Abstract
Ayurvedic and Siddha medicinal preparations
containing mercury have been used over centuries in India. The recent WHO
guidelines on the use of mercurials as well as actions by other international
organizations into eliminating mercury in all forms have put the people
practicing Rasa Shastra in a quandary. Active research in the mechanism of
curative actions of mercurials is very much essential, to have widespread
acceptance of the ancient practice. The toxicity of a substance depends on its
bio-availability; the chemical form in which it is present and the biochemical
reactions it participates. Mercury is usually administered as mercuric sulfide (Rasasindura or Linga Chendooram) which has a KSP
value of 10–54. Despite this
extreme insolubility, how mercury becomes bio-available under enzymatic
conditions needs to be studied. Its bioaccumulation in critical organs and
excretory pathways are to be ascertained. Research is also needed to establish
whether Rasasindura or equivalent
medicines induce the (excess) synthesis of sulfur containing biomolecules in
human systems, which act as cell protectors against free radical-induced cell
damage. The antioxidants themselves could be the curative agents; mercury being
just a catalyst. It may also be possible that the exposure to mercury, even in
very small amounts, could lead to the synthesis of specific metallothioneins in
the human system, helping to detoxify the mercury exposure. The author is of
the opinion that Ayurvedic practitioners/researchers should carry out long-term
follow-up studies on human patients. The superiority of mercury based Ayurvedic
preparations, as against modern allopathic medicines, in providing rapid and
long lasting cure for specific diseases needs to document and published. In the
absence of such supportive research literature, the use of mercury will become
untenable, even for medicinal purposes.
Introduction
Ayurvedic and Siddha medicinal preparations
containing mercury have been prepared and used over centuries in India. Similar
preparations exist in China and Japan too. The preparatory methods are based on
various classical texts and administered to patients along with various
adjuvants depending on the type of disease. The types of diseases treated with
mercurials range from tuberculosis to diarrhea. The mercury-containing
preparations are many: Ayurveda has Kajjali, Parpati, Rasasindura, and Makaradhwaja, (which are
essentially a combination of mercury and sulfur) and some medicines like Garbhapala Rasa which have
lower mercury contents. Similar mercury medicines like Linga Chendooram exist in
Siddha traditions.
All forms of mercury (vapor, inorganic salts, and organic forms) are considered as toxic to human beings and in-depth reports exist detailing the deleterious effects of these various forms both in animal studies and in humans inadvertently exposed to mercury. The Minamata episode in Japan and the poisonous effects on children born to mothers who had consumed organic mercury contaminated wheat in Iraq are well documented and the recent outcry in the USA on the use of Thimerosal as a preservative of vaccines and the suspected link to autism in children, is the latest in the campaign against the use of mercury in any form and at any dose levels for medicinal purposes. The WHO mentions that exposure to mercury – even small amounts – may cause serious health problems, and is a threat to the development of the child in uteroand early in life; mercury may have toxic effects on the nervous, digestive and immune systems, and on lungs, kidneys, skin, and eyes; and mercury is considered by WHO as one of the top 10 chemicals or groups of chemicals of major public health concern (WHO fact sheet No. 261, updated September 2013). Studies have indicated at least in animal experiments that mercury affects the nervous system and has been shown to accumulate in kidneys leading to atrophy and failure. The WHO/JECFA has set a limit of 4 µg/kg bw for inorganic mercury.[1] This limit has been arrived at based on experiments
using mercuric chloride (HgCl2), a soluble salt of mercury. The PTWI for methyl mercury it is 1.6 µg/kg bw. The literature is also replete with toxicity suffered by patients who have consumed Ayurvedic preparations containing heavy metals particularly, mercury and lead. It is to be noted; however, that majority of these cases are due to self-medication by the people and not under conditions of supervision under an Ayurvedic doctor.
It is in this background, the claim of Ayurvedic and Siddha
practitioners on the safety of their preparations containing mercury under
therapeutic doses is viewed with suspicion by modern medicine. However, many
journal publications in recent times have appeared, based on animals (mice,
rats, and dogs), reporting on the nontoxic effects of Ayurvedic and Siddha
mercurial preparations and changes in biochemical parameters. These studies can
help evolve therapeutic doses for humans.
The Need for Complete Chemical and Physical Characterization
of the Mercurials
Much of the fear induced on the use of mercury is
due to the inability of the most common analytical methods, which report on the
total elemental concentration,[2] (X-ray fluorescence, atomic absorption spectroscopy
[AAS], inductively coupled plasma atomic emission spectroscopy [ICP-AES]), and
not on the exact chemical form in which mercury is present. The exact chemical
form in which mercury is present has also to be analyzed by X-ray diffraction
(XRD), which provides the information on crystalline structure and X-Ray
photoelectron Spectroscopy (XPS), which provides information on the oxidation
state of the material, (especially where mercuric sulfide [HgS] is a major
constituent) and infrared spectroscopy/fourier transform infrared spectroscopy
for the presence of organics. The presence of free mercury/free sulfur should
also be ascertained in the preparations. Toxicity perception based total
concentration levels can be misleading because the toxicity of a substance
depends on its bio-availability; the chemical form in which it is present, the
biochemical reactions it participates, and the dose combined with age and other
medical conditions of the patient.
Bio-Availability of Mercury
The ancients brilliantly overcame the problem of mercury toxicity by severely reducing its bioavailability through the use of sulfur. They purified the raw mercury and sulfur through many steps using plants and salts and standardized the administered form of mercury as HgS, one of the least soluble substances. The KSP of HgS is 1 × 10–54. Thus, the quantum
of mercury ions that would be available on the administration of mercury as
sulfide can be much below the threshold of toxic limit (the use of arsenic, a
toxic substance, again used as a highly insoluble sulfide, Rasamanikya, is illustrative
of the concern of the ancient sages over the detoxification efforts needed,
before declaring a substance as a medicine). However, HgS may be more soluble
in the gastrointestinal (GI) tract due to the action of digestive enzymes,
changing pH conditions and complexation with other biomolecules present in the
food. This has to be determined upon by experimentation.
Experiments on the bio-availability of various
forms of mercury indicated the following percentages of absorption: Cinnabar
<0.2% in GI, mercury vapor 80% in lungs and <0.01% in GI, HgCl2 7–15% in GI and methyl mercury >95% in GI. The mercury thus adsorbed is found distributed to liver, kidney, and spleen while mercury vapor and methyl mercury result in accumulation in the brain.[3] Autopsy studies on diseased humans in Greenland,
exposed to mercury through food, have shown accumulation in kidney, spleen and
liver, with kidney exhibiting highest accumulation.[4] Neurotoxicity induced by cinnabar in guinea pigs has
also been reported.[5]
However, in the Indian context, all the animal studies have
invariably reported that Rasasindura has not been
found toxic under therapeutic doses;[6] even though no analytical studies on the accumulation
of mercury in different organs (in animal studies) have been published from
major Indian institutions. Reviews on beneficial applications of Rasasindura, on human patients,[7] as well as types of diseases it has been used have been
published.[8]
This dichotomous situation needs to be thoroughly examined to
establish the safety associated with the Indian practices.
Standardization of Preparation and Composition
Assay of purified mercury
Standard texts uniformly mention some 8 stages of
purification or mercury.[9] These steps are meant to remove natural impurities in mercury and make it “potent” but no high-quality assay on the purity (stoichiometrically) obtained after the 8 steps has been reported. Some authors surmise that while the inorganic metallic impurities are removed many organic entities get bound to the mercury up to even 4% by weight. There is also a mention that mercury purified by destructive distillation of Cinnabar after some specific treatment with plant juices can be used for medicinal preparations without the 8 steps. It is very essential to assay the purity of the mercury meant for medicinal preparation including the presences of other organics derived from treatment with plant extracts. Boiling point investigation and chromatographic techniques will help.
Purification steps have also been prescribed for sulfur which
is more or less standard among all practitioners.
Understanding the process of preparation of Kajjali
Intimate mixing of purified mercury and sulfur to
prepare the Kajjali seems to be
the first step in the preparation of many mercury-based preparations, except
for the use of mercurous chloride (Rasapushpa) and Hg2 Cl2 (Rasakarpura) in very small
amounts in certain cases. The compound of mercury and sulfur is prepared in
many ways, but one always finds the use of excess sulfur in the preparation of
a form called Kajjali, more than
required for the stoichiometric preparation of HgS (approximately sulfur at 1/6th of the weight
of mercury). Classical texts have recommended the use of 1:1, 1:6 or even 1:16
of mercury and sulfur by weight. Why this emphasis on excess sulfur? The Kajjali itself is
used as a simple medicine or forms the basis of preparations such as Parpati, Rasa Sindura,
Makaradwaja (the most
celebrated of all Ayurvedic medicines). Similar Siddha preparations are named
as Linga Chendooram and Poorna Chandrodayam. Many recent
reviews on the preparations and uses of these are found in literature.
In a study related immobilization and disposal of
mercury, detailed observations on the process of mixing mercury and sulfur have
been reported, using XRD and electron microscopy, as a function of grinding
time.[10] The grinding process slowly forms meta-cinnabar (black HgS) and up to 60 min of grinding, globules of mercury could be found to be present, using electron microscopy. After 90 min, free mercury could not be found but the most important observation is the formation of particles containing 2–15 weight% of mercuric oxide after 120 min of grinding. It is also found that the HgS particles are surrounded by sulfur particles. Aqueous extracts of this sample yielded <5 µg/L leachable mercury.
The study above used Hg: S in 1:1 weight proportion but in
Ayurvedic literature one finds the mention of 1:6 and higher ratios of mercury
and sulfur in the preparation of Kajjali. The idea could be
to prevent oxidation as well as to make available more sulfur. Studies similar
to the above should be done in so as to establish the desirable/optimum quantum
of grinding and prevention of oxidation of the mercury due to over grinding
under exposure to oxygen. It may possible to use mechanical grinders under an
inert atmosphere.
Mercury Speciation Studies in Body Fluids and Tissues
The major species of mercury one usually
encounters are the elemental (vapor), inorganic (Hg[I] and Hg[II]) and organic
forms (methyl and ethyl mercury). Mercury vapor can be very easily determined
by using cold vapor AAS (CVAAS) at nanogram levels and when combined with ICP-mass
spectrometry (ICP-MS), can be determined at parts per trillion levels.[11] Inorganic mercury is reduced to elemental mercury and
then determined using CVAAS or ICP-MS. Methods are available for the online
separation of inorganic and organic (methyl) mercury and sequential
determination of both in a single experimental step at parts per billion levels.[12] All the methods have been standardized and are routine
in many advanced analytical laboratories.
The uptake and distribution of mercury through the use of
mercurial can be easily determined through the analysis of body whole blood and
serum samples. The excretion can also be studied through the analysis of urine
and fecal matter which can kind of give a mass balance of the dose administered
and the mercury retained in the system. Such studies can go a long way in
determining the variation in the biological sorption of mercury when
administered as an insoluble sulfide (Rasasindura/Makaradwaja/Linga Chendooram) or as ionic salts
(chlorides of mercury). The enhanced sensitivity of the modern analytical
techniques enable the determination of mercury in biopsy samples of kidney,
liver, etc., without having to sacrifice the animals in such experiments.
In humans, it is possible to analyze head hair before, during
and after the stoppage of the mercury-based medicines, to follow-up
qualitatively, the sorption and excretion of mercury.
Analysis of Mercurials Prepared With Sulfur
For over a decade, our laboratory, the National
Centre for Compositional Characterisation of Materials, BARC, Hyderabad, has
been involved in the development of a standardized analytical procedure for
many mineral and metallic Ayurvedic medicines, as part of our association with
CCRAS in this activity. Mercurials such as Rasasindura, Makaradwaja and Rasa Gandhi Mezhugu (a Siddha
preparation) have been analyzed for the total content of mercury, sulfur and
trace elements based on solution-based techniques such as ICP-AES and AAS.
Scanning electron microscopy/EDAX has been used for rapid screening of the
major element contents. XRD and XPS have been utilized to find out about the
major crystalline phases and the oxidation states of the major elements,
respectively. These standardization efforts have been shared with the concerned
agencies. Rasasindura samples from many institutions were found to contain close to 81–83% of mercury and 14–16% of sulfur. The use of similar multi-technique approaches for the analytical characterization of Siddha medicines have been reported,[13] which is very encouraging.
However, there exist in literature, compounds named as Rasasindoor with only 9%
HgS and having a lot of organic matters still intact.[14] How the organics could survive the extremely high
temperatures used in the synthesis is a mystery! A study has reported that Siddha Makradwaja has only
mercury and sulfur but does not contain even traces of any other element.[15] However, Makaradwaja samples received from Gujarat Ayurved University, analyzed in our lab, have been found to contain gold at 20–270 ppm [Table 1]. It has been explained that the variation of gold content
depends on the type of gold used [16] or the extent sulfur used.[17] Some preparations even report Poorna Chandrodayam (a
preparation similar to that of Makaradwaja) having close to
9% gold![18]
Table
1: Analysis of mercury and gold in Makaradwaja (ICP-AES)
It is essential standard methods for preparations
and standard nomenclatures should be arrived at, well documented and be adopted
in pharmaceutical literature, for specific medicines, pertaining to the
discipline.
Analysis of Free Mercury and Sulfur in the Medicines
It has been our observation, in the analysis of Rasasindura and Makaradhwaja, that the contents
of the major constituents do not add up to 100%. The qualitative analysis did
not identify any extra constituents. This leads to the suspicion that there
could be free sulfur embedded onto the matrix of the HgS. In a study mentioned
earlier,[13] based on EDAX
it is found that the Linga Chendooram sample could have up to 5.8% excess sulfur than
calculated for the total mercury being in HgS form. Methods exist to analyze
free sulfur [19] which, when used will help investigate the thoroughly
the Kupipakwa procedure,
used by many for HgS based preparations. Free sulfur, if found, can help
explain the nontoxic nature of the mercurial as prepared and used by Indian
practitioners, as can be surmised in the subsequent sections of this paper.
Further Research Studies Needed to Make Mercurials Acceptable
on Par With Modern Medicines
The following suggestions are put forward for the
consideration of people working in biochemistry, pharmacology, and pharmacovigilance.
The curative action of mercurials will have to be explained
on molecular action basis. Certain actions like anti-bacterial activities are
explained based on cell wall damage or suppression of antioxidant activity when
soluble mercurials are used. However, when nominally insoluble sulfide is used,
it is very essential to quantify the dissolution and bioavailability in the GI
track in human studies. That orally administered Rasasindura or Makaradhwaja is
therapeutically active indicates that mercury is absorbed in the GI tract and
reaches the target organ/tissue. The mechanism of such transfer needs to be
understood first.
The Role of
Adjuvant (Anupama)
Each mercurial preparation is administered along
with a specific adjuvant, depending upon the disease.[8] Current
knowledge enables us to understand that many of these adjuvants, themselves
have many anti-oxidant molecular entities. Why the ancients chose a specific Anupananeeds to be
researched and explained, in medical parlance.
Role of Metallothioneins in Reducing/eliminating Mercury
Toxicity
Metallothioneins are small molecular weight
peptides containing close to 20 and above cysteine amino acid units and are
considered to play a central role in the physiology of detoxification of heavy
metals.[20] The SH group very strongly complexes mercury. Heavy
metals induce the synthesis of phytochelatines (cysteine containing peptides)
in plants; similarly it may be possible that the exposure to mercury, even in
very small amounts, could lead to the synthesis of specific metallothioneins in
the human system, helping to detoxify the mercury exposure. Metallothionein has
been shown to be responsible for binding most of the mercury in rat kidney when
HgCl2 was administered.[21] Further research in the mechanism of mercury
detoxification through metallothioneins is very much essential.
Whether Antioxidant Synthesis Is Induced by Consuming
Mercurials
As mentioned earlier, some mercurials like Kajjali have excess
sulfur, and even Linga Chendooram is reported to contain free sulfur, perhaps trapped in
the crystal lattice of HgS. It is well known that sulfur is a very important
nutrient and many biomolecules such as methionine, cysteine, cystin, taurine,
and antioxidant enzymes such as glutathione (GSH) and many more, contain sulfur.[22],[23] Thus, research is needed to establish whether Rasasindura or equivalent
medicines induce the (excess) synthesis of these sulfur-containing biomolecules
in human systems. Antioxidants are the cell protectors against free
radical-induced cell damage and it is quite possible that the rejuvenating
effects and the reversal of aging effects, alluded to Makaradhwaja could be due
to sulfur consumed along with. Detailed biochemical analyses will be the key to
answer these questions. The antioxidants themselves could be the curative
agents while mercury could serve as a transient catalyst. Enhanced production
of GSH production in the kidney due to HgCl2 orally given
than when HgS (mercuric salts of very different solubility) was administered,
has been observed.[24]
A Brief Summary of Works Carried Out at National Centre for
Compositional Characterisation of Materials, Hyderabad
- Toxicity of Rasasindura (HgS)
and Rasamanikya (arsenic trisulfide) were evaluated
through standard bacterial study procedures. While Rasasindura was
found not to show any bactericidal effects, inorganic mercury (Hg 2+)
species exhibited high toxicity. At 5 ppm of Hg +2completely
inhibited the growth of Pseudomonas aurgenosa and yeast
and at 1 ppm, a twofold and 4 fold decrease in the viability of P.
aurgenosa and yeast respectively, have been observed. Rasamanikya did not show any toxicity at 10 and 20 µg but showed slight toxicity at 30–50 µg levels, but much lower than the toxicity exhibited by gentamycin (5 µg) [Table
2]
- A study in our laboratory on the anti-oxidant
status of mice fed with Rasamanikya has shown that the
superoxide dismutase, GSH, and glutathione peroxidase (GPx) levels had
shown an increase in the liver and showed a significant decrease in liver
TBARS thus ensuring cell protection. In the case of the kidney, the GPx
levels were much reduced at the double dose level as well as elevation in
the kidney TBARS levels indicated that at double dose levels the kidneys
could be impaired. Such assessments are planned for Rasasindura,
but other research groups have reported on its nontoxic nature based on
biochemical parameters and histopathology observations [Figure
1].
Table 2: Toxicity studies on
three bacterial species w.r.t. Rasamanikya (As2S3)
Figure 1: Effect of Rasamanikya on
antioxidant status of mice: An in vivo study
These preliminary studies clearly indicate that
the synthesis of antioxidant molecules to get triggered on the exposure to
toxic elements but the response in liver and kidney are different. Much more
detailed studies are the need of the day.
Conclusions
Controlled experimentation with complete records
as well as follow-up of patients over a long period is essential when
mercurials have been used to treat specific diseases. The use of modern
analytical techniques is a must to characterize the drug, its interaction with
specific body tissues/organs and to provide a molecular basis for the curative
aspects. In the task of bringing into the mainstream, the unutilized potential
of the ancient science of healing, a close interaction of practitioners of
traditional Indian Systems of Medicine (ISM) and Allopathy and involvement of
national institutions is a must. Regional institutions with a suite of
sophisticated analytical instruments catering to the needs of ISM would go a
long way in supporting generating validated data.
The author is of the opinion that Ayurvedic
practitioners/researchers should carry out long-term follow-up studies on human
patients, and publish them in standard medical literature, rather than in
in-house or obscure journals. Therapeutic efficiencies of mercury based
preparations and modern Allopathic medicines in providing rapid and long
lasting cure for specific diseases need to be compared, documented and
published.
Acknowledgments
The author wishes to thank Dr. Aruna Jyothi Kora
and Ms. Lori Rastogi, (NCCCCM, Hyderabad) who have shared their works on
biochemical studies, which are briefly described in this article.
Financial
support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References Please
refer to PDF file of article.
To
read article in PDF format.
About Author: Ex-Head, National Centre for Compositional Characteristization of Materials, Hyderabad, Telangana, India.
Article
available online/offline on: AYU, Vol. 36, Issue-2, April-June 2015, Page
no.118-124, for more details please visit: www.ayujournal.org
Address for
correspondence: Dr.
J Arunachalam, 302, Jyothi Pearl Apts, Srinivassa Nagar, Kapra, ECIL
Post, Hyderabad - 500 062, Telangana, India.
No part of this article may be reproduced in full or part without written permission of the Ayu Journal who can be contacted at ayujournal@yahoo.com