REVIEW ARTICLE

Mercury-based traditional herbo-metallic preparations:a toxicological perspective

Sushant U. Kamath • Brindha Pemiah • Rajan K. Sekar •

Sridharan Krishnaswamy • Swaminathan Sethuraman •

Uma Maheswari Krishnan

Received: 3 February 2012 / Accepted: 27 February 2012 / Published online: 23 March 2012

� Springer-Verlag 2012

Abstract This review aims to explore the toxicological

aspects of mercury-based herbo-metallic preparations like

cinnabar and ‘‘Rasasindura’’ that are primarily composed

of mercuric sulfide (HgS). Cinnabar-containing prepara-

tions have been used extensively in Indian and Chinese

systems of medicine for treatment of chronic ailments like

syphilis, high fever, pneumonia, insomnia, nervous disor-

ders, deafness, and paralysis of the tongue. Contrary to

Western medicine, which does not promote the use of

mercury due to its toxic effects, Indian and Chinese tra-

ditional practitioners believe that mercury-based formula-

tions have potent therapeutic efficacy, while there is no

toxicity due to the unique and repeated purification pro-

cesses employed during preparation. However, lack of

proper pharmacovigilance and widespread self-medication

has resulted in undesirable effects to certain sections of the

consumers of these preparations, which have contributed to

the negative publicity for these forms of medicine. Varia-

tions in the quality of the preparations coupled with the

lack of understanding of the differences in the recom-

mended dosages and treatment strategies adopted by tra-

ditional medicine practitioners, further fuels concerns in

the Western world on the safety and efficacy of traditional

medicine. But in spite of these concerns, concerted efforts

to understand the biological interactions and transforma-

tions of these preparations are yet to gain momentum.

Although scattered reports on the toxicity of these prepa-

rations are available in literature, their mechanism of action

has not been conclusively established. Long-term phar-

macotherapeutic and in-depth toxicity studies are needed to

address the apprehensions raised by these herbo-metallic

preparations. This review highlights the lacunae in the

studies conducted thus far, and assesses the need for further

studies to provide significant data to establish the safety

and efficacy of such preparations, as well as develop gold

standards for stringent quality control of these preparations.

Keywords Mercury � Cinnabar � Rasasindura �Mercuric sulfide � Herbo-metallic preparations

Introduction

Since time immemorial, Indian and Chinese systems of

medicine have used herbo-metallic preparations for treat-

ment of chronic ailments (Singh et al. 2009; Wang et al.

2007). ‘‘Rasa Shastra’’ is one of the disciplines in Indian

system of medicine in which herbo-metallic preparations

made from incinerated metals were first described, such as

S. U. Kamath � R. K. Sekar � S. Sethuraman �U. M. Krishnan (&)

Centre for Nanotechnology & Advanced Biomaterials,

School of Chemical & Biotechnology, SASTRA University,

Thanjavur 613 401, Tamil Nadu, India

e-mail: umakrishnan@sastra.edu

S. U. Kamath

e-mail: sushantkamath@scbt.sastra.edu

R. K. Sekar

e-mail: ksrajan@chem.sastra.edu

S. Sethuraman

e-mail: swami@sastra.edu

B. Pemiah

Centre for Advanced Research in Indian System of Medicine,

School of Chemical & Biotechnology, SASTRA University,

Thanjavur 613 401, Tamil Nadu, India

e-mail: brindha@carism.sastra.edu

S. Krishnaswamy

School of Chemical & Biotechnology, SASTRA University,

Thanjavur 613 401, Tamil Nadu, India

e-mail: deanks@sastra.edu

123

Arch Toxicol (2012) 86:831–838

DOI 10.1007/s00204-012-0826-2

therapeutic formulations using gold, copper, iron, zinc,

mercury, etc. These were mixed with organic molecules

derived from plant extracts rendering them biocompatible

according to Ayurveda, a traditional form of medicine in

India (Paul and Chugh 2011). Ayurvedic procedures

involve extensive purification and preparation methods and

repeated incinerations at specified temperatures to make

the minerals ready for human consumption. According to

Ayurveda, a purified metal does not react adversely with

tissues of the body and, hence, a herbo-metallic drug is

considered to be more powerful than almost any other

medicinal preparation. Many metals, such as iron, copper,

zinc and cobalt, play a vital role in biological systems due

to their involvement in the biochemical processes. Ele-

ments such as sodium, potassium, magnesium and calcium

may aid in improving the bioavailability of drugs in the

body (Swamy and Ravikumar 2010). However, the role of

heavy metals in biological systems still remains shrouded

in controversy.

There are many documented reports on the toxic man-

ifestations of heavy metals such as mercury, lead, cadmium

and arsenic. Mercury, for instance has been reported to

cause dementia and neurological disorders, and it is also

wellknown that mercury (II) salts and organic mercury

(methyl mercury) are more toxic than elemental mercury

(Albers et al. 1988; Chuu et al. 2007). Hence, modern

medical practitioners are skeptical about use of mercury for

therapy—a notion not supported by the traditional medi-

cine practitioners. Ayurveda emphasizes the use of specific

plant products during the processing of these herbo-

metallic preparations—a trait that is common with other

forms of traditional medicine throughout the world (Saper

et al. 2008). These herbs are believed to assist the delivery

of the drugs to the body and also to contribute to the

therapeutic effects. This process of incineration and addi-

tion of medicinal herbs is believed to remove impurities

and eliminate the harmful effects of the metallic ingredi-

ents (Kumar et al. 2006). Unlike proteins, carbohydrates,

and lipids, the essential micronutrients for the human body

are not biosynthesized in vivo and need to be supplemented

through diet (Tontisirin et al. 2002). Traditional medicine

believes that the introduction of these ingredients through

proper routes and after careful purification can provide

ideal therapeutic effects with no toxicity. Interestingly,

honey, milk, butter, or ghee are used as the vehicle for most

of the Indian herbo-metallic preparations (Sarkar et al.

2010). These may serve as an excellent dispersing medium,

and aid delivery and bioavailability of these preparations

apart from mitigating any residual toxicity of these medi-

cines (Kumar et al. 2006).

Table 1 summarizes the various traditional medicine

preparations available in the Indian market containing

Rasasindura—a preparation containing mercuric sulfide. It

is evident that many preparations contain multiple ingre-

dients, both herbal as well as herbo-metallic, while a few

preparations contain only mercury and sulfur.

Toxicology aspects

Absence of significant toxicology data is a major lacuna in

herbo-metallic research despite being used since ancient

times. Availability of scientific evidence to testify the safety

and efficacy of these products is limited since, in most of the

reported cases, herbal remedies were self-administered by

patients without proper guidance (Chandramouli et al. 2010).

Even though the metals are purified and believed to be non-

toxic according to Ayurveda, this only refers to the clinical or

therapeutic dose, which is minimal. Self-medication may lead

to health complications and may prove to be fatal and, hence,

Ayurveda does not encourage unsolicited use of its formula-

tions. The permissible limit of heavy metals in dietary con-

tents as per the WHO is lead (10 ppm), cadmium (0.3 ppm),

arsenic (10 ppm), and mercury (1 ppm) (Swamy and

Ravikumar 2010). Although most of the traditional medicinal

preparations have metal contents far greater than the WHO

limits, the toxicity of a preparation need not directly correlate

with the metal content in the sample. The chemical nature of

the metal, route of administration, dosage, residence time

within the body, pharmacokinetics and dynamics, bioavail-

ability, metabolic transformations of the preparation, age,

gender, physiology, nature and stage of disease, and diet can

influence the toxic manifestations of the herbo-metallic

preparations (Hung et al. 1997). Therefore, a careful analysis

of all these parameters is required in order to establish the risk

involved in a given herbo-metallic preparation.

Cinnabar and Rasasindura

Naturally occurring mercuric sulfide (HgS) is a component

of cinnabar, a Chinese mineral medicine, which has been

used as a memory-enhancing drug for more than

2000 years (Young et al. 2002). It has been used as a

tranquilizer, and is still used in clinical practice in Asia and

the Middle East. In Ayurveda, cinnabar is used as the

source to isolate and purify the mercury, which is then

amalgamated with sulfur and transformed to ‘‘Rasasindura’’

(HgS) through mechanochemical processes. Mercury is

a well-known toxic element and hence various purification

processes exists in Ayurveda, which is believed to render it

non-toxic. It is ground with brick dust and garlic and boiled

in water after enclosing in a cloth over a gentle fire for 3 h.

After cooling, it is washed and dried in the sun (Niir Board

of Consultants and Engineers 2003). Mercury obtained by

sublimation of cinnabar is also considered to be pure.

832 Arch Toxicol (2012) 86:831–838

123

Table 1 Commercially available formulations of Rasasindura (containing HgS) in India

Drug name Formulation Components Indications

Rasasindur Powder Purified mercury, purified sulfur, ammonium chloride Bronchial asthma, pleurisy with effusion

Rasaraj ras Liquid Ras sindur, Motipishti, Suvarna bhasma, Abhrak

bhasma, Loh bhasma, Suvarnamakshika bhasma,

Praval Pishti, Vanga bhasma, Withania somnifera,Syzygium aromaticum, Myristica fragrans

Aloe vera juice, Solanum nigrum juice

Stroke, hypertension, diabetes, erectile dysfunction,

oligospermia, kidney disorders, vata disorders

Rasraj ras Tablet Rasa sindur, Abhrak bhasma, Swarna bhasma, Lauha

bhasma, Rajata bhasma, Vanga bhasma,

Ashvagandha, Lavanga, Jatiphala, Kshir kakoli

Paralysis, hemiplegia, lockjaw

Destone Capsules Rasasindur, Muthanga, Gandhaka, Punarva Urinary tract infections, kidney stones, prostate gland

inflammation and leucorrhoea

Ekangavir ras Tablets Rasa sindur, Shuddha, Gandhaka, Kanta Lauha

bhasma, Vanga bhasma, Naga bhasma, Tamra

bhasma, Abhraka bhasma, Tikshna Lauha bhasma,

Shunthi, Pippali, Maricha

Paralysis, Bell’s palsy, hemiplegia, brachial palsy and

sciatica

Carwin Capsule Extracts of spreading hoog weed, Indian drum stick

tree, mustard leaves, Buch-ham, Clove, Tecomaundulata, Sarveshvar parpati, Liquorice extract,

Rasasindur, Tinospora extract, purified mercury

chloride, extracts of malabar nut and winter cherry

root, Calcs of Mica (1,000 times calcined), Calcs of

copper, gold, diamond, emerald, turmeric and white

pepper

Deep seated wounds, tumors, loss of appetite,

diminished growth, strength and vital elements

along with haematopoiesis, physical and general ill

health due to radiation and chemotherapy of various

cancer patients

Addyzoa Capsules Purnachandrodaya ras, Suvarnavang,

Muktashukti bhasma, Suvarnamakshik bhasma,

Shilajit shuddha, Abhrak bhasma

Makardhwaj rasa, Rasa sindur

Increases sperm count

Enhances sperm motility

Improves sperm morphology (prevents DNA damage

to sperms)

Enhances the chances of pregnancy

Increases sexual desire

Rasa sindur Powder Purified mercury, purified sulfur HIV-AIDS

Brento Tablets Ashwagandha, Brahmi, Shankpushpi, Yashtimadhu,

Pushkarmool, Sarpagandha, Vacha, Jatiphala, Rasa

sindur

Impaired cognitive function, improves overall mental

performance, memory, concentration and learning

abilities

Mahayograj

guggul

Tablets Sunthi, Pippali, Cavya, Pippalimool, Citraka, Hingu,

Ajmoda, Sarsapa, Sveta Jiraka, Krsanjiraka,

Renuka, Indrayava, Patha, Vidanga, Gajapippli,

Katuka, Ativisa, Bharagngi, Vaca, Murva, Haritki,

Bibhitaka, Amalaki, Vangabhasma, Abraka

bhasma, Mandura bhasma, Parad (Rasa sindur),

Guggulu suddha

Used in muscular-skeletal disorders; Maha yogaraj

guggul is not only anti-inflammatory and safe in the

long run but has medicinal herbs which strengthen

the system and extend remission, through its health-

enhancing herbs

Rhumayog Tablets Abhrak bhasma, Bang bhasma, Loha bhasma,

Makshik bhasma, Mandur bhasma, Nag bhasma,

Rasa sindur, Yograj guggul, Maha rasnadi

quath (solid extract)

Coronary insufficiency and ischemic heart disease;

the oleoresin of guggul has a cholestrol lowering

effect. It has hypolipidaemic and anti-inflammatory

effects

Vrihat

Vatchintamani

ras

Tablets Swarna bhasma, Rajat bhasma, Abhraka bhasma,

Lauha bhasma, Pravala bhasma, Mukta bhasma,

Rasasindur

Improves sensory and motor performance in chronic

neurological conditions such as hysteria, insomnia

and paralysis

Purnachandra ras Tablets Rasa sindur, Abharaka Bhasma, Lauha bhasma,

Shudda shilajatu, Vidanga, Makeshika bhasma

Rejuvenator. Improves strength, stamina and energy

Vasant

Kusumakar

Ras

Tablets Swarna bhasma, Rajat bhasma, Vanga bhasma, Naga

bhasma, Lauha bhasma, Abhraka bhasma, Pravala

bhasma, Mukta bhasma, Rasa sindur

Diabetes, diabetic carbuncle, diabetic neuropathy,

diabetic and retinopathy

Trailokya

Chintamani

Ras

Tablets Swarna bhasma, Rajata bhasma, Abraka bhasma,

Lauha bhasma, Pravala bhasma, Mukta bhasma

Chronic and recurrent respiratory tract infection such

as influenza, pneumonia, cachexia, emaceration

associated with fever

Arch Toxicol (2012) 86:831–838 833

123

Cinnabar is rubbed with lemon juice for 3 h and then

sublimed. The black powder obtained is further triturated

with lemon juice and boiled in water (Dutt 1877). Ayurv-

edic herbo-metallic preparations are expected to be elimi-

nated from the body very quickly and have been envisaged

as carriers. The role of Rasasindura may be analogous to

this concept.

Another important aspect that needs to be probed

in-depth is the role of ingredients that are added at various

steps during the preparation. The preparation of Rasasin-

dura involves the purification of mercury and sulfur fol-

lowed by the reaction between purified mercury and sulfur

to produce Rasasindura. There are various purification

processes for mercury in Ayurveda. One of them involves

grinding mercury with calcium carbonate for 18 h (Fig. 1),

and then with rock salt and garlic for 12 h (Shastri 1962).

Washing with water separates mercury and the mercury

thus obtained is deemed to be pure according to Ayurveda.

The role of calcium carbonate in purifying mercury and in

the removal of impurities or toxins is not well understood.

It is more likely that metallic salts like lead or tin com-

monly associated with mercury can be removed as slags on

reaction with limestone (Meriam and Kraige 1986).

Garlic has been used as an antidote for mercury poisoning

for a great many years (Graeme and Pollack 1998). Although

the antioxidant glutathione can remove mercury toxins from

the body, high levels of mercury have been reported to

deplete the levels of glutathione. Therefore, we hypothesize

that the role of garlic might be to supplement the action of

glutathione. It is well established in modern science that

mercury binds to sulphydrl groups present in garlic and

thereby is excreted from the body (Belle et al. 2009).

Another fascinating aspect that needs to be considered

while assessing the toxicity of such preparations is the

inclusion of phytochemicals during the preparation pro-

cesses that may contribute to the therapeutic effect of the

preparation, unlike the case with pure mercuric sulfide. For

example, garlic contains allicin, ajoene, S-allyl cysteine,

bioactive selenium, etc., which can aid in mitigating not

just heavy metal toxicity but also oxidative stress induced

by arsenic and metals (Flora et al. 2009). These compo-

nents also possess medicinal properties that can serve to

treat various disorders. It is likely that such herbo-metallic

formulations can serve to potentiate the therapeutic effects

of individual phytoconstituents and may contribute to the

successful use of such formulations in treating various

chronic ailments for many centuries.

The purification of sulfur involves melting orthorhombic

sulfur with butter, which is then poured into fresh milk.

This will result in cooling of sulfur and its subsequent

solidification along with an allotropic transformation to its

amorphous form (Fig. 2). The components of milk are

believed to aid in the irreversible allotropic modification

and also get incorporated into sulfur to alter the pharma-

cokinetic and therapeutic index of the final product.

Finally, purified mercury and purified sulfur is ground

together to obtain a fine lusterless powder called ‘‘Kajjali’’

in Ayurveda, which is a-HgS (Fig. 3).

The extract from the aerial root of Ficus bengalensis

Linn is then added to this powder and ground until it

becomes dry. Ficus bengalensis has been proved to have

several medicinal properties and contains sterols like

Lupeol, b-sitosterol, and b-amyrin acetate. Although it may

impart medicinal properties to HgS and make it more

potent, studying its coordination chemistry to probe for-

mation of metal ion complexes may provide interesting

insights into the biological interactions of these prepara-

tions. This is because it has now been recognized that

Fig. 1 a Calcium carbonate and elemental mercury prior to the process of grinding, b calcium carbonate after the process of grinding with

mercury

834 Arch Toxicol (2012) 86:831–838

123

coordination complexes of metals have significant physi-

ological activities (Zang and Lippard 2003; Selvaraj et al.

2011, 2012). The transformation of beta to alpha HgS is

carried out by heating under controlled conditions with

mild, moderate, and intermittent heat, and the red-colored

product Rasasindura is obtained. However, investigations

on the interaction of these preparations on the biological

system have not been systematically carried out at the

molecular, cellular, and systemic levels, nor have any

efforts been directed to understand the chemical composi-

tion and constituents in these preparations.

Though not many in vivo studies with Rasasindura have

been reported in the literature, a few experiments to ascertain

the toxicity of mercuric sulfide-based preparations have been

carried out. Excretion of ‘‘Makaradhwaja’’, an Ayurvedic

formulation composed of mercuric sulfide, showed no traces

of mercury in urine samples of healthy men (Niir Board of

consultants and Engineers 2003).

Cinnabar is reported to be the most inert form of mer-

cury compounds and has been found to exhibit 5,000-fold

less toxicity when compared with methyl mercury, based

on the results obtained after exposure of brain and liver

cells for 48 h to cinnabar-containing traditional Chinese

medicine, An-Gong-Niu-Huang (AGNH) (Wu et al. 2011).

This makes clear that the chemical form of the metal is a

critical determinant in toxicity evaluation. Experiments

have been undertaken to study whether cinnabar was

converted to methyl mercury by human intestinal bacteria

(Zhou et al. 2010). Cinnabar was incubated with human

intestinal bacteria, and analyzed by gas chromatography–

mass spectrometry (GC-MS) for the formation of methyl

mercury. Cold vapor atomic absorption spectrometry was

used to analyze the content of mercury in the bacterial

media. The results revealed that no methyl mercury was

formed in the bacterial media, although a small amount of

Hg was released in the flora medium. The results showed

that cinnabar might be transformed into mercuric polysul-

fides rather than methyl mercury under gut flora conditions

(Zhou et al. 2010). The molecular mechanism by which

HgS may exert its pharmacological action is not yet clear.

Mercuric sulfide is insoluble and less toxic in vivo, but has

been proved to be toxic to the central nervous system.

According to previous studies, both cinnabar and mercuric

sulfide at a high dose of 1 g/kg induced dysfunction of the

vestibular ocular reflex system and disturbed motor per-

formance in guinea pigs, and caused abnormal auditory

brain stem response in mice (Young et al. 2002). It has also

been postulated that cinnabar and mercuric sulfide may

increase nitric oxide generation in the cerebral regulatory

system and decrease Na?/K? ATPase activity. Thus, dose

is a critical parameter in toxic manifestations of any

preparation. This highlights the harmful effects of unso-

licited medications.

The neurobehavioral toxicities of cinnabar (naturally

occurring HgS), mercuric sulfide (HgS), and methyl mer-

cury (MeHg) on rats have been studied (Chuu et al. 2001).

The results indicated that MeHg and cinnabar irreversibly

inhibited Na?/K? ATPase activity in the cerebral cortex

whereas HgS reversibly inhibited Na?/K? ATPase activity.

This suggests that insoluble HgS and cinnabar can be

absorbed from the gastrointestinal (GI) tract and distributed

to the brain (Chuu et al. 2001). Studies on neurotoxic

effects of MeHg and HgS have revealed that HgS

Fig. 2 Stages of sulfur purification: a sulfur with butter in a pan; b molten sulfur and butter; c quenching of sulfur in milk

Fig. 3 Kajjali preparation

Arch Toxicol (2012) 86:831–838 835

123

reversibly delayed the recovery of suppressed compound

muscle action potentials and inhibited sciatic nerve Na?/

K? ATPase activity, whereas, MeHg had an irreversible

effect (Chuu et al. 2007). The ototoxic effect of cinnabar in

rats was studied in the auditory brain stem response (ABR)

during 2–10 weeks administration at 10 mg/kg/day. The

results showed that the mercury content of brain stem

significantly increased, accompanied by gradual progres-

sive abnormality of ABR during 4–10 weeks of cinnabar

administration. The incidence of hearing impairment

occurred more in male mice. An altered Na?/K? ATPase

activity, increase of lipid peroxidation, and decrease of

nitric oxide levels were observed. Moreover, accumulation

of mercury in brain stem was found to be greater in male

mice. An amount of 10 mg/kg/day is equivalent to a clin-

ical dose, which produced ototoxicity after long-term

exposure. The study has also opened up the possibility of

gender difference in neurotoxic effects, which needs to be

investigated for all mercury-based preparations (Huang

et al. 2008).

The neuropharmacological mechanism of cinnabar was

studied wherein an elevated plus maze test was used to

evaluate the anxiolytic effect of cinnabar on anxiety-like

behaviors in mice (Wang et al. 2007). The results indicated

that cinnabar possessed anxiolytic effects after chronic

administration through a per oral route at effective doses in

association with the declined brain serotonin or 5-hydroxy

tryptamine (5-HT) level. Cinnabar showed no effect on the

5-HT metabolism pathway (Wang et al. 2007). Cinnabar at

oral doses of 50 and 100 mg/kg/day for 10 days signifi-

cantly improved the performance, but at 1,000 mg/kg, a

dose 100-fold higher than the human daily dose, it was

ineffective. This pharmacological action may be attributed

with the decrease in serotonin levels in mouse brain, but

the dose-dependent relationship is not clear. In mice, a low

dose of cinnabar (10 mg/kg/d) for 11 weeks of continuous

administration reduced the locomotor activity and

increased the pentobarbital sleeping time, suggesting sed-

ative or hypnotic effects (Liu et al. 2008).

The effect of an herbal formulation containing HgS on

Swiss albino mice was studied, and the results showed that

the drug, even at doses 5–10 times higher than the normal

dose (20–40 mg/100 g of mice), did not show any adverse

effects (Upadhyay et al. 2008). Histopathological studies

did not reveal any toxic effects of the drug. Genotoxic

evaluation of HgS-containing Ayurvedic formulations

using micronucleus and comet assay on rats have been

carried out (Sathya et al. 2009). The investigation revealed

no incidences of genotoxicity, in terms of micronuclei

induction or DNA damage in animals treated with Kajjali

bhasma (predominantly meta-cinnabar), which re-empha-

sized its safety despite its trace mercury content (Sathya

et al. 2009). Mahayograj guggulu, an Ayurvedic medicine

containing 48 g mercuric sulfide, was administered to

Charles Foster strain albino rats at the doses of 54, 270, and

540 mg/kg, with 54 mg/kg being equivalent to a human

therapeutic dose. Mahayograj guggulu was found to be

safe at all dose levels, although heavy metal estimation was

0.07 lg/g for mercury (Lavekar et al. 2010).

Toxicity in humans after consumption of traditional

medicines containing mercuric sulfide has been reported

(Kew et al. 1993). After consumption of red-brown-colored

pills, which primarily consisted of mercuric sulfide, a

32-year-old Asian man suffered from diarrhea, sweating,

tremor of the hands, and hypertension. Neurological

examination revealed reduced sensation in both feet.

Mercury concentration in the urine was found to be

105 lg/L 12 weeks after his last exposure to the medicine.

Such cases of mercury poisoning from ethnic medicines

indicate inappropriate preparation methods resulting in

exposure to inorganic mercury. In another report, an

87-year-old man developed a dry cough, fever, and dysp-

nea after inhaling mercury vapors from heated cinnabar,

which was prescribed for treating foot ulcers. Penicillamine

and 2,3-dimercapto-1-propanesulfonic acid (DMPS) was

administered as chelation therapy. Despite the therapy, the

patient died 39 days after being exposed to mercury vapors

(Ho et al. 2003). This is a classic case proving that mercury

vapors are more toxic than elemental mercury. The dis-

crepancies between the toxic manifestations in animal

models and human subjects cannot be attributed to a single

factor. The differences in absorption, distribution, metab-

olism, and excretion (ADME) characteristics, immune

response, diet, physical activity, and tolerance limits that

exist between animals and humans complicate any possible

extrapolation of the safety and toxicity data between the

two. Another hurdle in the evaluation of toxicity of these

preparations in humans is the lack of documented reports

and absence of long-term follow-ups in patients consuming

these preparations.

Pharmacokinetics and postulated mechanisms

Cinnabar contains more than 96% a-HgS and methylation

of cinnabar by microbes in the gut is impossible because

the poorly soluble HgS can hardly release mercury ions in

water. Herbo-metallic preparations involve conversion of

the metal into its mixed oxides. It is believed that the

zerovalent metal state is converted to a higher oxidation state.

This, in turn, completely destroys its toxic nature through

transformations into forms that can imbibe medicinal

properties into it (Sathya et al. 2009). However, free metal

ions have well-established toxicity profiles, and hence it is

probably the complexed forms that are not toxic. Though

some reports have indicated the possibility of existence of

836 Arch Toxicol (2012) 86:831–838

123

metal ion complexes in the herbo-mineral preparations, no

conclusive evidence has so far been presented, which is the

major stumbling block in the global acceptance of these

preparations.

The distribution pattern of mercury in humans is similar

to that of inorganic mercurials (Liu et al. 2008). Kidney is

the major organ where the concentration of mercury is

found to be high. Mercury salts undergo renal uptake by

two routes: initially, from luminal membranes in proximal

tubules to form cysteine S–conjugates (Cys–S–Hg–S–Cys),

and later through organic anion transporters from the

basolateral membrane (Bridges and Zalups 2005). The

blood–brain barrier and placenta do not allow the passage

of inorganic mercury, but a small portion of absorbed

inorganic mercury can be exhaled as mercury vapor due to

reduction in tissues. A significant portion of mercury vapor

has also been found to cross the blood–brain barrier

(Klaassen 2001). However, it has been reported that oral

administration of cinnabar results in its distribution in

brain, especially to the cerebral cortex and cerebellum

(Yen et al. 2002). Therefore, it is evident that the contro-

versy surrounding the toxicity of traditional medicine

preparation stems from the lack of systemic investigations

on their interactions with biological systems. The choice

and design of the experiments, the duration, route of

administration, concentration, and knowledge about the

composition of the preparation, are all critical parameters

in pharmacokinetic evaluation.

Conclusion

Most of the studies conducted thus far on mercury-based

traditional medicine preparations in experimental animals

have been short-term toxicity studies with use of high doses

of HgS, which cannot be correlated with humans. Variations

in therapeutic doses are recommended by practitioners for

different ailments. Practioners in traditional medicines adopt

a holistic approach to treatment and consider the physio-

logical aspects of an individual along with the type of disease

and stage of presentation. Diet restrictions also contribute to

alterations in the pharmacokinetics, and thus labeling a tra-

ditional medicine preparation as toxic based only on the

metal content seems inappropriate. However, in-depth and

systematic investigations are not available for these prepa-

rations. Pre-clinical studies are needed after conversion of

the human therapeutic dose to an animal dose, and both

short-term and long-term toxicity have to be evaluated.

Significant and substantial amount of data through these

studies can provide a platform for designing human clinical

trials. Even though cinnabar and ‘‘Rasasindura’’ have been

used for centuries in traditional medicine, pharmaco-vigi-

lance never existed then and does not even prevail in the

modern era. The need for patient follow-up after counseling

and drug therapy was rare in earlier times, and even now it is

not followed stringently. Hence, scientific evidence is lack-

ing to confirm the safety and efficacy of these drugs. Another

unexplored facet, which could affect the efficacy and toxicity

of such preparations, are drug-drug interaction that occurs

when they are given in combination with other herbal

preparations. The fact that mercury sulfide is insoluble and

does not get absorbed through blood circulation eliminates

its chances of providing therapeutic benefits, since it may not

react at all with the cell receptors. However, incorporation of

herbal ingredients in these preparations may alter the cell

uptake, distribution, and elimination profile as well as the

therapeutic properties. No pharmacotherapeutic studies exist

to analyze the benefits of these drugs. Shortcomings in

choice of animal models and proper design of experiments to

assess toxicity have hampered the risk assessment of these

traditional preparations, and hence there is a requirement for

more comprehensive studies to understand the ramifications

of these therapeutic processes.

Acknowledgments We would like to thank Drugs and Pharma-

ceuticals Research Programme (VI-D&P/267/08-09/TDT), Depart-

ment of Science and Technology, New Delhi. We gratefully

acknowledge the Nano Mission Council (SR/S5/NM-07/2006 & SR/

NM/PG-16-2007) and to SASTRA University for the infrastructure

and support.

Conflict of interest All the authors declare that they have no con-

flict of interest.

References

Albers JW, Kallenbach LE, Fine LJ, Langolf GD, Wolfe RA,

Donofrio PD et al (1988) Neurological abnormalities associated

with remote occupational elemental mercury exposure. Ann

Neurol 24:651–659

Belle LP, De Bona KS, Abdalla FH, Pimentel VC, Pigatto AS,

Moretto MB (2009) Comparative evaluation of adenosine

deaminase activity in cerebral cortex and hippocampus of young

and adult rats: effect of garlic extract (Allium sativum L.) on

their susceptibility to heavy metal exposure. Basic Clin

Pharmacol Toxicol 104:408–415

Bridges CC, Zalups RK (2005) Molecular and ionic mimicry and the

transport of toxic metals. Toxicol Appl Pharmacol 204:274–308

Chandramouli R, Thirunarayanan Mukeshbabu, Sriram R (2010)

Designing toxicological evaluation of Ayurveda and Siddha

products to cater to global compliance—current practical and

regulatory perspectives. J Pharm Sci Res 2:867–877

Chuu JJ, Liu SH, Shiau SYL (2001) Effects of methyl mercury,

mercuric sulfide and cinnabar on active avoidance responses,

Na ?/K ? -ATPase activities and tissue mercury contents in

rats. Proc Natl Sci Counc ROC(B) 25:128–136

Chuu JJ, Liu SH, Shiau SYL (2007) Differential neurotoxic effects of

methyl mercury and mercuric sulfide in rats. Toxicol Lett

169:109–120

Dutt UC (1877) The materia medica of the hindus. Thacker, Spink,

Calcutta

Arch Toxicol (2012) 86:831–838 837

123

Flora SJS, Mehta A, Gupta R (2009) Prevention of arsenic-induced

hepatic apoptosis by concomitant administration of garlic

extracts in mice. Chem Biol Interact 177:227–233

Graeme KA, Pollack CV (1998) Heavy metal toxicity, part

I: arsenic and mercury. J Emerg Med 16:45–56

Ho BSJ, Lin JL, Huang CC, Tsai YH, Lin MC (2003) Mercury vapour

inhalation from Chinese red (Cinnabar). J Toxicol ClinToxicol

41:75–78

Huang CF, Hsu CJ, Liu SH, Shiau SYL (2008) Ototoxicity induced by

cinnabar (a naturally occurring HgS) in mice through oxidative

stress and down-regulated Na ?/K ? -ATPase activities. Neu-

roToxicol 29:386–396

Hung OL, Shih RD, Chiang WK, Nelson LS, Hoffman RS, Goldfrank

LR (1997) Herbal preparation use among urban emergency

department patients. Acad Emerg Med 4:209–213

Kew J, Morris C, Aihie A, Fysh R, Jones S, Brooks D (1993) Arsenic

and mercury intoxication due to Indian ethnic remedies. Br Med

J 306:506–507

Klaassen CD (2001) Heavy metals and heavy-metal antagonists. In:

Hardman JG, Limbird LE, Gilman AG (eds) The pharmacolog-

ical basis of therapeutics. McGraw-Hill, New York

Kumar A, Nair AGC, Reddy AVR, Garg AN (2006) Bhasmas: unique

Ayurvedic metallic-herbal preparations, chemical characteriza-

tion. Biol Trace Elem Res 109:231–254

Lavekar GS, Ravishankar B, Gaidhani S, Shukla VJ, Ashok BK,

Padhi MM (2010) Mahayograj guggulu: heavy metal estimation

and safety studies. Int J Ayurveda Res 1:150–158

Liu J, Shi JZ, Yu LM, Goyer RA, Waalkes MP (2008) Mercury in

traditional medicines: is cinnabar toxicologically similar to

common mercurials? Exp Biol Med 33:810–817

Meriam JL, Kraige LG (1986) Engineering mechanics Vol 2:

dynamics. Wiley, New York

Niir Board of consultants and Engineers (2003) Handbook of Unani

medicines with formulae, processes, uses and analysis. Asia

Pacific Business Press, Delhi

Paul S, Chugh A (2011) Assessing the role of Ayurvedic ‘Bhasms’ as

ethno–medicine in the metal based nanomedicine patent regime.

J Intell Prop 16:509–515

Saper RB, Phillips RS, Sehgal A (2008) Lead, mercury and arsenic in

US- and Indian–manufactured Ayurvedic medicines sold via the

internet. J Am Med Assoc 300:915–923

Sarkar PK, Das S, Prajapati PK (2010) Ancient concept of metal

pharmacology based on Ayurvedic literature. Ancient Sci Life 29:1–6

Sathya TN, Murthy B, Vardhini NV (2009) Genotoxicity evaluation

of certain Bhasmas using micronucleus and comet assays.

Internet J of Altern Med 7

Selvaraj S, Krishnaswamy S, Devashya V, Sethuraman S, Krishnan

UM (2011) Investigations on membrane perturbation by chrysin

and its copper complex using self assembled lipid bilayers.

Langmuir 27:13374–13382

Selvaraj S, Krishnaswamy S, Devashya V, Sethuraman S, Krishnan

UM (2012) Synthesis, characterization and DNA binding

properties of rutin-iron complex. RSC Advances 1–6

Shastri RSV (1962) Aushadi yoga sangraha. Trichy Ayurveda Unani,

Tiruchirapalli

Singh SK, Chaudhary A, Rai DK, Rai SB (2009) Preparation and

characterization of a mercury based indian traditional drug Ras-

Sindoor. Indian J Trad Knowl 8:346–351

Swamy GYSK, Ravikumar K (2010) Characterization of Indian

Ayurvedic herbal medicines for their metal concentrations using

WD-XRF spectrometry. X-Ray Spectrom 39:216–220

Tontisirin K, Nantel G, Bhattacharjee L (2002) Food-based strategies

to meet the challenges of micronutrient malnutrition in the

developing world. Proc Nutr Soc 61:243–250

Upadhyay PS, Kumar M, Singh BM (2008) An experimental study

on shvasa-kasa-chintamani-rasa. J Res Educ Indian Med

2:21–26

Wang Q, Yang X, Zhang B, Yang X, Wang K (2007) The anxiolytic

effect of cinnabar involves changes of serotonin levels. Euro J

Pharmacol 565:132–137

Wu Q, Lu YF, Shi JZ, Liang SX, Shi JS, Liu J (2011) Chemical form

of metals in traditional medicines underlines potential toxicity in

cell cultures. J Ethnopharmacol 134:839–843

Yen CC, Liu SH, Chen WK, Lin RH, Lin-Shiau SY (2002) Tissue

distribution of different mercurial compounds analyzed by the

improved FI-CVAAS. J Anal Toxicol 26:286–295

Young YH, Chuu JJ, Liu SH, Shiau-Lin SY (2002) Neurotoxic

mechanism of cinnabar and mercuric sulfide on the vestibulo-ocular reflex system of guinea pigs. Toxicol Sci 67:256–263

Zang CX, Lippard SJ (2003) New metal complexes as potential

therapeutics. Curr Opin Chem Biol 7:481–489

Zhou X, Wang L, Suna X, Yang X, Chen C, Wang Q, Yang X (2010)

Cinnabar is not converted into methyl mercury by human

intestinal bacteria. J Ethnopharmacol 135:110–115

838 Arch Toxicol (2012) 86:831–838

123