|Year : 2015 | Volume
| Issue : 3 | Page : 115-128
Health issues among MIC exposed population 30 years post MIC disaster at Bhopal
Department of Community Medicine, Chirayu Medical College, Indore Bhopal Highway, Bairagarh, Bhopal, Madhya Pradesh, India
|Date of Web Publication||20-May-2015|
Department of Community Medicine, Chirayu Medical College, Indore Bhopal Highway, Near Bairagarh, Bhainsakhedi, Bhopal - 560 001, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Bhopal the capital city of Madhya Pradesh suffered an accidental toxic gas disaster 30 years back. The gases released included mainly Methyl Iso Cyanate (MIC), Hydrogen Cyanide (HCN) and Carbon Mono Oxide (CO). The left over stockpile and products of reactions posed threat to environmental contamination and gases lead to heavy toll on human and animal lives and injured people with long term consequences. People believed that the toxicants could cause irreversible damage to human health. Present review article is based on extensive review of the large number of research publications and reports appeared over last 29 years following MIC gas leak at Bhopal. The results of extensive review of literature reveal that fear of carcinogenesis, immune compromise status was unfounded and congenital malformations was not proved epidemiologically as well as experimentally. And as on today, thirty years' post disaster only three health problems as Reactive Airways Disease Syndrome, Pulmonary Fibrosis and Post Traumatic Stress Disorder need further attention, that too for their management. The result of present review also indicates that by and large no research need seems to emerge. However, to be sure, author recommend that a cohort of gas exposed people who were given Thiosulphate injection (N = 18000) and their exposed family members may be assembled and their health status be examined through a cross sectional study to come to final conclusion.
Keywords: Carbamoyaltion, Carbon Mono Oxide, Hydrogen Cyanide, Methyl Iso cyanate Cya MIC ≈ HCN adducts, sodium thiosulphate, thiocyanate, thiosulphate
|How to cite this article:|
Mishra B. Health issues among MIC exposed population 30 years post MIC disaster at Bhopal. Int J Health Syst Disaster Manage 2015;3:115-28
|How to cite this URL:|
Mishra B. Health issues among MIC exposed population 30 years post MIC disaster at Bhopal. Int J Health Syst Disaster Manage [serial online] 2015 [cited 2019 Mar 26];3:115-28. Available from: http://www.ijhsdm.org/text.asp?2015/3/3/115/157361
| Introduction|| |
More than a quarter century ago 29 years to be precise, Methyl Iso Cyanate (MIC) leak disaster took place at Bhopal at midnight of 2 nd /3 rd December 1984. Within 72 hours post disaster it killed more than 2000 people and 1000 cattle.  At acute stage disaster apparently targeted mainly respiratory, ophthalmic organs and manifested in form of troubled distressed breathing, respiratory collapse and visual difficulties following, irritation burning and difficulty in opening the eyes. Abortions and psychological symptoms following the post disaster stress were also observed.
In absence of clear information about the nature of released toxicants, fear of unknown prevailed. Surviving people, treating medicos, administrators and the NGOs feared that the unknown chemicals released during disaster may affect various system and cause long term damage. To be precise, in reference to the respiratory system it was a common fear as how long people will suffer with breathlessness? Would it be a permanent feature? Would people acquire other infections flowing compromised immunity or develop cancers related to the respiratory systems. Fears related to ophthalmic systems were mainly centered on blindness. It was also feared that there would be a state of temporary or permanent immune incompetence leading to acquisition of various infection. Would there be damage to chromosomes or chance of developing congenital malformation. Would the future progeny be affected? Would there be growth retardation? Would people suffer from cancers etc?
Immediately following the disaster, it was very difficult to answer the above raised concerns as nobody exactly knew what were the constituents of the toxic gases released and solid product of reaction left over after the midnight disaster, nor anybody had any idea about the quantity and nature of the leftover toxicants at factory site, procured for the production of Sevin over the 15 years (1969-84) of its operation.
The 3 rd December 2014 observed 30 th anniversary of ill famous disaster. The global research on gas disaster and effect of MIC on human as well as experimental animals have answered almost all the queries, however, fears are still prevailing in the minds of the lay people about the further damage. This paper is an attempt to take stock of intellectual inventory developed since 1984 and an attempt to find out the answers and ultimate fate of many symptoms people of Bhopal suffered with during acute phase of the disaster. Present paper would also examine persisting health problems need research to understand something or simply need management approach for solution.
The present review would try to examine the Bhopal MIC leak in a logical manner as below:
- What were the toxic products that were generated at the time of the accident, and what were the products remained at the site of accident after the disaster?
- Did these toxicants contaminate water or food chain?
- Were these toxic product of reaction found in cadavers, human being and animals
- Is there any evidence of clearance of these chemicals from the human body?
- What were their effects on human being and on experimental animals? And lastly, what impact they may have on human health after 30 years post disaster?
- After 30 years do the remaining morbidity issues need research approach to understand and find solution or a management approach for appropriate redressal?
This paper would also aim to attempt to inform all the stakeholders and community about the same so that unwarranted fears among concerned groups could be alleviated.
| Methodology|| |
The fear of unknown, still (after 29 years following accident) prevails among toxic gases exposed population of Bhopal accident. Hence this review article based on secondary review is written to find out the facts from the large body of scientific literature published over 29 years in peer reviewed journals and through various reports to answer the factual position regarding the various morbidities appeared following the MIC accident. Attempts were also made to categories the health problems if any in to two broad categories of: 1. Those health problems which needed research for solution; and 2. Those which required management approach for solution. This review covers the period and publications appeared in last 29 years between 1984-2013. Extensive literature search was conducted to find out the answers to the questions raised above.
What were the toxic products that were generated at the time of the accident, and what were the products remained at the site of accident after the disaster?
0Immediately after the disaster the exact cause of the sufferings was not clear. Union Carbide was insisting that the leaked chemical was MIC and it was simply a potent tear gas which in contact with water would convert in to harmless products like Di and Tri Methyl Urea. However it was far from fact. By 5 th and 6 th December 1984 presence of Cyanide (4533 mcg. and 2533 mcg. per cubic meter respectively) was confirmed at two sites, one near the MIC storage tank in plant and 50 meter away from the plant during one sampling hour. And during same period presence of Urea: A product of reaction between excessive MIC and scanty water was confirmed inside the plant as well as outside.  Hence, one can say that of the chemicals released in the environment, at least two were MIC and the HCN. Quantum of each gas was also enquired in to. By different calculation it seems that of the 40 tonnes MIC stored, about 12087 kg of MIC reacted with water and about 28 tonnes of MIC escaped after exothermic reaction. 
It is known that on exposure to high temperature MIC breaks down to HCN and at +200°C, 3% HCN is produced.  On experiment it was found that on pyrolysis at 350 o C, MIC generated 4.7% HCN.  And this way even if we take MIC generation to higher 5%, than amount of HCN thus produced during reaction would have been about 605 kg. Hence it was wrong to presume that only MIC escaped. In fact it was a mixture of toxic gases as mentioned in [Table 1].
|Table 1: Inventory of Toxic chemicals in Union Carbide factory (1969-1984) and toxic substances generated during disaster|
Click here to view
When one pursues the issue of long term effect of the disaster one should not forget that besides the gases, stored chemicals inside the factory premises and the products of reaction in the tank too were likely to contribute to the ill health effect through mixing in water and entering the food chain [Table 1] particularly on long term.
Did these toxicants contaminate water or food chain?
Various non-governmental organizations (NGOs) have expressed and substantiated the presence of such chemicals in soil and groundwater. It was and has been believed that these stored chemicals could leach in to ground water and cause ill effect on long term.
In 2002, GREENPEACE found that toxic substances were present but in their opinion concentration was too low to show acute toxicity. 
On review it has been found that the water collected from affected area was analysed for Cyanide and found free of Cyanide by 5-6 December1984 just after 3 days post disaster.  However water analysis was continued being done during 1985-2013 by various agencies like National Environmental Engineering Research Institute (NEERI) (at least six times), MP Pollution Control Board (at least five times) GREENPEACE, National Institute of Occupational Health, CSIR-Indian Institute of Toxicology Research (at least once each). During the period of 1985-2006, of the 13 examinations at least six times water was found of drinking Quality.  However Sristhi an NGO in 2002, found it contaminated with Chloroform and Nickel.  NEERI in 2010 observed that ground water from the bore wells constructed by NGRI within UCIL premises and the existing wells around UCIL premises in general were not contaminated due to seepage of contaminants from UCIL dumps. And isolated contamination of 5 bore wells in terms of pesticide cannot be attributed to UCIL dumps.  Lastly, in 2013 CSIR-Indian Institute of Toxicology Research found the presence of inorganic Lead above the permissible limits for drinking water-(BIS IS 10500:2012) in samples collected from outside the UCIL premises and concluded that its presence had no relation with past UCIL activities. Presence of organics like HCH (a, β, δ) in more than permissible limits and HCH γ (under permissible limits), could be due to past UCIL activities as well as due to usage of HCH in other agricultural/Horticultural practices in surrounding areas. On the basis of above CSIR-IITR suggested non potable use of ground water. 
From above review, it appears that stored chemicals or products of reactions have not yet reached the ground water table nor they could reach food chain as the affected area is densely populated and nothing edible is grown there. Lastly affected people living in close vicinity of the factory are provided piped drinking water brought from distant places. Hence, what so ever ill health effects are seen in the exposed are mainly or solely due to the toxic gasses like MIC, HCN, MIC ≈ HCN adducts and Carbon Mono Oxide (CO) absorbed in the human body during the disaster as below:
Were these toxic product of reaction found in cadavers, human being and animals?
Presence of Cyanide was confirmed in blood of toxic gas exposed dead victims with help of Drager tubes as early as on 8 th December 1984.  Cyanide levels study in cadaveric blood among 43 affected and 31 control was conducted and it was found that the blood Cyanide levels among exposed were ranging between 60-360 mg % (average of 150 mg %) against the range of 10-50 mg% (average 25 mg %) among control and presence of trapped Cyanide in lungs too was confirmed.  Among human subjects arterialisations of venous blood drawn from hospitalised cases was observed on 5-6 th December 1984.  Raised HCN levels of 70 mg % in blood of exposed (N = 34) were more than double of 20 mg % of control group (N = 15) indicating Cyanide toxicity.  An indirect evidence of presence of Cyanide in toxic gas exposed survivors was confirmed through a study in January 1985. In this study, of the 14 gas exposed symptomatic cases, 10 cases showed 50% increase in urinary Thiocyanate excretion when given intravenous injection of Thiosulphate. 
The Carbamoylation of the postmortem blood and tissue was demonstrated in 1984, as all the seven cadaveric blood samples and 17 of the 35 tissue samples were positive for Carbamoylation. In 1985, out of the nine cadaveric blood samples four were positive while of the 18 cadaveric tissues tested four were found positive for Carbamoylation.  Demonstration of 'N Carbamoylated end-terminal valine residue of haemoglobin' in the blood samples of cadavers and survivors confirmed widespread presence of MIC in body. Initially a reduction of free amino groups of haemoglobin was demonstrated by TNBS reaction; later chromatographic studies confirmed MIC binding with end-terminal Valine residue. One and a half month following disaster vMVH was demonstrated in 19 out of 60 exposed persons and seven out of 11 cord blood samples. These observations confirmed that MIC not only crossed alveolar‐capillary barrier but had also crossed placental barrier. Carbamoylation of terminal valine residue of myoglobin could explain the extreme muscle weakness. 
Presence of Carbon mono Oxide
The gas exposed human subjects living in railway colony region were evaluated for respiratory changes within 7-90 days post exposure. It was found that of the 70 evaluated 94.3% had raised carboxyhaemoglobin (COHb) and among 11.4% the level was higher than 6% and MetHb was found raised in 83% of 111 subjects' tested.  Observation of presence of CO in form of Carboxyhaemoglobin in blood of exposed animals was also confirmed. 
Breakdown product of MIC
Methyl Amine, smelling like rotten, fish was found in one autopsy done on 20 th December 1984. 
Autopsies and blood samples collected from cadavers in 1984-85 showed presence of MICT, DMIT, 2,4-Dione, compound m/z 279 and compound m/z 269. 
Is there any evidence of clearance of these chemicals from the human body?
Of the above toxic products natural or attempted clearances of some of above chemicals from body were also monitored and in some this clearance was found with noticeable clinical improvement.
To overcome the cyanide poisoning in one trial patients were given intravenous challenge of thiosulphate injections. The treatment with thiosulphate revealed symptomatic improvement along with increased excretion of urinary thiocyanates. However effect of thiosulphate injections gradually tapered off and the results of third double blind study conducted during October-November 1985 indicated that circulating toxic material has been flushed out, hence it was suggested that thiosulphate injection may be continued in only those symptomatics having elevated level of urinary Thiocyanate of more than 1 mg %. And finally fourth trial in March 1986 indicated that there is no further need of thiosulphate injections following poor thiocyanate excretion following exhaustion of cyanide in body.  Another study confirmed that by three years post exposure urinary thiocyanate excretion came down to normal. 
The phenomena of N-carbamoylation came to end by March 1985 as none of the other end terminal amino acids of autopsy protein were found to be positive after March 1985. 
One study reported significant decline in the level of COHb and MetHb after three months post disaster.  In a group of patients Compensatory erythropoesis evidenced by increased 2-3 DPG level returned to normal by 1 year and raised Hb level persisted till 1-1½ years post disaster. 
In nutshell, it can be summarised that there are evidences to believe that the human body was clear of the toxicants by as late as one and half to three year post disaster and there was no information or possibility that the solid chemicals have yet reached the water/food chain and then to human body in toxic doses to cause any damage to human health on long term. Hence, it can be presumed that what so ever long term effect have been seen or would occur in future would solely be due MIC, HCN and CO. Hence in next pages long term effect of mainly MIC and HCN and CO on various target organs, on human, animal and in vitro models vis a vis existing situation seen in Bhopal would be reviewed.
What were their effects on human being and on experimental animals? And lastly, what impact they may have on human health after 30 years post disaster?
Acute stage symptomatic morbidities
During acute stage in all the three exposed areas 96-99% people had both eyes and lung symptoms, while 74% suffered with gastrointestinal symptoms in severely exposed area, whereas, in moderate and mild area it was 48 and 14% respectively. Morbidity related to skin was 1.2% in exposed area. The control area had very low morbidity during the same period. 
Chronic symptomatic morbidities
Indian council of Medical Research conducted long term symptomatic morbidity study and published two documents. The excerpts given below in four para are sufficient to understand the immediate and long term morbidities.
Respiratory morbidities came down from 96.87 in 1984 to 20.41, 16.99, and 16.46% in severely, moderately and mildly affected area in comparison to 4.37% in control area. Since 1997, these morbidity rates are seen fluctuating between 20.31-15.42% in severely, 15.43-9.63% in moderately 16.41-13.02% in mildly affected area. However, respiratory morbidity rates remained high in all affected areas in comparison to control area (0.06-4.37%) throughout 1984-2010. 
Ophthalmic morbidities during acute phase in 1984 were 98.50, 98.08 and 99.00% in severely, moderately and mildly affected area respectively in comparison to 0.07% experience by control area population. By 1996, ophthalmic morbidity rate came down to 16.60, 12.41 and 14.98% in the same areas in comparison to 4.31% observed in control area during the same period. These rates declined further and have been seen fluctuating between 11.46-15.85% in severely affected area, between 9.00-11.07% in moderately affected area and 13.99-17.89% in mildly affected area in comparison to 2.84-3.43% in control area during 2005-2010. 
During acute phase in 1984, 73.53, 26.36 and 15% suffered with gastrointestinal morbidities in severely moderately and mildly affected areas in comparison to 0.01% in control area. However, within 5 years by 1991, these morbidity rates fell down to 7.99, 6.52 and 5.88% in the same areas in comparison to increased GI Morbidity rate of 5.80% in control area. Later since 1996-2010, GI morbidity rates have been seen fluctuating 6.48-4.49, 5.21-3.29 and 4.5613.61% in severely, moderately and mildly affected area in comparison to 1.24-2.77% in control area. The peaks of rise in morbidity rates in mild area were further analysed and it was found that these peaks relate to abdominal pain and gastritis. 
Skin morbidities were observed in less than 1.82% in all area during acute phase observed in 1984, during acute phase no morbidity was reported in control area. Morbidity rates were marginally higher in all areas including control in 1996 which later except one peak in 1998 (2.24%) in severe area remained at the level or less than 1.63% in severe area and less than 1% in all areas including control. Since 2007 to till date even in severely affected area skin morbidity rate remained under 1%. 
Above recorded symptomatic morbidities were based the interview of the patients which have may have certain limitations to examine the basis of these morbidities especially when one has to review the future prospect of these morbidities 30 years post disaster.
Long term respiratory toxicity
Lung was the most common and most severely affected organ during acute phase of the disaster. Kamat et al., studied 78 patients during acute phase and found that 79% had respiratory  morbidities. Mishra et al., during acute stage reported among 544 patients examined in OPD, 99% suffered with breathlessness, 95% with cough, 46% had choking and irritation, 25% had chest pain, 21% were listless, 16% suffered with hypersomnolence, 7% were brought in coma, 92% suffered with loss of appetite 52% had nausea and vomiting, 82% had ronchi and crepts 80% had techypnoea, 54% had tachycardia and 2% had fever. 
Kamat et al., found that 78% showed restrictive pulmonary impairment with reversible airflow obstruction, in 24% reduced oxygen uptake on exercise, among 55% raised levels of Carboxyhaemoglobin, and Methaemoglobin.  Among 500 chest radiographs of patients taken within 72 hours of gas disaster, 98% showed abnormalities of interstitial and alveolar lesions and destructive lesions of pre-existing lung diseases. 
But the above surveys mainly reflect the quantitative picture and to understand the qualitative aspect of the lung injuries one has to examine the issue more closely. From the review it is known that the body was practically clear of the toxic chemicals like MIC, Cyanide, COHb and MetHb-4 month post disaster and their effect by one and half year post disaster (Cited above). However, the respiratory morbidities persisted and one has to look for the factors contributing to long term morbidities among the exposed population? To get some answer one has to review the experimental data on MIC as well. It has been found that when F334/N rats and B6C3F1 mice were experimentally exposed to acute lethal and sub lethal dose of MIC, animals developed peribronchial and intra luminal fibrosis.  B6C3F1 mice exposed to near fatal concentration (30 ppm) of MIC, developed persistent fibrosis of major bronchi, while at lower dose lesions were much less severe and recovery seemed complete at 91 days. The spectrum of lesion ranged from acute bronchitis, chronic bronchitis, bronchial mucosal/and bronchial intra luminal fibrosis, chronic alveolitis and atelectasis  almost similar to seen among gas exposed. In another study among F344 rats, pathological changes following two hour single dose exposure of MIC at 30 ppm exposure resulted in development of obstructive lung disease.  Another study found that rats exposed to MIC developed and progressed to severe Obstructive Airway lesion in MIC exposure concentration response relationship manner.  In Indian Council of Medical Research (ICMR) sponsored studies done at variable intervals showed progression of lesions in lungs. Autopsies done on victims died within 72 hrs. post-exposure revealed necrotizing lesions affecting bronchioles, alveoli, capillaries with excessive fluid flow in to alveoli. Interstitial fibrosis and bronchiolitis obliterans was a predominant feature seen in 12 out of 15 autopsies done 2 weeks post disaster. By third week on histology, alveoli were found to be thickened and filled with necrotic debris. The bronchioles showed necrotic epithelial debris embedded in mucin. Six to eight month post exposure open lung biopsy in a four cases showed characteristic picture/features ofbronchiolitis obliterans in fairly large sized terminal bronchioles. Later in another series three case on open lung biopsies in 1987 revealed features of subpleural/septal fibrosis, interstitial aggregates, compensatory emphysema bronchiolitis and peribronchial and perivascualar fibrosis.  Lastly, in a broncho-alveolar lavage study it has been found that macrophage neutrophilic alveolitis was present in proportion of severely exposed subjects evaluated 1-6 years post disaster and higher cellularity among exposed smokers indicated that smoking was a risk factor and lastly, exaggerated number of alveolar macrophages and neutrophils in lower respiratory tract along with abnormally elevated levels of fibronectin indicated that alveolitis might have caused further injury and fibrosis of lung parenchyma.  ICMR sponsored studies conclude that healing of acute lung injury had resulted in alveolo-pleural fibrosis and bronchiolitis obliterans mainly in airways less than 2 mm. in diameter. Possibility of such cases running a clinical course similar to COPD with recurrent respiratory illness was also expressed. Other diagnoses like Reactive Airway Dysfunction Syndrome (RADS) classified as bronchial asthma were also seen.  Incidentally, Indian council of Medical Research has already published a guide line for management of respiratory problem in gas affected population.  Here it is worth mentioning that HCN is not known to cause any long term respiratory effect  and no data on long term effect of acute CO Poisoning on lung could be obtained.
Symptomatically eye was the second most commonly involved organ. Ophthalmic morbidities were seen in 98-99% of the affected population during acute stage.  Kamat et al., studied 78 patients during acute phase and found that 74% had ophthalmic symptoms. 
Immediately following disaster, 6000 persons visited department of ophthalmology at Gandhi Medical College, mainly complained of excessive lacrimation, photophobia profuse lid oedema, and corneal ulcerations.  In another study of the 544 patients visited hospital immediately after the disaster complains among 80-85% were related to eyes and these were foreign body sensation, burning, and blurring of the vision.
On detail examination 60-70% had conjunctival and circumcorneal congestion with relatively little oedema. A fair number of cases had superficial corneal ulcers mostly in central zone and interpalpabral region.  On long term follow‐up, higher proportion of cataracts and cataracts in comparatively younger age groups in exposed was notice and in some cases these cataracts were found with polychromatic lusture suggesting complicated nature.  MIC induced cataract formation was seen experimentally as well. Catractogenesis following experimental application of MIC to rodent eyes has been observed.  Cataract formation in young rat lenses was noticed when these were incubated in 50 mmol/L MIC. 
After three year post disaster a survey of affected population found population suffering with photophobia, burning and watering sensation, sign of red eye, superficial interpalpabral erosions corneal opacity, discharge and fundal changes. This survey indicated increased risk of eye infection, hyper responsive phenomena, excess cataracts, and resolution of corneal erosions in exposed persons thus collectively postulated as Bhopal eye syndrome.  Damaging effect of MIC at 3-30 ppm for 2 hrs on eyes of Fischer rats was evaluated. The study concluded that there was no apparent irreversible eye damage following MIC exposure.  Lastly, in one study authors concluded that disaster has not caused blindness or irreversible eye damage. 
Since 1985, Isocyanates are recognised to cause immunologic sensitisation. And besides this Isocyanates are also known to cause respiratory hypersensitivity, including immediate and delayed pulmonary reaction and hypersensitivity pneumonitis. Dermal sensitisation too has been reported to other Iso Cyanates. Theoretically, MIC, due to its low molecular weight of 57.1 cannot act as antigen on its own, however, through animal studies it was found that MIC was immunogenic in guinea pigs and inhibition assays indicated that antibodies did recognise MIC.  With these findings in mind possibility of MIC affecting the human immune system could not be ruled out. Hence, immunological parameters were studies in gas exposed individuals and experiments were conducted to evaluate the cellular as well as humoral immunity and some other related parameters to evaluate immune competence in experimental animals.
In a separate experiment 7 days of post exposure to MIC rats revealed increase in weight of liver and thymus along with impaired alveolar and peritoneal macrophage functions and impaired delayed hypersensitivity against sheep RBCs.  In another experiment effect of MIC on immune system of rat after two weeks of exposure was evaluated. It was observed that there was a marked suppression of phagocytosis of sheep erythrocytes by peritoneal and alveolar macrophages. The animals were highly susceptible to bacterial E coli endotoxin. The local immunity of lung was found to be significantly suppressed. Delayed Type Hypersensitivity (DTH) response also showed suppression. However there was no effect on mitogenic response (PHA, ConA or LPS) of peripheral blood lymphocytes.  Immunological response on B6C3F1 mice exposed to sub lethal dose for four consecutive days was evaluated through battery of tests. The antibody response to sheep erythrocytes and natural killer cell activity was not altered. Although lymhoproliferative response to mitogens showed moderate suppression, however, resistance to the infectious agents like Listeria monocytogenes, mouse malaria parasite, and influenza virus, or to transplantable tumor cells was not compromised. Authors concluded that Immune system does not seem to be primary target of MIC. 
Cellular immunity was evaluated among gas exposed persons. In a study conducted 4-8 weeks post disaster among gas exposed revealed increased T cells and T H cell population while B cells and CD 8 were within normal range.  However, in another study conducted among the MIC gas exposed individuals two and half months post disaster (Feb-April 1985) showed significant depression in phagocytosis and T cell rosettes, indicating occurrence of suppressed cell mediated immune response among exposed individuals.  It was also noted that peripheral blood lymphocytes of 67 exposed individuals collected 4-8 weeks post exposure revealed that only 18 (29%) individuals responded normally to both T and B cell mitogens, while in rest of the individuals lymphocytes were hyporesponsive to both of these mitogens. Lastly, DTH response to PPD and Viridase were found unaltered. 
MIC did produce MIC specific antibodies belonging to IgG, IgM, IgE class in 11 of 99 gas exposed, though in low titers and transient manner and thus confirmed immunogenic potential of MIC.  While in another study it has been reported that MIC-specific antibodies have been detected in the serum of some of the victims and the antibody titer seems to correlate with the severity of the lung injury.  Contrary to this observation, another study did not find any deviation in immunoglobulin levels indicating unaltered immune response to MIC by exposed people.  Lastly, the effect of MIC on the humoral immunity of the malnourished (protein deficient) subjects was also investigated. It appears that MIC has no synergistic effect with protein deficiency on the humoral immunity of the protein malnourished individuals.  Lastly, it was noted that out of 229 sera collected from MIC exposed individuals only 12 individuals demonstrated presence of MIC antibodies. These antibodies belonged to several classes and in all cases titers were low and their levels declined with time from exposure. The study concluded that low titers and transient nature of antibody response suggest that there is little health implication of antibody response to MIC. 
From the above it could be inferred that MIC was found to behave like hapten and therefore was immunogenic both in disaster-exposed humans as well as in experimental animals. It also appeared that in animal models, especially lungs were more sensitive to MIC challenge. From the observations it can be concluded that immune system was not the primary target of MIC, and except early cellular immune suppression and immune depression locally in animal lungs, immune system did not suffer in major way. And in gas exposed persons except early cellular depression in one study, cellular as well as humoral immunity by and large remained undamaged.
Genotoxicity following MIC exposure could be studied from two angles. The first one is the outcome among the gas exposed population and second is observations made in vivo or in vitro experimentations.
A study was conducted as early as two and half month post disaster on lymphocytes of 31 gas exposed individuals and the study found that exposure to toxic gases caused significant degree of chromosomal aberrations.  Similar observations were seen in a study conducted 1114 days post disaster which too reported higher frequency of chromosomal aberration in lymphocytes of exposed individuals (N = 83) with females showing a higher incidence. Authors suggested that persistence of chromosomal aberration even after 1114 days may indicate a residual effect of toxic gas on T cell precursors.  Contrary to this in leucocyte culture of another group of 35 gas exposed patients no increase in chromosomal aberrations was found.  In another study, samples collected between 10 days post disaster to a month revealed that single exposure of MIC did not cause significant chromosomal aberration.  Experimentally MIC at 10-20 ug/ml and 15-25 ug/ml has been found to induce chromosomal aberration without and with metabolic activation in cultured Chinese hamster ovary cells.  An American Review on genotoxic evaluation found that MIC did induce chromosomal aberrations and sister-chromatid exchanges.  Effect of MIC on rat bone marrow cells was studied and it was found that MIC did lead to chromosomal aberration, there were few numerical and structural abnormalities and aberrations were of mainly of chromatid type. Further quantitative analysis did not reveal any significant increase in aberration rates and numerical abnormalities were within the control range.  Sister chromatid exchange is a sensitive indicator of chromosomal damage. Following MIC exposure it was studied in various systems. In a study conducted on blood samples of exposed cases within 10 days to a month post disaster, SCE frequencies in majority of exposed cases were found to be lower than those seen in the control population.  In another study done on blood leucocyte culture of survivors exposed to MIC revealed no significant effect on SCEs suggesting acute exposure to MIC does not lead to increased frequencies of SCEs.  In another study conducted on survivors reveled that SCEs frequencies could not be related to MIC exposure.  Experimentally, MIC did induce SCEs in cultured Chinese hamster ovary cells with or without metabolic activation.  American group while conducting genotoxic evaluation too found that MIC induced Sister-Chromatid Exchanges.  MIC caused a small but significant increase in SCE frequency of cultured lung cells from mice exposed to 1, 3, or 6 ppm MIC, but it did not significantly increase SCE levels in PBLs of mice exposed to concentrations as high as 6 ppm. 
Cell cycle kinetics was studied following MIC exposure. MIC is found to slow cell cycle in peripheral lymphocytes of the affected persons.  Similarly in another experimental study MIC was found to delay the cell cycle in bone marrow  and contrary to these two observation, in one study following experimental exposure to MIC, cell cycle kinetics were found unaffected by MIC exposure in murine alveolar macrophages. 
Mutagenic response to MIC was evaluated using different systems. In human no mutagens were found in urine of exposed patients by Ames test.  Mutagenic response found negative in Salmonella More Details/mammalian microsome assay.  In another study mutagenic response of MIC was evaluated on Ames Salmonella/microsome liquid pre-incubation with some modifications in test conditions. It was found that MIC did induce mutagenic response, however, it was variable under different test conditions.  American group while conducting genotoxic evaluation found that MIC failed to induce significant mutagenic response in the Salmonella assay under standard test conditions, it was found negative in the Drosophila test for sex-linked recessive lethal mutations. 
Genotoxic effect of MIC was also evaluated in somatic cells of mice through micronucleus test. MIC did not influence the frequency of cells with micronuclei and polychromatic/normochromatic ratio in control or exposed.  Another group assessing mutagenic response and cytotoxic effect of MIC in vivo, in mouse by assessing the induction of micronuclei and depression of polychromatic erythrocytes in bone marrow and peripheral blood smears. Study revealed that it did not significantly increase frequencies of micronucleated polychromatic erythrocytes and micronucleated normochromatic erythrocytes in bone marrow and peripheral blood samples. However, significant dose-dependent depression in percentage polychromatic erythrocytes was observed.  In a inhalational toxicity study and its effect on femur bone marrow of rats, no micronucleus formation was observed in 7 and 14 days post exposure.  To explore the genotoxicity of MIC, M13mp9 RF DNA was modified with MIC and then introduced into E. coli. It was found that the plaque-forming efficiencies of DNA decreased with increasing dose levels, thus demonstrating genotoxic response of MIC-modified DNA in E. coli.  Another study demonstrated that MIC inhalation led to bone marrow depression indicating systemic genotoxic/cytotoxic effect.  Lastly, following a battery of tests in vivo and in vitro genetic toxicity studies a group concluded that MIC has capacity to affect chromosome structure but not to induce gene mutation. 
Cytogenetic parameters are very sensitive and unless put in and observed in proper standardised reference base line values of the population in question one may miss the logical interpretation. As finding 4-5 sister chromatid exchange per chromosome pair, per mitosis is considered as normal distribution. Cell Cycle kinetics vary from cell line to cell line but are pretty constant within the same cell line under normal conditions. Hence keeping this as back drop some marginal deviations from the normal may not be treated as alarming unless associated with verifiable clinical presentation. Secondly, from the above studies a general consensus seems to emerge that MIC in spite of being a cytotoxic substance may cause only chromosomal damage to some extent but it is not capable of causing any genotoxic effect  and gene mutation.  Lastly, at this juncture one has to agree that all above study were cross sectional and on the basis these studies it is difficult to make future predictions. Here can 25 years of observation help? It is known that cytotoxic and genetic damage, slow cell cycle kinetics may result in tumor formation, occurrence of cancers, abortions or congenital malformation etc., Has it happened to exposed population at Bhopal. Can twenty nine years of scientific observations provide answer to it. One has to see?
To review the issue of reproductive toxicity in totality it would be better if all aspects including testicular/sperm damage, sexual performance, pregnancy and pregnancy outcome and lastly the perinatal and infant mortality issues are examined.
Effect of MIC exposure was evaluated and it was found that 100-120 days post exposure sperm morphology, motility and counts among exposed human cases were comparable to normal.  And similar observation on sperm count, sperm motility, seminal cytology or number of F-bodies was noted among 6 months post exposed 18 fertile males.  The authors recommended DNA studies on sperms to rule out long term damage.  Similar observations were made on experimental animals. Mice experimentally exposed to MIC 134 mgm -3 for 30 minutes revealed no significant change in relative testicular weight, however, spermatozoa in the seminiferous tubules disappeared 3 days post exposure. Primary and secondary spermatocytes were hypertrophied. Normalisation occurred after 15 days.  Morphological changes induced by MIC in the seminiferous tissues of rats maintained on normal and protein deficient diets were investigated. The authors conclude that MIC exposure causes testicular damage which appears to be reversible and that protein deficiency potentiates the effects of MIC.  In another study, adult male Wistar rats exposed to single inhalation of MIC at 3.2 mg/l, for 8 min under static condition and necropsied 21 days post exposure showed no effect of MIC on epididymal sperm density and morphology. Further absence of germ cell mutagenicity following exposure to MIC among male wister rats was ascribed to poor biodistribution of MIC.  The female animals exposed experimentally to MIC at varied doses and for varied period during non gestational stage did not affect the pregnancy or the live liter size, however animals exposed during gestational stages did result in foetal loss. 
Effect of MIC on copulation and reproductive performance was evaluated in mice and the reduced sexual performance and reproductive performance among male rats was found to be result of general stress and disconsolate copulation.  While in another study it was found that MIC inhalation at 1,3 ppm/6 hrs/day on 4 consecutive days to male and female mice had no effect on reproduction mating trials after 1,8 and 17 weeks post exposure and fertility too remained unaltered. 
Following toxic gas leak unpublished data indicated occurrence of menstrual cycle disruption, leucorrhoea and dysmenorrhoea among gas affected females.  In a family survey of 3270 families, 865 reportedly pregnant at the time of disaster, 43.8% did not deliver a live child. This was more than three to four times higher than the normal incidence of 6-10% as estimated by ICMR.  Of the 638 women pregnant at the time of the accident; 315 (49.4%) did not deliver a live births. Pregnancy loss was higher in first (58.8%) second (42.1%) or third (40.1%) trimester respectively.  The rates of foetal loss among Bhopal gas victims from 1984 to 1989 were compared to those of a control group. Among, 136 eligible women in the affected area and 139 women in the control area the fetal loss rate were (26.3%) compared to that of women in the control area (7.8%) respectively. 
Experimental animals too suffered similar fetal losses. On exposure to MIC (9 and 15 ppm) for 3 hours, there was a complete loss of all fetuses in more than 75% of animals. Decrease in foetal and placental weights was observed at 2-5 ppm of MIC exposure.  Exposure to MIC at 1 ppm for 6 hrs/day during gestation days 14-17 led to led to an increased incidence of foetal deaths among female mice while at 3 ppm, the average number of pups/litter decreased. 
Child survival among children born to gas exposed women was studied and it was found that rate of infant mortality within 30 days of birth was 5-6 times higher than recorded for year 1983 and 1984.  ICMR studies documented significant increase in perinatal and neonatal mortality in a pregnancy outcome study carried out in 18, 978 households. 
In another study out of 323 live births, 12.1% died within 30 days of birth and additional 8 died between one and 18 month of age. 1-30-day mortality was significantly higher than the same recorded for previous 2 years (2.7% in 1984 and 3% in 1983). Of the 273 surviving children born to MIC-exposed women, the status of 200 could be determined in 1990; 20 of these 200 had died before reaching the age of 5 years.  Experimental animals too suffered similar fate. Swiss (CD-1) mice exposed to MIC inhalation at 0, 1, 3 ppm/6 hrs/day during days 14 through 17 of gestation in resulted in significant decrease in neonatal survival during lactation.  Children of mother exposed to gas were found suffering with excessive morbidity. On basis of history given by the mother of the children it was noted that 122 out of 273 and 108 out of 200 children were sick in 1986 and 1990, respectively. 
In summary, it is observed that MIC induced stress resulted in poor sexual performance among experimental animals, however MIC exposure in male/female animals in pre gestational stage did not contribute to foetotoxicity in any manner and in non toxic and doses up to 3 ppm MIC did not result in adverse reproductive out come.  Further from studies reviewed above it can be deduced that exposure to MIC both in humans and experimental animals during gestational period had result in significant higher pregnancy loss and neonatal/infant mortality and morbidity in infancy. Decreased foetal and placental weight was noticed in animals exposed to 2-5 ppm of MIC for 3 hours.  Lastly, gestational exposure to MIC did result in pregnancy loss/foetal death and morbidity in infancy.  Mechanism of this loss was attributed to MIC reaching placenta and further interacting with foetal tissue. 
Congenital malformation following MIC exposure too was studied. In a study Charles Foster female rats were exposed to 0.212, 0.256 and 0.353 ppm of MIC vapors of MIC and matted with normal of male of same strain. Teratological anomalies like wrist drop, averted claw, valgus deformity, syndactyly, blood clot formation, liver enlargement, cleft palate formation and unequal ribs were observed in fetuses.  However, in one epidemiological study pregnancy outcome among women exposed to toxic gas was studied and the no significant difference in congenital malformation among the off springs of the exposed and non exposed mothers was found. 
Neuro-muscular and psychiatric toxicity
During acute phase immediately following gas disaster of the 978 patients seen in the OPD of Hamidia Hospital suffered with extreme myasthenia like weakness (25%), tremors (2%), tetany (09.9%), apathy and listlessness (21.9%), hypersomnolence (16%), neurotic depression, anxiety state adjustment reaction (19.6%). 
In another study done later during 1985-87, on a group of 113 exposed patients muscle weakness and poor memory was seen worsening with time and 75% were found with psychiatric morbidities.  In one psychiatric study ending May 1985 main diagnostic categories were found to be anxiety state (24.9%) neurotic depression (37.3%) adjustment reaction- prolonged depressive type depression (19.7%) and adjustment reaction with predominant disturbance of emotion (15.5%). 
In another study conducted during March-April 1985 reveled memory, mainly visual perceptual and attention/response speed along with attention/vigilance were severely affected among gas exposed population.  One year post disaster studies on examination of cognitive functions among 52 gas exposed cases, 15 severely gas exposed were found with significant cognitive impairment.  Toxic gas exposed patients were found to suffer with Post Traumatic Stress Disorder, pathological grief reaction, emotional reaction to physical problems.  In a psychiatric evaluation done in February-May 1985 prevalence of psychiatric morbidity was found to be 23.6% among 855 patients screened in 10 clinics. The diagnoses observed were anxiety neurosis (25%), depressive neurosis (37%), adjustment reaction with prolong depression (20%) adjustment reaction with predominant disturbance of emotions (16%).  In paediatric age-group (0-16 years) of the 252 children belonging to 100 gas affected families 12.66% children were found suffering with psychiatric disorder significantly higher in comparison to 2.4% seen in control group. Statistically significant problems noted among affect children were enuresis/encopreasis (5.55%), disobedient/Stubborn (4.36%), tremor tentrum (4.36%), mental retardation (2.3%) and delayed/poor development of speech (1.98%). Lastly children in exposed area were found to have significant lower intellectual levels in comparison to same in control area.  ICMR sponsored studies conclude that in the immediate post exposure period 50% of the population including children suffered from mental health and most of them recovered.  In January 1994, International Medical Commission conducted epidemiological and clinical studies. It found that 7.27% suffered with current post traumatic stress disorder and 15.19% suffered with life time post traumatic stress disorder. Rates among males and females were comparable. In a community sample of adolescent life time prevalence of PTSD was reported as 6.3%. 
Experimentally effect of MIC on rat brain mitochondrial function was studied. From the study it has been inferred that MIC can induce ischemia of brain leading to cerebral hypoxia.  In another study it has been found that MIC at lower dose can prevent rat muscle fibers growth and at higher doses it causes death of fibroblast and myoblasts.  Muscle aches and repeated episodes of extreme muscular weakness (cited above) have been the most frequently observed symptoms reported by gas disaster victims and muscle weakness has been generally attributed to the binding of MIC to the terminal valine residue of myoglobin and reversible S Carbamoylation of acetylcholine esterase and aldolase.  However, it is worth mentioning that increased levels of COHb have been found in toxic gas victims indicating concurrent CO poisoning. Has CO poisoning contributed to muscle weakness? If yes to what extent in Bhopal is not clear, but in another study persistent muscle weakness, lasting from 1-60 months following exposure to CO has been observed. 
The biggest fear in the mind of gas exposed persons following MIC leak was that of carcinogenesis. Though in experimental animal MIC has been found to cause marginally increased rates of Pheochromocytomas and adenomas of pancreatic acinar cell in male rats but in general no neoplastic lesions were significantly associated with MIC exposure.  In another study induction of bile duct hyperplasia and transient liver parenchymal alteration by MIC in different concentration was noted in Swiss albino mice. The authors concluded that the proliferation of bile duct metaplastic changes and transient cytoplasmic vacuolation is caused by MIC were of transient nature and does dependent.  In one inhalation study performed with 3 ppm MIC to study the development of microscopic lesions in rat respiratory tract. It was observed that inflammation and metaplasia in the respiratory tract decreased in frequency or severity in survivors during 85 days of post exposure period and regenerative type epithelial changes were noticed. 
To observe the effect of gas exposure on cancer occurrence an epidemiological study among the males from the affected municipal wards of Bhopal was planned. Relative risks (RR) using cases from the cancer registry and controls from a tobacco survey were estimated for the gas-affected regions. Based on a descriptive study the relative risks of 1.4, 1.3 and 0.7 for lung, oropharynx and oral cavity cancer, respectively, for gas- affected regions in the year 1992 in comparison to gas-unaffected regions in the year 1987-1990 combined were estimated. The authors concluded that the full potential of excess risk if any may not manifest for 15-20 years post disaster.  This period ended in 2004. In a 2010 report, Cancer Registry of ICMR reported that cancers of tongue, mouth, hypopharynx, oesophagus and lung showed higher incidence in affected area in comparison to same in MIC unaffected area. However, when the tobacco habits of the population in two areas were taken in to account the higher rate observed in the MIC affected area was essentially neutralised. This suggests that higher age adjusted rate observed in the MIC affected area was due to higher proportion of the population consuming tobacco rather than due to the effect of MIC per se.  Lastly MIC is not classified as carcinogenic by International Agency for Research in Cancer / and Environment Protection Agency (EPA) USA. 
After 30 years do the remaining morbidity issues need research approach to understand and find solution or a management approach for appropriate redressal?
From the above review it becomes amply clear that damage to human health in majority of cases was self limiting and the exhaustive research done on human and animal models globally has almost answered all the issues of major concerns as above.
While evaluating the research need of MIC exposed population in reference to human health it is pertinent to note that of late many cases of renal failure have come to the attention of health authorities. It may not be out of place to mention that ICMR studies did notice interstitial oedema in kidney and acute tubular necrosis particularly in proximal convoluted tubules in three cases,  and in another study tubulorhexis with degeneration seen in rat kidney was considered to be manifestation of initial shock, however, authors could not rule out direct effect of MIC.  Besides these early findings, has excessive use of drugs by gas exposed population for their morbidities contributed to renal failure is yet to be found out? This can be an area for research with clinical care to the affected population. Maternal and child survival parameters if needed can be studied through retrospective studies but following cohort shift to higher ages, practically this exercise has only academic relevance and no future application.
From the present review it appears that pulmonary fibrosis and may be RADS of variable degree and Post Traumatic Stress Disorder are the three medical diagnoses which need management/rehabilitation approach for care of affected gas victims to allow them to lead a life of dignity and comfort. And this must be provided to them immediately.
Lastly, it is submitted that present review may not be taken as last verdict. At this juncture It is worth mentioning that in Bhopal over 18 months post disaster, about 18,000 urine samples were taken for urinary thiocyanate levels.  If a retrospective cohort of such people and their close exposed family members can be assembled and restudied now on cross section basis for their health status may answer above issues with finality.
Author feels that thirty years' post disaster exposed people deserve and need to be told about the true scientific status so that unfounded fear in their minds could be put to the rest. Gas exposed population at Bhopal may be suffering with other common health disorders seen in non exposed population as well, hence they should be told not to link every morbidity they come across to link with gas exposure and should be provided with adequate curative rehabilitative and promotive support through existing health system.
| Discussion|| |
From extensive review of the literature it is clear that on the night of 2 nd /3 rd December 1984 a concoction of MIC, HCN, MIC ≈ HCN and CO, besides some other gases  escaped following accident. Presence of Cyanide in the factory premises was verified.  Indian Scientists besides MIC ,, also confirmed presence of other toxic gases like HCN and CO in cadavers/affected persons/animals. ,,,,,,,
The review of literature and findings of some NGOs in 2002, revealed that toxic substances present in the soil were not capable of causing acute toxicity  and CSIR-IITR after testing the underground water in 2013 reported that by and large water was not excessively contaminated and was fit for non potable use.  Lastly, there is little chance that the toxic material  present in the factory premises or other solid products of reaction , would have entered the food chain, and water has not proven to be a effective vehicle for these chemicals.
With this background in mind one can say that whatsoever toxicity seen in affected population acute or chronic was mainly caused by MIC, HCN, MIC ≈ HCN and CO alone or in combination as below:
Lung or to be precise in the respiratory tract was the main target organ for MIC and MIC induced exothermic reaction, when it came in contact with the humidity in the respiratory tract. The autopsy studies and the animal experiments revealed that sub-lethal dose of MIC led to pulmonary fibrosis of varied degree in the animals, with gradual recovery overtime. However, the human story continues and the broncho alveolar lavage study indicated that the smoking may worsen clinical impact of pulmonary fibrosis in survivors. And pollution may complicate the situation even further. Secondly, following immune sensitising nature of thiocyanates phenomenon like reversible air ways obstruction  and RADS  too were observed among the gas affected population. However, above mentioned observations made on small samples under particular study cannot be generalised or applied universally to gas exposed population, as cases coming from designated severely, moderately and mildly affected area may or may not match clinically severe, moderate or mild clinic-pathological damage respectively. However, drawing parallels to observations seen in animal models, autopsies, histopathology and clinical studies a simile can be drawn that some of the patients, (howsoever small or big their number may be) exposed to sub lethal dose of MIC and other gases may have developed Reactive Airways Dysfunction Syndrome and fibrosis of pulmonary tissues to variable extent and the mildly affected may even have improved fully. Author strongly suggests that now it is time to find out the severely affected cases with above problems and their management by treatment and rehabilitation with available modalities should be started with immediately effect if not done already. Fortunately, ICMR has already taken steps in this direction.  And equally important management of such cases should be complemented with environmental improvement.
Ophthalmic morbidities were second in proportion at acute stage and the investigator did found catractogenesis in younger age‐group.  And except this finding researchers came to conclusion that MIC has not caused blindness or irreversible eye damage.  Cataracts, now are a manageable problem under national programme may it be at any age and of any type.
In initial stages it appeared that MIC did lead to immunotoxicity. In animal models local pulmonary sensitisation and immunogenicity was seen. In human sufferers as well cell-mediated immune response was seen compromised and transient appearance of antibodies was noticed. However, experimental findings conclude that immune system was not a primary target of MIC and immune involvement following MIC exposure was of little health consequence. 
Genotoxicity was the most feared aspect of MIC exposure. It was believed that MIC exposure may lead to tumors/cancers or congenital malformation in the future progeny. The studies concluded that though some aberration were found in chromosomes, however in practice these were never found associated with any disease. At least has not been reported yet. Cell kinetics were found slowed down in some cases and unaffected in some cases. No mutagens were found in human urine  and mutagenesis was equivocal in most of the studies. And looking in to these findings after thirty years one can say these findings have not affected the exposed population or their progeny. Lastly HCN  and CO  are not mutagenic and no genetic syndrome has been reported to be associated with MIC till date.
After the disaster, sperm profile of the victims were found as normal and even in experimental animals normalization was seen to occur within 15 days post exposure. Non gestational exposure in animals did not affect pregnancy, but gestational exposure did result in abortion in both experimental animals as well as in exposed women more in their first trimester. The mechanism for this abortion was postulated to be MIC's interaction with the placenta and the physical stress. Incidentally CO is known to be associated with abortion, low birth and learning disabilities in later life.  What was its contribution to load of reproductive toxicity is now difficult to imagine. Child survival was found to be poor among off spring of the gas affected women. How long these parameters remained affected following MIC exposure is now a difficult question to answer. A good retrospective analysis of these parameter vis a vis parameters obtained under NRHM programme may probably answer the issue. But even if done this exercise may be of academic value only. Lastly, congenital malformations were not found significantly higher among progeny of exposed animals or the exposed women. 
Neuro psychiatric toxicity
The Post Traumatic Stress Disorder was one major clinical entity which was noted earlier as well as recently. And besides other if any, it is one issue which needs immediate attention for management. It is learned that competent authorities are active to address it. 
Experimentally and epidemiologically MIC is not known to and not described to cause cancers at least not after 30 years post exposure. This is a big relief. Secondly HCN  and CO  too are not known to be carcinogenic.
Through the extensive review done in present paper it can be concluded that 30 years post exposure to toxicant gases following MIC leak disaster only respiratory and psychiatric issues need to be addressed for their management and major concerns like blindness, carcinogenesis, immuno-incompetence, genotoxicity and reproductive toxicity etc., do not seem to pose any threat to human health any more. Author recommends that such information should be communicated to gas exposed victims in their own language to alleviate unfounded fears in their minds to lead a normal life. Lastly, to be sure it is recommend that a cohort of gas exposed people who were given thiosulphate injection (N = 18000) and their exposed family members may be assembled and their health status be examined through a cross sectional study to come to final conclusion.
| References|| |
Indian Council of Medical Research. Health effect of toxic gas leak from Union Carbide Methyl Isocyanate plant in Bhopal: Technical report on Population Based Long Term Epidemiological studies; Ed. S. Sriramachari; Indian Council of Medical Research, New Delhi - 110029; 2007. p. 13-18.
Report of Central Water and Air Pollution Control Board (CWAPCB). (Gas Leak Episode at Bhopal) Quoted in The Bhopal Tragedy: One year after. Published by Sahabat Alam Malasia: Asia pacific Environment Network; 1985. p. 113-120.
Varadrajan S, Doraiswami LK, Ayyangar NR, Iyer CS, Khan AA, Lahiri AK, et al
. CSIR′s contribution to understanding the chemical phenomena leading to the tragic toxic gas leakage at the union carbide pesticide plant Bhopal and aftermath. Council for Scientific and Industrial Research; 1985;1:89-92.
Kulling P, Lorin H. The Toxic Gas Disaster in Bhopal December 2-3, 1984. Stockholm: National Defense Research Institute; 1987.
Bhattacharya BK, Malhotra RC, Chattopadhyay DP. Inhibition of rat brain cytochrome oxidase activity by pyrolised product of methyl isocyanate. Toxicol Lett 1987;37:131-4.
National Environmental Engineering Research Institute: Assessment and remediation of hazardous waste contaminated areas in and around M/s Union Carbide India ltd., Bhopal; June 2010. p. 8. http://www.indiaenvironmentportal.org.in/files/full_report_1.pdf.
Varadrajan S, Doraiswami LK, Ayyangar NR, Iyer CS, Khan AA, Lahiri AK, et al
. CSIR′s contribution to understanding the chemical phenomena leading to the tragic toxic gas leakage at the union carbide pesticide plant Bhopal and aftermath. Council for Scientific and Industrial Research; 1985. p. 73-83.
Varadrajan S, Doraiswami LK, Ayyangar NR, Iyer CS, Khan AA, Lahiri AK, et al
. CSIR′s contribution to understanding the chemical phenomena leading to the tragic toxic gas leakage at the union carbide pesticide plant Bhopal and aftermath. Council for Scientific and Industrial Research; 1985;1:53-72.
In: Sriramachari S, editor. Tank Residue Analysis: Health effects of toxic gas leak from Union carbide Methyl Isocyanate plant in Bhopal: Technical report on Pathology and Toxicology; Indian Council of Medical Research, New Delhi-110029; 2010. p. 122-132.
GREENPEACE 2002 Chemical stockpile at Union carbide India limited in Bhopal: Quoted by Bhopal Medical Appeal: Analysis of chemical contaminants in ground water and assessment of qualitative and quantitative drinking water supply situation in the communities surrounding Union carbide India Ltd. (UCIL) plant site in Bhopal; Main Report 2009. p. 42. Report by Bhopal medical Appeal. Sambhavna Trust Clinic. Bhopal Sambhavna Trust clinic
Department of Gas Relief and Rehabilitation Govt. of M. P.: An epidemiological study of symptomatic morbidities in communities living around solar evaporation ponds and behind the Union Carbide factory; 2008. p. 75-76.
Sristhi 2002. A report on human and environmental chemicals contamination around the Bhopal disaster site. Quoted by Bhopal Medical Appeal: Analysis of chemical contaminants in ground water and assessment of qualitative and quantitative drinking water supply situation in the communities surrounding Union carbide India Ltd. (UCIL) plant site in Bhopal; Main report. 2009. p. 43. Report by Bhopal medical Appeal. Sambhavna Trust Clinic. Bhopal Sambhavna Trust clinic
CSIR-Indian Institute of Toxicology Research Lucknow: Analysis of soil and ground water samples in Bhopal; 2013. p. 13. Central Pollution Control Board Parivesh Bhawan, East Arjun Nagar. Delhi-110032
Hawkinson J. The Cyanide controversy: A toxicology report on the Bhopal gas disaster. Washington: The Bhopal Project Washington Research Institute; 1986.
In: Sriramachari S, Editor. Studies on Urinary Thiocyanate and Cyanide: Pathology and Toxicology. Health eff ects of toxic gas leak from Union carbide Methyl Iso Cyanate plant in Bhopal. Technical report on Pathology and Toxicology; Indian Council of Medical Research, New Delhi - 110029; 2010. p. 69-78.
Dureja GP, Saxsena RS. The Methyl Isocyanate (MIC) gas tragedy in Bhopal (India). Ind J Anaesth 1987;35:264-8.
Sriramachari S. The Bhopal gas tragedy: An Environmental disaster. Health eff ects of toxic gas leak from Union Carbide Methyl Isocyanate plant in Bhopal: Technical report on Pathology and Toxicology; Ed. Sriramachari S Indian Council of Medical Research, New Delhi-110029. 2010. p. 31-46.
Indian Council of Medical Research. First double blind clinical trial on the excretion of Thiocyanate by patients exposed to Bhopal gas tragedy in response to intravenous injection of Thiocyanate. Health effects of the toxic gas leak from Union carbide methyl Iso Cyanate plant in Bhopal: Technical report on Pathology and Toxicology (1984-1992); Ed. Sriramachari S Indian Council of Medical Research, New Delhi - 110029 2010. p. 79-82.
Sriramachari S, Chandra H. Pathology and toxicology of Methyl Iso Cyanate and MIC derivatives in Bhopal disaster. Health eff ects of the toxic gas leak from Union carbide methyl isocyanate plant in Bhopal: Technical report on Pathology and Toxicology (1984-1992); Ed. Sriramachari S Indian Council of Medical Research, New Delhi-110029; 2010. p. 29-30.
Kamat SR, Patel MH, Kolhatkar VP, Dave AA, Mahasur AA. Sequential respiratory changes in those exposed to the gas leak at Bhopal. Indian J Med Res 1987;86:20-38.
Indian Veterinary Research Institute Izatnagar. Report on immediate and residual effects of MIC exposure on animals of Bhopal Gas tragedy; 1984-86. Quoted in Pathophysiology and inhalation toxicology: Health effects of toxic gas leak from Union carbide Methyl Isocyanate plant in Bhopal: Technical report on Pathology and Toxicology; Ed. Sriramachari S Indian Council of Medical Research, New Delhi-110029; 2010. p. 62-68.
Sriramachari S. Pathophysiology and inhalation toxicology: Health eff ects of toxic gas leak from Union carbide Methyl Isocyanate plant in Bhopal: Technical report on Pathology and Toxicology; Ed. Sriramachari S Indian Council of Medical Research, New Delhi-110029; 2010. p. 62-8.
Indian Council of Medical Research. Health eff ect of toxic gas leak from Union Carbide Methyl Isocyanate plant in Bhopal: Technical report on population based long term epidemiological studies 1996-2010; Ed. Dr. Sushil Singh. NIREH, GMC Campus Bhopal 462001; 2013. p. 12-31.
Kamat SR, Mahasur AA, Tiwari AK, Potdar PV, Gaur M, Kolahtkar VP, et al
. Early observations on pulmonary changes and clinical morbidity due to isocyanate gas leak at Bhopal. J Postgrad Med 1986;31:63-72.
Mishra NP, Pathak R, Gaur KJ, Jain SC, Yeshikar SS, Manoriya PC, et al
. Clinical profile of gas leak victims in acute phase after Bhopal episode. Indian J Med Res 1987;86:11-9.
Sharma PN, Gaur KJ. Radiological spectrum of lung changes in gas exposed victims. Indian J Med Res 1987;86:39-44.
Bucher JR, Gupta BN, Adkins B Jr, Thompson M, Jameson CW, Thigpen JE, et al
. Toxicity of inhaled methyl isocyanate in F334/N rats and B6C3F1 mice. I. Acute exposure and recovery studies. Environ Health Perspect 1987;72:53-61.
Boorman GA, Uraih LC, Gupta BN, Bucher JR. Two-hour methyl isocyanate inhalation and 90 days recovery study in B6C3F1 mice. Environ Health Perspect 1987;72:63-9.
Bucher JR, Boorman GA, Gupta BN, Uraih LC, Hall LB, Stefanski SA. Two hour methyl isocyanate inhalation and 91-days recovery: A preliminary description of pathologic changes in F344 Rats. Environ Health Perspect 1987;72:71-5.
Stevens MA, Fitzgerald S, Ménache MG, Costa DL, Bucher JR. Functional evidence of persistent airway obstruction in rats following a two-hour inhalation exposure to methyl isocyanate. Environ Health Perspect 1987;72:89-94.
Indian Council of Medical Research. Ch. 4. Histopathological and Experimental Studies. Health eff ects of the toxic gas leak from Union Carbide methyl isocyanate plant in Bhopal: Technical report on Pathology and Toxicology (1984-1992); Ed. Sriramachari S Indian Council of Medical Research, New Delhi-110029; 2010. p. 24-28.
Indian Council of Medical Research. Ch. 4. Broncho-Alveolar Lavage (BAL) studies in MIC/Toxic gas aff ected people at Bhopal. Health eff ects of the toxic gas leak from Union Carbide Methyl Isocyanate plant in Bhopal: Technical report on Population based long term clinical studies (1985-1994); Ed. Sriramachari S Indian Council of Medical Research, New Delhi-110029 2008. p. 70-77.
Indian Council of Medical Research. Synopsis of clinical studies in methyl isocyante (MIC) Toxic gas exposed population in Bhopal. Health eff ects of the toxic gas leak from Union Carbide methyl Isocyanate plant in Bhopal: Technical report on Population based long term clinical studies (1985-1994); Ed. Sriramachari S Indian Council of Medical Research, New Delhi-110029; 2008. p. 3-22.
National Institute for Research in Environmental Health (ICMR): Guidelines for management of Chronic Obstructive Pulmonary Disease (COPD) in MIC Exposed subjects at Bhopal; 2013.
Andersson N, Kerr Muir M, Mehra V, Salmon AG. Exposure and response to methyl isocyanate: Result of community based survey in Bhopal. Br J Ind Med 1988;45:469-75.
Raizada JK, Mittal PC, Hafeez A. Follow up studies of ocular changes in MIC/Toxic gas exposed population of Bhopal on long term basis. The Health effects of the toxic gas leak from the union carbide Methyl Isocyanate Plant in Bhopal. Technical report on population based long term clinical studies (1985-1994). Indian Council of Medical Research; Ed. Sriramachari S Indian Council of Medical Research, New Delhi-110029; 2008. p. 147.
Pozzani UC, Kinked ER. Animal and human response to Methyl Isocyanate presented at the annual meeting of the American Industrial Hygiene Association Pittesb; 1966. p. 16-20. as quoted by Pushpa S Mehta et al.,
in Bhopal Tragedy′s health effect. JAMA 1990;264:2781-7.
Harding JJ. Rixon KC. Lens opacities induced in rat lenses by methyl isocyanate. Lancet 1985;1:762.
Andersson N, Ajwani MK, Mahashabde S, Tiwari MK, Muir MK, Mehra V, et al
. Delayed eye and other consequences from exposure to methyl isocyanate: 93% follow up of exposed and unexposed cohorts in Bhopal. Br J Ind Med 1990;47:553-8.
Gupta BN, SStefanski A, Butcher JR, Hall LB. Effect of methyl isocyanate (MIC) gas on eyes of Fischer 344 rats. Enviorn Health Perspect 1987;72:105-8.
Karol MH, Taskar S, Gangal S, Rubanoff BF, Kamat SR. The antibody response to methyl isocyanate: An experimental and clinical findings. Eviron Health Perspect 1987;72:169-75.
Dwivedi PD, Mishra A, Gupta GS, Dutta KK, Das SN, Ray PK. Inhalation toxicity studies of methyl isocyanate (MIC) in rats: Part IV--Immunologic response of rats one week post exposure: Effect on body and organ weights, phagocytic and DTH response. Indian J Exp Biol 1988;26:191-4.
Saxena AK, Singh KP, Dutta KK, Gupta GS, Nagle SL, Mishra A, et al
. Inhalation toxicity of methyl isocyanate (MIC) in rats Part V--immunologic response of rats two weeks after exposure; Phagocytic response, endotoxin susceptibility, local lung immunity, mitogenic and DTH response. Indian J Exp Biol 1988;26:195-200.
Tucker AN, Bucher JR, Germolec DR, Silver MT, Vore SJ, Luster MI. Immunological studies on mice exposed subacutely to methyl isocyanate. Environ Health Perspect 1987;72:139-41.
Deo MG, Gangal S, Bhisey AN, Somsundaram R, Balsara B, Gulwani B, et al
. Immunological, mutagenic and genotoxic investigations in gas exposed population of Bhopal. Indian J Med Res 1987;86:63-76.
Saxena AK, Singh KP, Nagle SL, Gupta BN, Ray PK, Srivastav RK, et al
. Effect of exposure to toxic gas on the population of Bhopal: Part IV-Immunological and chromosomal studies. Indian J Exp Biol 1988;26:173-6.
Karol MH, Kamat SR. The antibody response to methyl isocyanate: Experimental and clinical findings. Bull Eur Physiopathol Respir 1987;23:591-7.
In: Krieger R, Ed. Handbook of Pesticide Toxicology. 2 nd
ed. Vol. 1. San Diego: Academic Press; 2001. p. 597.
Saxena AK, Paul BN, Sinha M, Dutta KK, Das SN, Ray PK. A study on the B cell activity in protein deficient rats exposed to methyl isocyanate vapour. Immunopharmacol Immunotoxicol 1991;13:413-24.
Ghosh BB, Sengupta S, Roy A, Maity S, Ghosh S, Talukder G, et al
. Cytogenetic studies in human populations exposed to gas leak at Bhopal, India. Environ Health Perspect 1990;86:323-6.
Lakkad BC, Karnik AB, Shishir N, Suthar AM, Patel MM, Desai UM, et al
. Cytogenetic evaluation of persons exposed to methyl isocyanate at Bhopal. Indian J Indust Med 1996;42:203-5.
Mason JM, Zeiger E, Haworth S, Ivett J, Valencia R. Genotoxicity studies of methyl isocyanate in Salmonella, Drosophila, and cultured Chinese hamster ovary cells. Environ Mutagen 1987;9:19-28.
American Conference of Governmental Industrial Hygienists. Documentation of the TLV′s and BEI′s with Other World Wide Occupational Exposure Values. CD-ROM OH 45240-1634 Cincinnati; 2005. p. 2. http://toxnet.nlm.nih.gov/cgi-
Kar RN, Khan KA, Sethi N. Genotoxicity studies on mice after short term inhalation exposure to methyl isocyanate. Cytobios 1989;59:167-76.
Kligerman D, Campbell JA, Erexson GL, Allen JW, Shelby MD. Sister chromatid exchange analysis in lung and peripheral blood lymphocytes of mice exposed to methyl isocyanate by inhalation. Environ Mutagen 1987;9:29-36.
Tice RR, Luke CA, Shelby MD. Methyl isocyanate: An evaluation of in vivo
cytogenetic activity. Environ Mutagen 1987;9:37-58.
Conner MK, Rubinson HF, Ferguson JS, Stock MF, Alarie Y. Evaluation of sister chromatid exchange, and cytotoxicity in murine tissue in vivo
and Lymphocytes in vitro
following methyl isocyanate exposure. Environ Health Perspect 1987;72:177-82.
Meshram GP, Rao KM. Mutagenicity of methyl isocyanate in the modified test conditions of Ames Salmonella/microsome liquid-preincubation procedure. Mutat Res 1988;204:123-9.
Meshram GP, Rao KM. Cytogenetic activity of methyl isocyanate in vivo
in the mouse micronucleus test. Toxicol Lett 1988;42:65-71.
Dutta KK, Gupta GS, Mishra A, Joshi A, Tandon GS, Roy PK. Inhalation toxicity study of methyl isocyanate (MIC) in rats: Part I-Pulmonary pathology and genotoxicity evaluation. Indian J Exp Biol 1988;26:177-82.
Tamura N, Aoki K, Lee MS. Selective reactivities of isocyanates towards DNA bases and genotoxicity of methylcarbamoylation of DNA. Mutat Res 1992;283:97-106.
Shelby MD, Allen JW, Caspary WJ, Howerth S, Ivett J, Kligerman A, et al
. Results of in vitro
and in vivo
, genetic toxicity tests on methyl isocyanate. Enviorn Health Perspect 1987;72:183-7.
Daniel CS, Singh AK, Siddiqui P, Mathur BB, Das SK, Agarwal SS. Prelimanary report on the spermatogenic function of male subjects exposed to gas at Bhopal. Indian J Med Res 1987;86:83-6.
Arora U, Vijayaragahvan R. Effect of subacute exposure to methyl isocyanate on testicular histomorphology in mice. Indian J Exp Biol 1989;27:347-9.
Bose M, Vachhrajani KD, Jha BS, Dutta KK. Methyl isocyanate induced morphological changes in the seminiferous epithelium of rats maintained on normal or protein deficient diets. Bull Environ Contam Toxicol 1994;52:656-61.
Agarwal DK, Bose M. Inhalation toxicity of methylisocyanate: Assessment of germ cell mutagenicity and reproductive effects in rats. Indian J Exp Biol 1992;30:504-8.
Schwetz BA, Adkins B Jr, Harris M, Moorman M, Sloane R. Methyl isocyanate: Reproductive and developmental toxicology studies in Swiss mice. Environ Health Perspect 1987;72:149-52.
Bang R, Sadgopal M. Effect of Bhopal disaster on women′s health: An epidemic of gynecological diseases. In: Distorted Lives: Women′s Reproductive Health and Bhopal Disaster. Part I. Medico Friend Circle, Oct. 1990.
Verma DR. Epidemiology and experimental studies on the effect of methyl isocyanate on the course of Pregnancy. Environ Health Perspect 1987;72:153-7.
Varma DR. Pregnancy complications in Bhopal women exposed to methyl isocyanate vapor. J Environ Sci Health 1991;26:1437-47.
Kapoor R. Fetal loss and contraceptive acceptance among the Bhopal gas victims. Soc Biol 1991 Fall-Winter; 38:242-8.
Bhandari NR, Syal AK, Kambo I, Nair A, Beohar V, Sexena NC, et al
. Pregnancy outcome survey in women exposed to toxic gas at Bhopal. Indian J Med Res 1990;92:28-33.
Varma DR, Guest I, Smith S, Mulay S. Dissociation between maternal and fetal toxicity of methyl isocyanate in mice and rats. J Toxicol Environ Health 1990;30:1-14.
Singh RK, Srivastava A, Sethi N, Dayal R. Teratological studies on methylisocyanate in Charles Foster rats (part - II). Biol Mem 1996;22:21-5.
Indian Council of Medical Research. Health effect of toxic gas leak from Union Carbide Methyl Isocyanate plant in Bhopal: Technical report on population based long term clinical studies (1985-1994). Ed. Sriramachari S Indian Council of Medical Research, New Delhi-110029; p. 116-121.
Sethi BB, Sharma M, Trivedi JK, Singh H. Psychiatirc morbidities in patients attending clinics in gas affected areas in Bhopal. Indian J Med Res 1987;86:45-50.
Gupta BN, Rastogi SK, Chandra H, Mathur AK, Mathur N, Mahendra PN, et al
. Effect of exposure to toxic gas on the population of Bhopal: Part I--Epidemiological, clinical, radiological, and behavioral studies. Indian J Exp Biol 1988;26:149-60.
Misra UK, Kalita J. A study of cognitive functions in methyl-iso-cyanate victims one year after Bhopal accident. Neurotoxicology 1997;18:381-6.
Indian Council of Medical Research. Health effect of toxic gas leak from Union Carbide Methyl Isocyanate plant in Bhopal: Technical report on population based long term clinical studies (1985-1994). Ed. Sriramachari S Indian Council of Medical Research, New Delhi-110029; 2008. p. 132-146.
In report of International Medical Commission on Bhopal (1994) as quoted by Mental Health Care for Medical Officers of Bhopal: Manual; Jan. 2013 unpublished draft.
Jeevaratnam K, Vidya S. In vitro
and in vivo
effects of methyl isocyanate on rat brain mitochondrial respiration. Arch Environ Contam Toxicol 1994;27:272-5.
Anderson D, Goyle S, Philips BJ, Tee A, Beech L, Butler WH. Effect of methyl isocyanate on rat muscle cells in culture. Br J Ind Med 1988;45:269-74.
Huang SH, Chang WN, Chen SF, Wang PW, Lui CC, Tu MC, et al
. Tc99m-sestamibi thigh SPECT/CT images for noninvasive assessment of skeletal muscle injury in carbon monoxide intoxication with clinical and pathological correlation. Clin Nucl Med 2011;36:199-205.
Bucher JR, Uraih LC, Hildebrandt PK, Sauer RM, Seely JC. Carcinogenicity and pulmonary pathology associated with a single 2-hour inhalation exposure of laboratory rodents to methyl isocyanate. J Natl Cancer Inst 1989;81:1586-7.
Arora U, Vijayaraghavan R, Sugendran K, Mathur R. Bile duct hyperplasia and transient liver parenchymal cell alteration by methylisocyanate. Bull Environ Contam Toxicol 1993;51:211-8.
Dikshit RP, Kanhere S. Cancer patterns of lung, oropharynx and oral cavity cancer in relation to gas exposure at Bhopal. Cancer Causes Control 1999;10:627-36.
National Cancer Registry Programme. Cancer in Bhopal: Comparision of cancer pattern in MIC affected and unaffected areas (1988-2007). Indian Council of Medical Research, Banglore; 2010.
IARC. Monograph on the evaluation of the carcinogenic risk of chemicals to man. Vol. 49 international agency for research on cancer, Lyon; 1982. p. 14. http://monographs.iarc.fr/ENG
U. S. Environmental Protection Agency. Health and Environmental Effects Profile for Methyl Isocyanate. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment. Cincinnati: Office of Research and Development; 1986.
Jeevaratnam K, Sriramachari S. Acute histopathological changes induced by methyl isocyanatein lungs, liver and kidneys and spleen of rats. Indian J Med Res 1994;99:231-5.