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-----------------------Bhopal Gas Tragedy: Scientific Challenges & Lessons for Future.
Dr. S. Sriramachari, MD, DSc, FNA.
Honorary Advisor, ICMR and Former INSA Honorary Scientist
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INTRODUCTION:
Even after the lapse of 20 years, BGT of 3rd December 1984 due to the
sudden leak of 42 tons of Methyl Isocyanate (MIC) is unparalleled in the annals of
history of chemical disasters. Over 3000 people died and many more were
condemned to long-term morbidity. The loss of human life and life-long crippling of
many survivors have been.
unprecedented and the sheer magnitude of the
catastrophe in the industry has roused the conscience of the world. In many cases,
the sole bread earner of the entire family died: many have been widowed: and many
of the survivors are either infants or minor children. The medical profession at
Bhopal faced a situation, which few others in their fraternity ever had to in the
annals of history. In the early hours of the morning of 3rd December 1984 hundreds
and soon thousands of innocent people crowded in on the doctors in the Hospitals gasping for breath frothing in the mouth, retching, fear and panic writ on their faces
hoping against hope to cling on to life. The helpless doctors, neither were aware
about the killer gas which had escaped into the air from the Union Carbide India
Ltd. factory, nor could they have an idea about antidotes to be administered. They
did : whatever they could -symptomatic treatment to make the last few minutes on
earth more comfortable for the victims'. As a result of these concerted efforts
including autopsies, toxicological studies, clinical management of the victims and
epidemiological investigations, many positive results have been obtained which have
helped to unravel some of the mysteries of this major industrial disaster.
DEATH RATES:
In the immediate wake of the disaster in the first 48 hrs, the death rate in
some of the worst affected areas ranged as high as 20 per thousand of population.
For the month of December 1984 the death rate was about 24 per thousand as
compared with the national average of 1 per thousand for a ~ corresponding period.
The worst affected victims belonged to the age group less than 5 years, with death
rate of 33 per ", thousand, followed by a figure of 15 per thousand both in the age
group of 15-40 years and above 45 years. Mortality in children and young and active
adults was very high affecting the future of many families. Although all dead bodies
were not brought to the morgue, 311 bodies were received on 3.12.1984 followed by
250 bodies on 4.12.1984. Thereafter the number of dead bodies brought into the
morgue declined. A total of 837 dead bodies were received in the morgue in
December 1984 following the gas disaster. The most poignant of the effects is total
disruption of a large number of families, in some with all children dying, in others
with both parents dying leaving the children as orphans.
Acting promptly, ICMR launched over 25 Research Projects, including two
multi-disciplinary ones on Pathology & Toxicology and Pathophysiology of
inhalation of noxious gases. The real scientific challenges were more than
adequately accomplished, Unlike other disasters involving single chemicals, the
aerosol inhaled by the Bhopal victims contained a mixture of MIC and its trimers &
dimers, as well as aqueous and thermal decomposition products, including HCN.
First a coordinated study by GC-MS technique of the Tank residue as well as the
blood and autopsy tissues of exposees and victims established the involvement of the
chemicals in the human tragedy.
HUMAN AUTOPSY STUDIES:
Within hours of the deadly leak, hundreds perished and scores of dead
bodies started pouring into the morgue. Late Prof. Heeresh Chandra and his
dedicated team at the Medico Legal Institute, Bhopal, subjected them to meticulous
Post-Mortems. He described vividly the "Cherry Red" discoloration of the blood
and lungs, in particular. This unique finding set the pace for a multi-pronged
Toxicological investigation. Indeed, I was fortunate to participate actively in these
studies right from the inception. My colleagues, Dr. H.M.K.Saxena and Dr. Ashok
Mukherjee & Dr. A.K.Jain from the Institute of Pathology also joined the team to
help us in Light & Electron microscopic studies.
Histopathology: Literally, the hundreds of Aut.opsies were categorized into Acute,
Sub-acute and Chronic phases. Apart from the univ~;s-a:i 'o~ar involvement, cough
and severe dyspnoea at rest, which was accentuated on exertion characterized the
"Acute phase". Clinically, the situation was comparable to ARDS (Acute
Respiratory Distress Syndrome). Yet another striking feature was extreme muscular
weakness. Autopsies in this early phase revealed generalized edema and marked
congestion of the viscera, especially of the respiratory tract and the brain. The lung,
which was the most damaged organ, weighed over twice the normal.
Microscopically, there was widespread intra-alveolar & interstitial transudation of
albuminous fluid and emphysematous bullae. Inflammatory changes were minimal.
In fact, at that early stage up to January 1985, while the hazard of severe hypoxia
was recognized, even some Indian scientists envisaged a good prognosis for the
Bhopal survivors, on the analogy of HAPO! It was even doubted whether the severe
pulmonary edema caused by the chemical MIC could really lead to any permanent
tissue damage.
But these hopes were soon belied by the findings in the subsequent "Subacute phase". The lungs showed progressive exudative changes, with varying
degrees of bronchitis, bronchiolitis and widespread pneumonitis. Still later, in the
"Chronic phase", there was evidence of organization and consolidation, with
widespread diffuse interstitial pneumonitis and fibrosis (DIPF & GIPF), clinically
corresponding to COPD. While a small group had persistent damage, surprisingly
enough, a large proportion of people slowly recovered. The brain was edematous to
the naked eye and had extensive hemorrhages, both grossly and microscopically.
Ring hemorrhages and Pericellular and Pericapillary edema were observed under
Light & Electron microscopy. All these features were suggestive of acute anoxic or
histo-toxic damage. A study of several hundred cases in the acute, sub-acute and
chronic phases revealed progressive changes of pulmonary edema and bronchiolitis,
followed by chronic fibrosis. Apart from widespread visceral hemorrhages, cerebral
edema and ‘selective neuronal damage’ indicated ‘acute histotoxic anoxia’
Experimental Studies: Dr. K Jeevaratnam of DRDE, Gwalior and myself
successfully developed a rat model. Following single exposures of MIC or its
derivatives, MA & DMU, over a period of 10weeks, the entire spectrum of lesions,
from pulmonary edema to fibrosis, were reproduced.
Scope for Molecular Biology: It may be added, in parenthesis, that the two
significant observations of BGT viz., massive edema of the lungs and brain and
widespread hemorrhages, are of universal applicability in future chemical disasters.
Detailed experimental studies with the newer tools of molecular biology such as
Interleukin–1 and TNF of the “acute phase response” and adhesion molecule,
ICAM – 1 might explain the pathogenesis of edema and hemorrhage respectively.
The protective role of anti-inflammatory Cytokines, like Interleukin–6 and Heat
Shock Proteins might help, not only in understanding the pathogenesis of such
lesions, but also in developing newer therapeutic remedies in combating such
disasters.
ISSUE OF CYANIDE TOXICITY:
As already stated, a glaring feature of the pulmonary damage was the
"Cherry Red" discoloration of the lung as well as the contained blood. Traditional
and newer causes for the same were explored in a systematic manner
(a) The possibility of Carbon Monoxide as the primary, though transient: cause was
ruled out after preliminary spectroscopic examination.
(b) Hence, Prof. Chandra strongly invoked a possible exposure to HCN (Hydrogen
Cyanide). This resulted in a needless major controversy, in spite of a paper as recent
as 1982 by Blake & Ijadi-Maghsoodi. In fact, subsequent analysis of preserved
blood samples of Bhopal victims also showed elevated cyanide levels.
(c). With a view to explore other causes of cyanide-generating chemicals, detailed
forensic chemical analysis of the “Tank Residue was carried out. CC-MS studies
yielded valuable evidence about the presence of over 20 different chemicals, many of
which could be traced to the bodies of victims.
(d) Recalling the old adage that “the dead teach the living”, the alarming finding of
cherry-red discoloration of lungs, in the initial autopsies, led to the suspicion of
cyanide toxicity. The same was soon confirmed unequivocally by the demonstration
of elevated cyanide levels in the blood and tissues of the victims. The prompt
therapeutic response to NaTS (Sodium Thiosulphate), substantiated the hypothesis,
which was further confirmed by elevated levels of urinary SCN (Thiocyanate), in
individual cases and in "Controlled Double Blind Trials”, before undertaking its
wider use.
(e) Interestingly enough, the marked muscle weakness dramatically improved
indicating pari passu involvement of Myoglobin and/or circulatory disturbances.
(f) Pulmonary Physiology: All relevant studies were carried out concurrently.
Firstly, for over a year, there was marked and sustained elevation of Hb
(Hemoglobin). Secondly, Late Prof. P. S. Narayanan demonstrated significant
alterations in the Blood Gases of 'Acute' cases. Both Arterial and Venous Oxygen
(O2) were lowered surprisingly alongside lowered of Arterial/Venous levels of CO2
(Carbon Dioxide), which did not increase after exercise. However, NaTS therapy
was accompanied by substantial improvement following exercise, in the Oxygen
carrying capacity as well as Venous CO2, both in the Peripheral & Central Venous
Pool.
(g 2-3 DPG(Di Phospho Glycerate) levels were estimated with the help of Shri. K.
Sridharan & Dr. Patil of DIPAS. Initially, the values were found to be elevated to
more than twice the normal, as in cases of HAPO, as if the patient had been exposed
to an f HA (High Altitudes) Environment of about 14,000 feet. .
(h) However, all the aforesaid physiological alterations of the blood caused by MIC
exposure, tended to return to normal with the passage of time
(i) The Phenomenon of Recurrence: But one disturbing fact was the episodes of
periodic recurrence of respiratory symptoms, which often responded to repeat
NaTS therapy with simultaneous elevated urinary SCN. Such a phenomenon could
not be accounted for in the absence of repeated-exposures to HCN.
(j) Carbamoylation: As reported in the literature and urged by Dr. Sriramachari
from the beginning, there was a need to explore possible direct binding of MIC to
Hb and tissue proteins. In view of the phenomenon of recurrence, this line was
pursued more vigorously. With the help of Prof. Ramaiah of AIIMS and later the
DRDE team under Dr. P.K Ramachandran, the binding of MIC to the end-terminal
Valine residues of the Hemoglobin chains was first established. The consequent
failure to pick up CO2, which in turn impaired the release of Oxygen (02), finally
seemed to explain the enigma of the "Cherry Red Discoloration..
(k) Tissue N-Carbamoylation: Extended studies on deceased victims and survivors
in the Bhopal Projects fully confirmed that MIC binds, not only to Hb, but several
other end- terminal amino acids of tissue proteins.
Interestingly, it was found in the initial phases that several 'Erythrocytes
appeared Electron-lucent under EM, suggestive of leaching out of some substance
possibly S-Carbamoylated Glutothione. From a review of the literature, it is well
known that, unlike irreversible N-Carbamoylation, the binding of MIC to
Sulphydryl groups is not only fast but reversible and could act as 'depots' for
'ferrying around' the MIC molecule. Thus, the underlying causes of reversible
muscular weakness and the protracted excretion of thiocyanate might have been
elucidated. Indeed, Baillie and Slatter confirmed such a possibility with the help of
the sophisticated C.I.-M.S. technique.
Unfortunately, due to want of appropriate equipment we could not fulfill our
dream of demonstration of S-Carbamoylation of not only Glutathione but also SHcontaining enzymes like Rhodanese, Cholinesterase and Aldolase of muscle. The
underlying causes of reversible muscular weakness and the protracted excretion of
thiocyanate might explain the unusual type chronic cyanide toxicity. It was
unfortunate that due to lack of access to appropriate equipment, we could not fulfill
our original dream of establishing the "Biochemical Lesion of Bhopal Gas
Tragedy". It would also appear that the Environmental Disaster of Bhopal was
unique in that the "MIC was not cold but pyrolysed" and contained, apart from
HCN, more reactive "chemical adducts ".
The Bhopal Gas Disaster - Lessons for Chemical Disasters in Future.
1. The importance of CLINICAL PATHOLOGY & TOXICOLOGY
2. The need for cumulative study & analyses
Of each & all “on-site accidents”
3. Studies and collection of data and samples from sporadic severely and
moderately ill patients and controls
4. Detailed information of associated chemicals record of chemical-induced deaths
& sickness onsite
5. Clinical toxicology of patients exposed to chemicals.
5.1. Clinico-pathological guidelines
5.2. Clinical illustrations & x-rays
5.3. Continuing studies of individuals at risk
5.4. Long-term follow-up studies
5.5. Clinical Biochemistry
6. Post-mortem or autopsy studies
6.1. Photographs for identification of victims
6.2. Forensic examination of the body
6.3. X-ray records
6.4. Detailed autopsies
7. Histopathology
7.1. Light & electron microscopy
7.2. Routine and special staining procedures
7.3. Immuno-histochemistry mmunolocial studies
7.4. Biochemical analysis of tissue samples
8. Continued post-mortem studies
9. Teratogenic and mutagenic studies
10. Experimental studies & animal tissues
11. Detoxication measures
12. Establishing the “Biochemical Lesion”.
Note: All Illustrations & Key References are available in the Author’s recent
comprehensive publication entitled “The Bhopal Gas Tragedy: An Environmental
Disaster”, CURRENT SCIENCE, 86: 905-20, 2004 (10th April Issue).
Website:
www.ias.ac.in/currsci OR www.iisc.ernet.in.currsci/ With a view to conserve space,
they are not being repeated.
SUMMARY & CONCLUSIONS:
Thus the Scientific Challenges posed by the Bhopal Gas Tragedy have been
almost fulfilled by the coordinated studies based on Toxicology, Autopsy & HistoPathology, Respiratory Physiology and Clinical & Forensic Biochemistry. This is
perhaps the first Chemical Accident where the offending Chemicals have been
traced into the body of the victims and appropriate Measures of Detoxification were
evolved. Although accident involving may not recur, these experiences are of
immense value while encountering Future Chemical Disasters.
Acknowledgements: The author wishes to thank Prof. J.P. Gupta for
prevailing upon submission of the Abstract as well as the full paper. Special thanks
are due for the continued encouragement and sustained support by Prof.
N.K.Ganguly, D.G. and his colleagues Dr. Bela Shah & Dr. D.K. Shukla of the
ICMR, enabling participation in the historical event of the 20th Anniversary of
BGT. This presentation is a tribute to the memory of the departed victims and
exposees of Bhopal.
Keywords: Bhopal Gas Tragedy, Acute & Chronic Cyanide Toxicity,
N-& S-Carbamoylation