household items to industrial applica-
tions, it is imperative to examine their bioavailability.
Lithium belongs to the group IA and also has wider uses such
as in batteries, air conditioners to atomic reactors. Lithium
occurs naturally in soil and water, mostly at low concentra-
tions, and enters the food chain. It is not one of the essential
minerals though various studies indicate that low levels of Li
have beneficial effects on living organisms, whereas high
levels expose them to toxicity and related detrimental effects.
This review suggests that Li could be biologically important to
living organism depending upon its concentration/exposure.
Little is known about its biological importance and molecular
understanding of its accumulation and mode of action, which
Responsible editor: Philippe Garrigues
* Babar Shahzad
* Mudassar Niaz Mughal
mudassarniaz619@webmail.hzau.edu.com
Mohsin Tanveer
mohsin_1728@webmail.hzau.edu.cn; mohsin.tanveer@utas.edu.au
1
Department of Agronomy, University of Agriculture Faisalabad,
Faisalabad, Pakistan
2
State Key Laboratory of Agricultural Microbiology, Huazhong
Agricultural University, Wuhan, China
3
School of Land and Food, University of Tasmania, Hobart, Australia
4
Faculty of Veterinary and Agricultural Sciences, University of
Melbourne, Melbourne, Australia
5
The Equine Centre, San Luis Obispo, CA, USA
might have future implications for Li’s long-term effects on
living organisms.
Keywords Biology . Food chain . Metal . Lithium . Living
organism
Introduction
Lithium (Li), an alkali metal, belongs to the group IA of peri-
odic system and has similar properties with other members of
group IA and some of group IIA. Natural Li exists as a mixture
of the isotopes 7Li (92 %) and 6Li (8 %) and is mined from
petalite, triphylite, lepidolite, spodumene, and amblygonite
(Léonard et al. 1995). Li has numerous industrial applications
such as Li batteries, detectors for radionuclide Li-based alloys,
in air conditioners as humectants, in ceramics, atomic reactors,
and future fusion reactors, etc. (Léonard et al. 1995; Scrosati
and Garche 2010; Bonino et al. 2011). Lithium is present in
trace amounts in soil (7–200 g/kg), mainly in clay fraction of
soil (Morris 1958; Tölgyesi and Die Verbreitung des 1983). It
is also present in surface water (1–10 g/L) and in seawater
(0.18 g/L) (Lambert 1983). Surprisingly, higher lithium levels
(up to 100 mg/L) are found in some natural mineral waters
(Dawson 1991). The occurrence of Li in soil and water, and its
uptake through plants, lets it enter in the food chain. Total Li
intake up to 10 mg/day has not shown any adverse effect on
human health. Though biological functions and essentiality of
Li in living organisms are not fully studied, however, Li has
remarkably high affinity for replacing cations (Na+, K+, Mg2+,
and Ca2+) in living organism due to its smaller radius and high
polarizing strength (Sapse and Schleyer 1995). Lithium can
act as substitute for K+ or Mg2+ and can also bind to sites not
occupied by K+ or Mg2+ (Birch 2012). Li can substitute up to
50 % of K+ in plants (Shahzad et al. 2016). Furthermore,

amiloride-sensitive sodium channel (ENaC) is a key transporter
that is involved in Na+ homeostasis observed in pancreatic duct
cells and has approximately equal permeability to Li, thus can
alter Na+ homeostasis (Lenox et al. 1998; Holstein-Rathlou
1990). Greger (1990) also suggested that Li can enter in cells
through Na+/H+ transporter by replacing Na+, although the max-
imal transport rate is 2-fold slower for Li than Na+ and is a major
pathway for lithium transport into cells. Lithium also interferes
with magnesium ion (Mg2+); Birch (1976) found that all alkali
metal ions are exchanged more than 1000 times more rapidly
than Mg2+; this may explain why Li preferably affects the activity
of Mg2+ containing enzymes. Although Li is not required bio-
logically for plant growth and development, however, some pos-
itive effects of Li on plant growth have been observed under low
Li concentration (Schrauzer et al. 1992), while high concentra-
tions of Li are toxic to plants and cause chlorosis-like conditions
(Naranjo et al. 2003). In humans and animals, Li in high concen-
trations disrupts numerous biological functions and causes acute
to chronic toxicity (Timmer and Sands 1999). This review article
provides an overview of various detrimental or beneficial effects
of Li and also some of known basic mechanisms in different
living organisms. We aim to pull together so far the most of
available information/data to understand the role of Li as biolog-
ically important and/or detrimental toxic element.
Lithium in microbes and model organisms
Positive effects of lithium
Biologically, lithium (Li) is known to bind with selective DNA
(Kuznetsov et al. 1971) and competes with magnesium ions, thus
may involve in DNA synthesis and repair (Becker and Tyobeka
1990). These results stimulated the studies on microbes and bio-
logical model organisms to investigate the potential effects of Li.
Studies mainly focused on the mutagenic changes on molecular
level but did not reveal any significant changes in Bacillus
aluminum strain with the LiCl treatment (Nishioka 1975;
Kanematsux et al. 1980). King et al. (1979) also performed var-
ious in vitro biological tests by using lithium citrate, including
Salmonella typhimurium Ames test, Escherichia coli test, and
host and mice assay with E. coli, but could not detect any
DNA malformation or synthesis defect. Related to developmen-
tal biology, Caenorhabditis elegans, a free-living nematode mod-
el, suffered significantly decreased growth, maturation, and re-
productive capacity upon treatment of 313, 1250, and 10,000 μm
concentration of LiCl, and a similar effect was observed follow-
ing lithium carbonate treatment, as well. In the same study, au-
thors have utilized an ecotoxicogenomic approach and per-
formed DNA microarray analysis to represent a number of
downregulated genes related to metabolism upon Li treatments
(Inokuchi et al. 2015). This may indicate an essential role of Li in
biological and physiological activities in C. elegans.
Environ Sci Pollut Res
Another laboratory model, Drosophila melanogaster, is wide-
ly used in the studies for promoting longevity and increasing the
healthy life span. Upon treating with Li, inhibition of glycogen
synthase kinase (GSK-3) and activation of a nuclear factor
(NRF-2) are found responsible for extending the life span of both
genders of Drosophila (Castillo-Quan et al. 2016). As GSK-3 is a
well-known therapeutic target for aging, thus possibly have same
life-extending role in mammalian individuals, however this may
needs continuous Li therapy, which also have some drawbacks to
use. In stark contrast, Zhu et al. (2015) demonstrated diminishing
effect of LiCl treatment on the D. melanogaster female’s aging
process. However, the results regarding aging process and its
mechanisms are still inconclusive but proposes lithium vital role
in healthy life span thus if goes unmaintained could lead to health
issues in mammals.
Negative effects of lithium
In comparison, the presence of significantly increased number of
polychromatic erythrocytes in mice treated with an intraperitone-
al injection of 1.1 g/kg lithium twice provided some evidence of
lithium effect on chromosome distribution (King et al. 1979).
Keeping in mind the potential role of Li in nervous system and
in quest to explore the underlying mechanism, recent study has
characterized the selective dysfunction of ASJ chemosensory
neurons and suggested selective toxicity to the specific neurons
in C. elegans (Meisel and Kim 2016). Tsuruta (2005) studied Li
accumulation in 70 strains of different microorganism including
20 bacteria, 18 actinomycetes, 18 fungi, and 14 yeasts and found
that a high Li accumulation ability was exhibited preferably by
strains of the bacteria Arthrobacter nicotianae (1.0 mg/g dry
weight cells) and Brevibacterium helvovolum (0.7 mg/g dry
weight cells). These results suggest some species predilection
phenomenon existing specific for such species of organisms,
which needs to be determined with threshold concentration caus-
ing them more prone to the toxicity level.
Lithium in aquatic environment
Naturally occurring aquatic Li concentration has been neglected
for years because of its usually minor quantities and importance
at ecological level. Lithium is present in surface water at levels
between 1 and 10 g/L and in seawater at 0.18 g/L (Weiner 1991).
The lithium concentrations in groundwater may reach 500 mg/L,
whereas in the lithium-rich regions of northern Chile, the lithium
content of the surface waters could be as high as 5.2 mg/L
(Zaldivar 1989; Schrauzer 2002). Worldwide, mineral water re-
sources contain 0.05–1 mg/L Li; however, higher levels up to
100 mg/L can be found in some natural mineral waters
(Schrauzer 2002). A review of lithium in the aquatic environment
in the USA (Kszos and Stewart 2003a) found that lithium was
detected at low concentrations (0.002 mg/L) in the major rivers
of the USA. Further studies (Kszos et al. 2003b) identified
Environ Sci Pollut Res

lithium concentrations in surface waters that were 0.04 mg/L but
could be elevated in contaminated streams. In addition to the
surface water, Li and its isotopes have been identified in the
lower half of the 13 world’s major rivers (Huh et al. 1998), where
their concentrations appeared to be associated with fractionation
processes (aluminosilicate rocks weathering to clays) and in the
formation of evaporates (mineral rocks formed by mineralized
water evaporation). Moreover, the bedrock type effect has made
the composition of the Li isotopes much complicated to be
assessed in lower level water specimens and thus, nothing is
known about its beneficial properties for water living organisms
(Aral and Vecchio-Sadus 2008).
Negative effects of lithium
Lithium toxicity in aquatic environment should be addressed
to examine the effect of Li on aquatic life. Different studies
have reported concentration-based Li toxic effects on different
aquatic species. For instance, sensitivity of different species of
fish was ranged from 13 to >100 mg/L based on Li lethal
concentration (LC50) in growth medium (Dwyer et al. 1992;
Hamilton 1995; Long et al. 1998). Similarly, Emery et al.
(1981) noted lowest observed effect concentration (LOEC)
of 0.6 mg/L in Oncorhynchus mykiss (juvenile rainbow trout).
Numerous studies indicated toxic effects of Li at different
LOC and LOEC on different aquatic organisms (Table 1).
Importantly, exposure duration of aquatic species to Li dos-
ages also influenced the magnitude of Li toxicity. Lenntech
(2007) noted that Pimephales promelas showed LC50 of 1.2–
8.7 mg/L when exposed for 26 days to Li stress, while
Tanichthys albonubes exhibited 9.2–62 mg/L LC50 after
48 h of exposure to Li stress.
In a study from algae, Pseudo-nitzschia multiseries (a dia-
tom) was tested in marine-enriched cultures for the assessment
of Li toxicity levels, and results indicated the release of sig-
nificant higher levels of domoic acid (a neurotoxin) (Rao et al.
1998), which suggested an association between significant
releases of domoic acid with the influx of Li. This might be
an explanation of how Li may contribute to different toxicity
levels by stimulating the growth of naturally inhabiting toxic
organisms.
In amphibians, studies about Li toxicity levels mainly have
focused on its effects at embryonic development stage
(Backstrom 1954; Bustuoabad et al. 1977; Biwa and
Gimlich 1989) and plasma membrane proteins in early embry-
os (Lazou and Beis 1993). Induced microcephaly was also
observed in frogs (Rana pipiens, Rana catesbiana, Rana
sylvatica, Rana clamitans) and in salamanders (Ambylstoma
tigrinum, Ambylstoma punctatum) (Hall 1942).
Recent studies aiming to determine the threshold levels for
inducing Li toxicity identified 33 to 197 mg/L as acute Li
concentration range for Daphnia magna (freshwater flea; rec-
ognized as laboratory animal), which is about 10-fold higher
than commonly observed level in freshwater reservoirs
(Lenntech 2007; US EPA 2008).
Poor waste disposal or recycling facilities and chemical or
manufacturing spills are the main anthropogenic sources of Li
entry to freshwater and groundwater. However, we suggest
that putting the efforts for critical investigation of Li toxicity
levels especially for endangered aquatic species would be of
great value for the protection of biodiversity at ecosystem
level; this should be done with given priority in known Li-
rich areas, at least. Following determination of Li toxic levels,
evaluation criteria can be designed to regulate its level either
by avoiding water pollution or by mechanical measures to
regulate alkali metals.
Lithium in humans and animals
Lithium is a microelement required in minute quantity to
maintain body functions, as it plays an important role in me-
tabolism, neural communication, and cell proliferation
(Schrauzer 2002; Birch 2012). Studies delineating potential
causes, effects, and consequences of Li residues also revealed

Table 1 Experimental determination of lithium toxicity in aquatic species

Experimental species English name Lithium concentration (mg/L) Experiment endpoint Reference

Chironomus spp. Insect larvae 0.4 15-day LOEC (habitation) Emery et al. (1981)
Oncorhynchus mykiss Rainbow trout 0.6 10-day LOEC (juvenile survival)
Ptychocheilus lucius Colorado squawfish 41 96-h LC50 Hamilton (1995)
Xyrauchen texanus Razorback sucker 156 96-h LC50
Pimephales promelas Fathead minnow 42 96-h LC50 Long et al. (1998)
Gila elegans Bonytail 65 96-h LC50
Fundulus heteroclitus Mummichog 1.7 Embryo development Stockard (1906)
Morone saxatilis Striped bass >105 96-h LC50 Dwyer et al. (1992)
Daphnia magna Freshwater flea <1.2 64-h immobilization Anderson (1948)
Periphyton 3.5 10-day LOEC (algal biomas)

the therapeutic levels of Li, which can inhibit functions of
multiple enzymes in mammals (Busa and Gimlich 1989).
Moreover, multiple effects of Li (regardless of Li concentra-
tion) on hematopoiesis, differentiation of stem cells, fetal de-
velopment, and glycogen synthesis have been reported (Phiel
and Klein 2001).
Oral intake of metallic Li toxicity can be of varying degree
from mild to chronic in humans; however, individual meta-
bolic rate and tolerance level differ among individuals. In
humans, ingestion of 5 g of LiCl can result in fatal toxicity
(Aral and Vecchio-Sadus 2008). Published literature does not
have sufficient information on the mode of action and biolog-
ical assimilation of Li, which is quite understandable as it is
often neglected due to the general acceptance for lithium as
non-essential element for life (Léonard et al. 1995; Lenntech
2007). Hence it has been recommended as 1 mg/day for an
adult of 70 kg in dietary intake (Schrauzer 2002).
Positive effects of lithium
Lithium has been recognized as a pharmacological therapeutic
option for more than 45 years, especially in patients with
bipolar disorder for which it is recognized as treatment of
choice (Léonard et al. 1995). In this aspect, some behavioral
disorders have been observed in individuals with Li deficien-
cy (Aral and Vecchio-Sadus 2008). As the primary target site
for its action is the central nervous system in the body, there-
fore, it has been recommended as psychiatry therapeutics in
the form of lithium carbonate for the patients of manic depres-
sion (Kjølholt et al. 2003). Lithium being a univalent cation
should always be administered orally with an anion, either in
the form of capsule (lithium carbonate) or as a liquid prepara-
tion (lithium citrate). A tablet of lithium carbonate encloses
8.12 mEq (56.36 mg) of Li ion (Okusa and Crystal 1994) and
is often recommended by the physicians when indicated. The
role of Li in altering mood is still enigmatic; however, signif-
icant higher rate of suicides, crimes, and drug addiction was
observed in countries where Li level in drinking water was
below than normal (0.07–0.170 mg/L) (Schrauzer and
Shrestha 1990). Therefore, it has been advised to the people
who are residing in Li-deficient areas to include special diets
in their regular meal to take sufficient and regular Li supple-
ments (Aral and Vecchio-Sadus 2008).
Normal Li level in the body influences the metabolism and is
mainly assimilated through the gastrointestinal tract (GIT) and
excreted out of the body via kidneys within 24–48 h (Casarett
and Doull 1987; Schrauzer 2002; Linakis 2007). Following in-
gestion, Li does not bind to the serum proteins but resolves
completely in total body water, thus has a volume of distribution
of about 0.7 to 0.9 l/kg (Okusa and Crystal 1994). Li attains
equilibration between extracellular and intracellular spaces slow-
ly and may take 6 to 10 days to reach Li concentration balance
(Sadosty et al. 1999), which justifies prolonged dosage of Li
Environ Sci Pollut Res
supplements for attaining a therapeutic response in humans.
Chemically, Li resembles Na+, but Li is relatively more toxic,
and other heavy (toxic) metals and essential elements have also
been reported to interact with Li metabolism at renal/glomerular
level as it also competes with sodium, calcium, magnesium, and
potassium (Chmielnicka and Nasiadek 2003). Lithium uptake is
preferred by thyroid, kidney, and bone over liver and muscles
(Finley et al. 1995). Biological activities of Li in the body of
living organism have been summarized in Fig. 1, illustrating
the biological importance of Li.
Normally, serum therapeutic concentration of Li is about
5.6–8.4 mg/L; however; clinical signs of mild toxicity are
observed at 10.5–17.5 mg/L which can lead to severe toxicity
symptoms at >24.5 mg/L (Jaeger 2003), and toxicological
symptoms in kidneys like tubular damage and sclerotic glo-
meruli can be observed with Li intoxication cases
(Chmielnicka and Nasiadek 2003). Routinely, physiological
Li level may occur above normal following strenuous physical
exertion and in patients under dialysis treatment.
In animals, experimental evidence for the Li deficiency has
been observed in the form of the poor conception rate and high
abortion rate. Furthermore, reduced milk production and over-
all fat content in milk have been observed in lithium-deficit
lactating goats (Schrauzer 2002). To the best of our knowl-
edge, there is no information about the normal Li concentra-
tions in animals and its recommended proportion in the daily
feed intake as food additives.
Negative effects of lithium
GIT disturbances, hand tremor, and edema are the common side
effects of the Li overdose (Kato et al. 1996; Tandon et al. 1998).
Cardiac arrhythmia, hypothyroidism, and convulsion are also
reported with the frequent Li intakes (Chan et al. 2000). The
most common source of exposure for its toxicological effects
may be its psychotropic properties, as lithium salts like lithium
acetate and lithium carbonate are being extensively used in
manic-depressive ailments in humans (Schou 1968). In one case
study, majority of the patients (75–90 %) become Li toxic taking
therapy dosage for bipolar disorder (Amdisen 1988). A total of
5120 cases of lithium intolerance were reported to the American
Association of Poison Control Centers merely in 1996, of which
75 % people were seeking serious medical attention (Litovitz
et al. 1997); however, this intoxication can turn into fatal toxicity
upon ingestion of 5 g of lithium chloride (Aral and Vecchio-
Sadus 2008).
Lithium has wide industrial applications including
manufacturing of ceramics, batteries of laptops and mobile
phones, polymers, and pharmaceuticals, and its use is still in-
creasing in modern age (Saeidnia and Abdollahi 2013).
Professional personnel intoxication from industrial sources along
with its major contributing factors may be among the reasons
why Li was banned in the USA due to its potential toxic threats
Environ Sci Pollut Res
Fig. 1 Biological role of Li in living organism (adapted from Klemfuss and Schrauzer 1995; Schrauzer 2002)
in 1949 (Strobusch and Jefferson 1980). Recently, Australian
Inventory of Chemical Substance (AICS 2007) also classified
Li in the physiochemical and ecotoxicological/environmental
hazard category under the criteria approved by National
Occupational Health and Safety Commission (Kjølholt et al.
2003). Li toxicity caused numerous detrimental effects in human
body based on its acute or chronic toxicity (Fig. 2), indicated that
human nervous system is highly sensitive to Li stress while he-
matology of human is minimally affected. However, other sites
of Li toxic effects was also noted in renal, gastrointestinal, cardi-
ac, endocrine, and neuromuscular system (Fig. 2).
Clinically, information pertaining to Li concentration in
body is more important for medical nephrologists as medi-
cines from acetyl cholinesterase (ACE) inhibitors, thiazide
diuretics, and non-steroidal anti-inflammatory drugs
(NSAID) class can alter the sodium and potassium levels in
the kidneys, thus altering Li reabsorption and increasing the
risk for chronic Li intoxication (Okusa and Crystal 1994;
Lehmann and Ritz 1995; Alderman and Lindsay 1996).
Further, on continuing such medications can increase the in-
teraction of ACE inhibitors with Li concentration increased by
36 %, and its clearance through kidneys was reduced by 26 %
in patients of lithium intoxication (Finley et al. 1996).
Similarly, thiazide diuretics induce natriuresis that leads to a
compensatory mechanism resulting in the increase of the Na+
(and/or Li) reabsorption in the proximal tubule of the kidneys
thus can cause chronic Li toxicity (Finley et al. 1995).
NSAIDs also pose a significant threat of causing lithium tox-
icity because of its extra-label use especially in patients taking
doses without realizing its effect on lithium metabolism.
Therefore, potential drug interaction with Li intake should
be monitored carefully to ensure the availability of adequate
Li serum concentration (Table 2).
To date, little information is available about lithium toxicity
in animals; however, studies presenting toxicological effects
in rats can be traced back in literature. A study examining
lithium carbonate at 1.1 g/kg in formulized food containing
variable protein ratios indicated a significant rise (53 %) of
lipid peroxidation in rats fed with low-protein diets (Tandon
et al. 1998). Terao et al. (2006) showed that a potentially
beneficial effect of lithium is that it may block the accumula-
tion of amyloid-b (Ab) peptides that cause dementia in mice.
Renal toxicity has been reported in rats by the oral adminis-
tration of lithium carbonate (Chmielnicka and Nasiadek
2003), and lithium deficiency also caused significant negative
effect on the litter size and weight at birth (Schrauzer 2002).
Genetically, pregnant mice supplemented with lithium car-
bonate for many days did not reveal any significant effect,
whereas six times higher dosages produced drastic offspring’s
malformations (Smithberg and Dixit 1982). Lithium
 Environ Sci Pollut Res

Fig. 2 Semiology associated with lithium intoxication with organ system affected arranged in descending order (nervous and renal symptoms are
commonly observed). Acute intoxication can lead to chronic intoxication if goes unattended (adapted from Timmer and Sands 1999).

concentration in environment is expected to increase with its Lithium in plants

broader impact on environmental and ecological pollution
(Schrauzer 2002; Shahzad et al. 2016). Therefore, there is
sufficient room for the future research to establish the lithium
requirement in the maintenance and productivity of food ani-
mals to prevent its toxicity and/or to establish species-specific
safe dosage levels. The outcomes from these studies would
also provide more explicit understanding for the mode of ac-
tion of Li, as these are the key mediators for maintaining a
healthy food chain in the ecosystem.
Positive effects of Li in plants
Though, the essentiality and/or positive effects of Li in higher
plants are not yet clear. Nonetheless, some evidences showed
plant growth stimulation when exposed to Li at lower concen-
trations, for instance, Kalinowska et al. (2013) noted stimula-
tory effects on the elongation of lettuce roots and shoots with
higher relative water contents under low Li level (2.5 mg

Table 2 Interaction of various

drugs with Li (Timmer and Sands Drugs known to increase the Li Drugs do not effect with Li Drugs known to decrease the Li
1999) concentration concentration concentration

NSAIDs NSAIDs Diuretics

Mefenamic acid Aspirin Loop diuretics
Ibuprofen Sulindac Acetazolamide
Naproxen Methyl xanthine
Indomethacin Osmotic diuretics
Diuretics Potassium sparing
Thiazide
ACE inhibitors (acetylcholinesterase
inhibitors)
Environ Sci Pollut Res
Li dm−3). Lettuce shoots and roots exhibited higher water
content when exposed to low concentration of LiCl or LiOH
as compared to the higher concentrations of Li (Kalinowska
et al. 2013). Vlasyuk et al. (1979) suggested that increased
water absorbance under low Li concentration could be asso-
ciated with the increase in the amount of water adsorbed to
macromolecules, but at high concentrations, Li competed for
water and acted as a dehydrating agent. Hawrylak-Nowak
et al. (2012) observed enhanced maize and sunflower growth
when exposed to Li at low concentration of Li. They found
that shoot biomass was increased by 15 and 32 % in maize and
sunflower, respectively, under low Li level (5 mg dm−3).
Apocynum venetum showed non-significant response to Li at
low concentration (50 mg kg−1) while exhibited significant
reduction at high Li concentrations (100 and 200 mg kg−1)
(Jiang et al. 2014). Anderson et al. (1988) documented that
under low concentration of Li, plants display improved pro-
ductivity, faster maturation, and an increased resistance to dis-
eases. Besides its positive effects under normal conditions, Li
also plays crucial role in plant growth even under stress con-
ditions. For instance in spinach, freezing, dehydration, and
supercooling cause depolarization of microtubules in meso-
phyll cells of spinach (Bartolo and Carter 1991), while treat-
ment with Li decreased the amount of microtubule depoly-
merization in cells subjected to low temperature, suggesting
that the microtubules in these cells may not be inherently cold
labile (Bartolo and Carter 1991). Reasons behind decrease in
depolarization under cold stress due to Li could be due to the
following: (a) Li-induced ethylene may enhance microtubule
cold stability (Roberts et al. 1985; Sato and Theologis 1989)
or (b) Li may stabilize microtubules against cold-induced de-
polymerization by stabilizing microfilaments (Colombo et al.
1991; Paves et al. 1990; Bartolo and Carter 1991).
Concentration of Li in growth medium considerably influ-
ences numerous plant morphological growth processes
(Shahzad et al. 2016). Gaillochet (1981) noted that Li inhibits
the nyctinastic closure of folioles of the excised leaves of
Cassia fistula and enhances their opening at minimal concen-
tration for significant effects on closure that is 0.03 mM, and
on opening 0.3 mM; the mechanism of its effect would be
different from those of fusicoccin effect in the pulvini of
Mimosa pudica (Roblin 1980) because it is inactive on plas-
malemma K+-ATPase and appears to have no significant ef-
fect on proton extrusion (Marre et al. 1974). Moreover, though
Li can leak through the cellular membrane easily but expelled
from the cells rather slowly in comparison to some other ions
such as Na+ and K+, such an accumulation of Li could always
be accompanied with a decrease in cellular K+ contents
(Gaillochet 1981). Additionally, opening movement of
folioles was not only promoted by Li but also by Ca2+ salt
(Gaillochet 1981); however, these results are contradictory
with Satter et al. (1973) who showed that divalent cations
are more effective than monovalent ones in the promoting of
the rhythmic leaflet opening of excised leaves of Albizzia
juiibrissin. According to these authors, divalent cations would
alter the conformation of membrane macromolecules by alter-
ing electrostatic interactions that occur only during the open
phase of the rhythm. These results show that Li has a role in
leaf movement; further studies are required to further investi-
gate the role of Li in plant morphology.
Negative effects of Li in plants
Morphological alterations in plants
Li salts are highly toxic and trigger chlorosis-like symptoms
(Makus et al. 2006). Nonetheless, Asteraceae and Solanaceae
families showed tolerance against Li toxicity and exhibited
normal plant growth (Kabata-Pendias and Mukherjee 2007),
while Aral and Vecchio-Sadus (2008) found that citrus plants
are sensitive to Li stress. Some plants, notably Cirsium
arvense and Solanum dulcamera, accumulated Li 3-fold to
6-folds over other plants. Halophilic plants such as Carduus
arvense and Holoschoenus vulgaris may reach lithium con-
tents of 99.6–226.4 g/kg (Anke et al. 1991). Tobacco plants
exhibited necrotic spots and reduced growth associated with
altered rhythmic movements, abnormal pollen germination,
and development under Li toxicity (Naranjo et al. 2003).
Lithium at higher concentrations reduced the assimilating or-
gan area of sunflower and maize plants by 27 and 31 % with
increasing concentrations of Li (Hawrylak-Nowak et al.
2012). Furthermore, reduction of leaf area of maize plants
was also observed by 29 % after exposure to 25 mg Li dm−3
stress level (Hawrylak-Nowak et al. 2012). Reduction in water
contents is another toxic effect of Li thus reduces tissue tur-
gidity and growth, (e.g.,) higher concentration of Li in wheat
reduced net water content and dry weight; however, it was not
clear whether desiccation of tissues under Li stress was due to
reduced water uptake or elevated transpiration rate (Kent
1941). However, Vlasyuk et al. (1979) suggested that in-
creased water absorbance under low Li concentration could
be associated with the increase in the amount of water
adsorbed to macromolecules, but at high concentrations, Li
competed for water and acted as a dehydrating agent.
Magalhães et al. (1990) noted reduced dry weight of the
roots and leaves of radish and leaves of watercress under Li
stress, which resulted due to reduced water retention in tissues.
Duff et al. (2014) substantiated that when plants of
Arabidopsis were exposed to Li for a period of 3 weeks, low
values of relative water content and structural independent
pigment index were observed.
Physiological alterations in plants
Different studies reported different detrimental effects of Li on
numerous physiological processes in plants such as Li-

induced alteration in photoperiodic control of flowering
(Kandeler 1970), precedence between axillary buds (Desbiez
and Thellier 1975), circadian rhythms (Engelmann 1972,
1973), the thygmomorphogenetic response (Boyer et al.
1979), the development of a methyl glucose permeation sys-
tem (Carlier and Thellier 1979), and solute uptake mecha-
nisms (Thellier et al. 1980). The period of the circadian petal
movements of Kalanchoe is increased by about 2 h in 5 mM
LiCl (Engelmann 1972). Li is also known to have consider-
able effects on stomatal regulation and transpiration oscilla-
tion, as Brogarh and Johnsson (1974) found that upon the
treatment of the seedlings of Avena sativa with Li, stomata
needed longer time to start the opening under Li; however,
once opening has begun, the opening and the subsequent clos-
ing movements were fairly independent of the Li concentra-
tion. During the stomatal regulation, K+ is transported across
the guard cell membranes and water passively follows this ion
(Roelfsema and Hedrich 2005). Therefore, it is reasonable to
suggest that K+ activated reaction could be responsible for the
rate-limiting processes of the oscillatory system and Li might
then act as an inhibitor and slow down the oscillations.
The plant endogenous movement named circumnutation is
commonly considered as an inevitable consequence of organ
growth (Stolarz et al. 2008), but its quantitative relation to
growth is still not well established (Stolarz et al. 2010). In
sunflower, Li significantly reduced circumnutation intensity
when supplied in high concentration, for instance, under
0.2–20 mM, circumnutation intensity was maintained at a
constant level (0.12 h−1), but it started to decrease significantly
under 40 and 60 mM LiCl, and under 80 mM LiCl,
circumnutation stopped completely (Stolarz et al. 2015). A
similar effect was observed in sunflower seedlings under Li
treatment (Zachariassen and Johnsson 1988). The same effect
of Li was observed in circumnutating shoots of Phaseolus
vulgaris (Millet and Badot 1996). Therefore, Li in high con-
centration causes considerable alterations in the growth and
circumnutation mechanism in plants.
Lithium toxicity can also lead to the inhibition of glycogen
synthase kinase-3b (Klein and Melton 1996), Hal2-like nucle-
otidases (Murguía et al. 1996), and/or ribosomal RNA
(rRNA)-processing enzymes (Dichtl et al. 1997) and inhibi-
tion of inositol monophosphatases, leading to depletion of
cellular inositol and a rundown of the inositol cycle and cal-
cium signaling (Berridge 1993). Inhibition of Hal2-like nucle-
otidases would also influence S-transferase reactions and
rRNA processing (Dichtl et al. 1997; Gil-Mascarell et al.
1999). Recently, pre-mRNA splicing in eukaryotic cells also
found to be a target of Li toxicity (Forment et al. 2002).
The exact mechanism behind growth stimulation at low con-
centration of Li or growth inhibition at high concentration of Li is
not clear, though results from some other studies demonstrated
that Li affects plant metabolism at a membrane level; however,
its role seems to be non-specific as it substitutes other
Environ Sci Pollut Res
monovalent cations in plant cells (Kabata-Pendias and
Mukherjee 2007). Allender et al. (1997) suggested that adverse
effects of Li in cotton might be related to the readily movement
of Li ion across cell membranes and its potential interference
with calcium metabolism. Naranjo et al. (2003) reported interest-
ing results about Li toxicity in tobacco plants; they found that leaf
curling observed in tobacco plants treated with LiCl may reflect
ethylene production (Boller 1990; Conejero et al. 1990), and this
is one of the pathways triggered during pathogen invasion.
Actually, some plant defense genes are regulated by ethylene
(Ecker and Davis 1987). Li has already been reported to increase
ethylene production through induction of 1-aminocyclopropane-
1-carboxylate synthase genes (Boller 1984; Liang et al. 1996).
Further, the ensuing production of ethylene due to Li also in-
duced stress responsive genes, and these effects of Li depict the
phenotypes of transgenic plants with alterations in either the
ubiquitin system (Becker et al. 1993), proton transport (Mittler
et al. 1995), or sugar metabolism (Herbers et al. 1996; Tadege
et al. 1998). Myo-inositol monophosphatase (IMP) is a soluble
protein that catalyzes the removal of a phosphate from myo-
inositol phosphate substrates (Zonia and Tupy 1995b). IMP is
required for the de novo inositol synthesis from glucose C phos-
phate and for breakdown of inositol trisphosphate (Majerus
1992). Reduction of cellular inositol levels has been linked to
inhibition of cell division in plant tissue culture cells (Biffen and
Hanke 1990). The activity of inositol monophosphatases in plant
is Li sensitive (Gillaspy et al. 1995), and the effects of Li on
plants have also been interpreted in terms of inhibition of the
inositol cycle and calcium signaling (Zonia and Tupy 1995a;
Liang et al. 1996). Lithium interferes with the activity of dephos-
phorylation of inositol-1-phosphate which is required to yield
inositol free (Gillaspy et al. 1995).
Besides these findings, Li was also reported to induce ox-
idative damage to photosynthetic pigments and reduced pho-
tosynthetic activity. In a study, carotenoid contents were re-
ported to be considerably decreased (16 %) at the concentra-
tion of 25 mg Li dm−3, while at a higher Li concentration
(50 mg dm−3), maize showed a reduction of 47, 43, and
67 % in chlorophyll a, b and carotenoid content, respectively,
as compared to the control (Hawrylak-Nowak et al. 2012). Li
et al. (2009) noted that Li stress depressed chlorophyll con-
tents in different Brassica carinata seedlings. This depression
could be related to numerous physiological changes observed
in several other plant species under different forms of stresses,
such as the disintegration of chloroplast fine structure, insta-
bility of pigment protein complexes, or changes in the quan-
tity and composition of metabolites (Dubey 2005). Other pos-
sible reasons were also suggested and were associated with
chlorophyll degradation in necrotic regions, increase in cata-
lytic action of chlorophyllase, pheophorbide oxygenase, red
chlorophyll catabolite reductase, and Mg-dechelatase
(Harpaz-Saad et al. 2007). Li is considered a non-essential
element for plants, though there are some evidences of its
Environ Sci Pollut Res
effects on photosynthesis, biosynthesis of sugars, and several
enzymatic processes, which suggests that Li may have some
biological roles in plant growth and development.
Biochemical alterations in plants
Lithium toxicity has also been reported to lead to oxidative
conditions and lipid peroxidation in plants due to higher pro-
duction of reactive oxygen species (ROS) (Hawrylak-Nowak
et al. 2012). Tandon et al. (1998) noted that oxidative nature of
Li toxicity is mediated by the enhanced levels of lipid perox-
idation. These ROS react with numerous biological mem-
branes, cellular organelles, and biochemical molecules like
proteins, lipids, photosynthetic pigments, and nucleic acids
(DNA or RNA) and ultimately abrupt normal cell functions
and cell metabolism (Clemens 2006). Unsaturated fatty acids
are major parts of cell membranes. ROS under Li toxicity can
react with aldehydes and replace hydrogen from unsaturated
fatty acids, thus affecting cell membrane by distorting lipid
bilayer; however, the exact mechanism is still not clear. As an
adaptive nature of plants, antioxidants scavenge ROS in se-
vere conditions can also inhibit the production of enzymes
such as superoxide dismutase (SOD), glutathione peroxidase
(GPX), or catalase (CAT) (Richard et al. 1997; Erakovic et al.
2000). Nonetheless, some studies indicated upregulation or
downregulation of SOD, GPX, and catalase activities which
are closely related to Li concentrations and levels of ROS
production. For instance, GPX activity was inhibited at
1 mM Li concentration, but at the same time, SOD activity
was increased, affirming that Li caused the production of su-
peroxide ions (Nciri et al. 2012). Hawrylak-Nowak et al.
(2012) reported that the level of lipid peroxidation of the cell
membranes in the leaves of sunflower and maize plants
Fig. 3 Summary of the knowledge on the response of plants under lithium
increased significantly in the presence of 50 mg Li dm−3,
which suggests the disturbances of membrane integrity while
there was non-significant effect of Li on melanoaldehyde
(MDA) production in the roots of sunflower. L-Ascorbic acid
or vitamin C is another important compound and is involved
in the biosynthesis of neurotransmitters and collagen (Iqbal
et al. 2004). This compound can considerably scavenge
ROS due to Li stress. Kalinowska et al. (2013) noted no sig-
nificant effects of Li stress on L-ascorbic acid accumulation in
the lettuce plant leaves. These findings suggest that different
plants have different responses to Li stress, which is quite
understandable as genetic differences do play a significant role
in levels of tolerance to various stresses.
Lithium is also reported to influence DNA, RNA, and
protein biosynthesis. Weeks (1956) found that DNA conden-
sation is partially governed by Na+/K+ ratio; however, Li com-
petes with K+ and thus binds more readily and causes
alteration in the conformation of DNA. Vlasyuk et al. (1979)
reviewed some studies and suggested that Li in high
concentration interrupts protein and nucleic acid metabolism.
Evidences from Vlasyuk et al. (1975a,b, 1979) showed direct
toxic effects of Li on expression of some genes by influencing
transcription and translation process. They also found that Li
has primary effect on stability and conformational state of
DNA, and this, in turn, affects the metabolism of RNA and
proteins. Nonetheless, we have seen from literature that Li
may have both selective and non-selective effect; selective
might be because of its physiochemical properties, and non-
selective might be due to its monovalent nature (Gallicchio
1990; Bach and Gallicchio 2012). Further, it is well evident
that inhibitory and stimulatory effects of Li on plant growth
depend on Li concentration. Figure 3 is showing response of
plants under Li. Therefore, it could be speculated that the

adverse responses may be secondary manifestations of some
primary effects elsewhere in the system, which require deeper
understanding of Li effects on different physiological and bio-
chemical pathways at molecular level.
Conclusion and future research perspectives
The present overview provides a quick look over the role of Li
in living organisms. In aquatic living organisms, Li in high
concentrations cause significant release of domoic acid, re-
tards embryonic development stage, and induces microceph-
aly. Likewise, in humans and animals, Li shows a dose-
dependent influence on their physiology. A number of chronic
and acute effects of Li toxicity have also been summarized in
this review, which clearly explains the biological function of
Li in animals and humans. Lithium in the safe doses also
recognized as a pharmacological therapeutic option. Some
studies indicated the importance of Li in food and drinking
water as low Li diets were linked with mental retardation and
in severe cases lead to suicides. In plants, higher levels of Li
alter numerous metabolic processes like water relation, re-
duced enzymatic activities, disturbed membrane integrity, re-
duced photosynthetic activity, and ultimately reduced plant
growth. The results of the previous studies also confirmed that
elevated levels of Li triggers oxidative damage in the plants.
ROS damages many cellular organelles and macro molecules
such as DNA, proteins, lipids, and so on. From future research
perspective, Li should be studied extensively to understand its
biological functions. To date, available data on some living
organisms indicated that Li is biologically important, but at
lower concentrations and at higher concentrations, Li induced
numerous toxic effects.
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