COVID-19 mortality in 1984 Bhopal gas tragedy survivors: implications for chemically exposed populations.

Leakage of methyl isocyanate from the Union Carbide plant in Bhopal, India, killed thousands and left deleterious trans-generational effects. Gas-exposed populations experience higher rates of lung and metabolic diseases, and immune dysregulation, all associated with adverse outcomes in coronavirus disease 2019 (COVID-19). We used publicly available, official data from government sources to estimate COVID-19-associated crude mortality in populations with and without a history of gas exposure. Overall, there were 1240 deaths among patients hospitalized with known COVID-19 in Bhopal, of which 453 (36.53%) were in gas-exposed individuals, 726 (58.55%) were in gas-unexposed individuals and the exposure status of 61 (4.92%) individuals could not be determined. There were 351 and 375 deaths in gas-unexposed people in the first (April 2020-February 2021) and second (March 2021-July 2021) waves, respectively; in the gas-exposed population, there were 300 and 153 deaths in the two respective waves. The overall annualized crude mortality of COVID-19 was 3.84 (95% CI 3.41 to 4.33) times higher in the gas-exposed population at 83.6 (95% CI 76.1 to 91.7) per 100 000 compared with the gas-unexposed population, at 21.8 (95% CI 20.2 to 23.4) per 100,000. When stratified by age, compared with unexposed people, the gas-exposed individuals experienced 1.88 (95% CI 1.61 to 2.21) and 1.24 (95% CI 1.02 to 1.50) times the mortality rates in the age groups of 35-65 and >65 y, respectively. These findings indicate that gas-exposed individuals are likely to have a higher risk of severe COVID-19 and death and need to be specifically targeted and recognized for preventive and promotive efforts.

COVID-19: a review on SARS-CoV-2 origin, epidemiology, virology, clinical manifestations and complications with special emphasis on adverse outcome in Bhopal Gas Tragedy survivor.

After the global outbreak of coronaviruses caused diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), an outbreak due to these viruses occurred in December, 2019 in Wuhan, Hubei Province, China and led to a worldwide spread. Coronavirus 2019 disease (COVID-19) has emerged as a serious global health emergency and spread from a person to another who has the virus. But the scope of an intermediate host is not known. Population at higher risk includes individuals in higher age group (>60 years) or with comorbidities such as diabetes, hypertension, cardiovascular disease and weaker immune system. Many unknown and underestimate risk factors could be responsible for adverse outcomes in COVID-19. These risk factors should be appropriately identified, addressed and necessary actions should be taken to mitigate the effect of COVID-19 pandemic. Bhopal gas tragedy was one of the world's worst industrial chemical leak disaster. The survivors of this incident still suffer from the various complications such as increased rate of cancers, chronic illness like tuberculosis, respiratory diseases, birth defects, nerve injury, growth retardations, gynecological illness and many more. The survivors of Bhopal gas tragedy are at higher risk of developing COVID-19 related adverse outcome. One of the possible explanations can be long term effect of methyl isocyanate (MIC). MIC exposure can lead to possible toxic effect on genetic, epigenetic and non-genetic factors. In this review, we aim to establish the scientific basis for adverse outcome in COVID-19 patients who are also victims of Bhopal gas tragedy.

Chronic respiratory morbidity in the Bhopal gas disaster cohorts: a time-trend analysis of cross-sectional data (1986-2016).

OBJECTIVES: In 1984, nearly 500,000 inhabitants of Bhopal city, India, were exposed to toxic gases that leaked from a nearby pesticide manufacturing plant. In 1985, four cohorts were established to assess the long-term health impact of exposure, namely, mild, moderate, severely exposed and unexposed groups. The self-reported morbidity data of these cohorts were collected by follow-up cross-sectional surveys at regular intervals over the last 35 years. The present study aimed to analyse the long-term trend of chronic (duration of symptoms >3 months) respiratory morbidity in the four cohorts, stratified by age groups. STUDY DESIGN: The design of this study is a longitudinal analysis of cross-sectional respiratory morbidity data. METHODS: Chronic respiratory morbidity data within the cohorts were analysed at 5-year intervals (first recorded data from 1986). Based on age at the time of exposure, subjects were stratified into four age groups: children (aged <10 years), teenagers (aged ≥10 to <20 years), younger adults (aged ≥20 to <40 years) and older adults (aged ≥40 years). RESULTS: During the first decade, after exposure to the toxic gases, chronic respiratory morbidity in children and teenagers was high (up to 9.1%), which declined thereafter. Progressively increasing chronic respiratory morbidity was observed in both the younger and older adult age groups within all cohorts during the initial 5-10 years after exposure. Respiratory morbidity in both the younger and older adult age groups remained high for 15-20 years and thereafter recorded a declining trend. The highest respiratory morbidity observed during this study in the younger and older adult age groups was 38.6% and 59.5%, respectively; these values were both recorded in the severely exposed cohort. CONCLUSIONS: Exposure to toxic gases released during the Bhopal gas disaster has resulted in chronic respiratory morbidity of the exposed population; this morbidity has continued over decades. The age of the individuals at the time of exposure and exposure severity were crucial determinants of the long-term trend of respiratory morbidity.

Spectrum of health condition in methyl isocyanate (MIC)-exposed survivors measured after 30 years of disaster.

Health effects of methyl isocyanate (MIC) exposure were mostly reported on the one-time acute exposure in Bhopal population. Epidemiological survey conducted by the Indian apex body of health research has been reported as Technical Reports, which were lacking in peer review by the expert epidemiologic scientists. The present pilot survey was aimed to measure the health effects 30 years post disaster in MIC-exposed survivors. Questionnaire-based survey has captured every health complaint in 168 individuals and grouped as systemic functions for interpreting the long-term effects of MIC. Key health parameters, including reproductive outcome and respiratory/orthopedic/general morbidity, were prevalent among the severely exposed population compared to control and moderately exposed groups. The collective incidence of diabetes, hypertension, and cancer also was prevalent in the severely exposed group. Ophthalmic morbidity was almost similar in the three groups, rather with higher incidence in the control group, though not statistically significant. Among all health parameters, reproductive, ophthalmic, and respiratory effects were prevalent over others. Although the incidence of health problems has been declined among the survivors, long-term effect is apparent as scars of one-time acute exposure might trigger sequel of long-term effects. Additionally, acquisition of genetic rearrangements, survival of T cell sub-populations, variable latency of chemical effect on DNA nucleosides, nutritional status, occupational exposure, living environment, lifestyle, and overall gene-environment interaction might perturb individual immunity and favor onset of long-term illness in a scenario of background exposure to MIC. However, the exercise should be continued on a larger sample size for drawing a conclusive result on long-term MIC effect on survivors' health.

Cytogenetic changes in the Bhopal population exposed to methyl isocyanate (MIC) in 1984: Then and 30 years later.

Following the 1984 Bhopal methyl isocyanate (MIC) gas disaster, genetic alterations were sporadically reported on small cohorts. However, the outcome of the multi-center cytogenetic screening conducted at that time remains unknown and no follow-up studies on the long-term effects of MIC exposure have been published. The present work examines genetic changes in the exposed population,with the aim of identifying any long-term effects of MIC. G-Banded metaphases were studied in lymphocytes of 130 individuals. Chromosomal aberrations (CA) were broadly grouped as abnormal cells (Abc), aberrations (Abn), and aberration/abnormal cell (Abn/Abc). From the previous multi-center screening, 946 records were retrieved, from which CA, sister chromatid exchanges (SCE), and cell-cycle kinetics (RI) were computed. In our analysis of the previous study, Abc and Abn were higher in the moderately and severely exposed groups than in the unexposed population. Abc appeared uniform in all groups of the present study, although Abn and Abn/Abc were higher in the exposed groups. Aberrations were now significantly higher in the unexposed and moderately exposed groups than in the previous screening. Although Abn and Abc now appeared lower in severely exposed subjects, the Abn/Abc ratio was higher, perhaps due to more rearrangements and damage in a smaller number of Abc. This result may be attributed to differences between the methods used in the studies, then and now. Elevated SCEs and reduced RI were seen in the severely exposed population shortly after exposure, and stable/clonal rearrangements were seen 30 y later. Follow-up of index cases and their progenies is needed.

A comparative assessment of major international disasters: the need for exposure assessment, systematic emergency preparedness, and lifetime health care.

BACKGROUND: The disasters at Seveso, Three Mile Island, Bhopal, Chernobyl, the World Trade Center (WTC) and Fukushima had historic health and economic sequelae for large populations of workers, responders and community members. METHODS: Comparative data from these events were collected to derive indications for future preparedness. Information from the primary sources and a literature review addressed: i) exposure assessment; ii) exposed populations; iii) health surveillance; iv) follow-up and research outputs; v) observed physical and mental health effects; vi) treatment and benefits; and vii) outreach activities. RESULTS: Exposure assessment was conducted in Seveso, Chernobyl and Fukushima, although none benefited from a timely or systematic strategy, yielding immediate and sequential measurements after the disaster. Identification of exposed subjects was overall underestimated. Health surveillance, treatment and follow-up research were implemented in Seveso, Chernobyl, Fukushima, and at the WTC, mostly focusing on the workers and responders, and to a lesser extent on residents. Exposure-related physical and mental health consequences were identified, indicating the need for a long-term health care of the affected populations. Fukushima has generated the largest scientific output so far, followed by the WTCHP and Chernobyl. Benefits programs and active outreach figured prominently in only the WTC Health Program. The analysis of these programs yielded the following lessons: 1) Know who was there; 2) Have public health input to the disaster response; 3) Collect health and needs data rapidly; 4) Take care of the affected; 5) Emergency preparedness; 6) Data driven, needs assessment, advocacy. CONCLUSIONS: Given the long-lasting health consequences of natural and man-made disasters, health surveillance and treatment programs are critical for management of health conditions, and emergency preparedness plans are needed to prevent or minimize the impact of future threats.

On the long-term effects of methyl isocyanate on cell-mediated immunity in Bhopal gas-exposed long-term survivors and their offspring.

Methyl isocyanate (MIC) is a toxic industrial chemical that is documented as a potent respiratory toxicant. We investigated cell-mediated immunity (CMI) in the MIC-exposed long-term survivors and their offspring born after the Bhopal gas-leak tragedy in 1984. Several earlier reports show inconsistency in the assessment of immunological effects of MIC on the human population. In these studies, important factors including lifestyle attributes were overlooked. We incorporated these factors also in our study of the basic cell-mediated immune function in the Bhopal MIC-affected population. Twenty-seven years after exposure, we assessed the circulating T-lymphocyte frequency using E-Rosette assay. A total of 46 MIC-exposed healthy long-term survivors and their offspring were studied vis-a-vis parallel gender-age group-matched unexposed controls from Bhopal and various other regions of India. The influence of several lifestyle variabilities (smoking, alcohol intake, and tobacco chewing) on T-lymphocyte frequency was also taken into consideration. Our observations suggest that Erythrocyte-Rosette-forming cell (E-RFC) distribution frequency is largely insignificant in the MIC-affected population as compared to controls ( p > 0.05). In the MIC-affected tobacco chewers, there was a trend of suppression in CMI (relative decrease = 10.3%) as compared to nonchewers. Overall, our results show negligible long-term effect of MIC on CMI measured in terms of E-RFC frequency. These observations are not in agreement with earlier findings that immunosuppressive effects of MIC exposure persist in the T-cells of the affected population. However, atypical lymphocytes were frequently observed as E-RFC in the exposed females when compared to all other subgroups. Hematopoietic disorders (atypical lymphocytosis) in the MIC-affected population along with previous reports on the cytogenetic and humoral immune system linking cancer risk and chronic obstructive pulmonary disease (COPD) are important.

Cells With Chromosomal Aberrations Trigger Neoplastic Transformations in Humans.

Human population cytogenetic studies have revealed that a majority of persons who are prone to developing malignant features possess chromatin bodies termed as marker dots (MDs) measuring nearly 2 to 3 microns. These MDs are seen emanating from certain specific chromosomes, which may be early indicators of neoplastic transformation within cells.

Molecular bio-dosimetry for carcinogenic risk assessment in survivors of Bhopal gas tragedy.

December 2014 marked the 30th year anniversary of Bhopal gas tragedy. This sudden and accidental leakage of deadly poisonous methyl isocyanate (MIC) gas instigated research efforts to understand the nature, severity of health damage and sufferings of 570 000 ailing survivors of this tragedy. In a decade-long period, our systematic laboratory investigations coupled with long-term molecular surveillance studies have comprehensively demonstrated that the risk of developing an environmental associated aberrant disease phenotype, including cancer, involves complex interplay of genomic and epigenetic reprogramming. These findings poised us to translate this knowledge into an investigative framework of "molecular biodosimetry" in a strictly selected cohort of MIC exposed individuals. A pragmatic cancer risk-assessment strategy pursued in concert with a large-scale epidemiological study might unfold molecular underpinnings of host-susceptibility and exposureresponse relationship. The challenges are enormous, but we postulate that the study will be necessary to establish a direct initiation-promotion paradigm of environmental carcinogenesis. Given that mitochondrial retrograde signaling-induced epigenetic reprogramming is apparently linked to neoplasticity, a cutting-edge tailored approach by an expert pool of biomedical researchers will be fundamental to drive these strategies from planning to execution. Validating the epigenomic signatures will hopefully result in the development of biomarkers to better protect human lives in an overburdened ecosystem, such as India, which is continuously challenged to meet population demands. Besides, delineating the mechanistic links between MIC exposure and cancer morbidity, our investigative strategy might help to formulate suitable regulatory policies and measures to reduce the overall burden of occupational and environmental carcinogenesis.

Increased micronucleus frequency in peripheral blood lymphocytes contributes to cancer risk in the methyl isocyanate-affected population of Bhopal.

The Bhopal gas tragedy involving methyl isocyanate (MIC) is one of the most horrific industrial accidents in recent decades. We investigated the genotoxic effects of MIC in long-term survivors and their offspring born after the 1984 occurrence. There are a few cytogenetic reports showing genetic damage in the MIC-exposed survivors, but there is no information about the associated cancer risk. The same is true about offspring. For the first time, we here assessed the micronucleus (MN) frequency using cytokinesis-blocked micronucleus (CBMN) assay to predict cancer risk in the MIC-affected population of Bhopal. A total of 92 healthy volunteers (46 MIC- affected and 46 controls) from Bhopal and various regions of India were studied taking gender and age into consideration. Binucleated lymphocytes with micronuclei (BNMN), total number of micronuclei in lymphocytes (MNL), and nuclear division index (NDI) frequencies and their relationship to age, gender and several lifestyle variabilities (smoking, alcohol consumption and tobacco-chewing) were investigated. Our observations showed relatively higher BNMN and MNL (P<0.05) in the MIC-affected than in the controls. Exposed females (EF) exhibited significantly higher BNMN and MNL (P<0.01) than their unexposed counterparts. Similarly, female offspring of the exposed (FOE) also suffered higher BNMN and MNL (P<0.05) than in controls. A significant reduction in NDI (P<0.05) was found only in EF. The affected group of non-smokers and non-alcoholics featured a higher frequency of BNMN and MNL than the control group of non-smokers and non-alcoholics (P<0.01). Similarly, the affected group of tobacco chewers showed significantly higher BNMN and MNL (P<0.001) than the non-chewers. Amongst the affected, smoking and alcohol consumption were not associated with statistically significant differences in BNMN, MNL and NDI. Nevertheless, tobacco-chewing had a preponderant effect with respect to MNL. A reasonable correlation between MNL and lifestyle habits (smoking, alcohol consumption and tobacco-chewing) was observed only in the controls. Our results suggest that EF and FOE are more susceptible to cancer development, as compared to EM and MOE. The genotoxic outcome detected in FOE reflects their parental exposure to MIC. Briefly, the observed cytogenetic damage to the MIC-affected could contribute to cancer risk, especially in the EF and FOE.

A retrospective review of cytogenetic studies on methyl isocyanate with special reference to the Bhopal gas tragedy: is the next generation also at risk?

The world's worst industrial disaster, at Union Carbide, Bhopal, India, took place on 2-3 December 1984, leading to the leakage of poisonous methyl-isocyanate into the environment, causing thousands of deaths, pregnancy loss and for some, incapacitation for life. More than a quarter of a century later, the Indian Council of Medical Research undertook to redefine the abysmal consequences of the toxic gas exposure on the exposed population. This invigorated the interest of scientific community in the evaluation of the long-term effects, with reference to cytogenetic parameters. The thrust area was identified in terms of genetic disorders, low birth weight, developmental/growth disorders and congenital malformations. Also the impact on epigenetic factors, which may have contributed to variations in the functional expression of genes, was not negated, stimulating intense scientific research on in utero exposure and the progeny of the exposed population. To accomplish this mammoth task, molecular cytogenetic investigations must be undertaken in conjunction with conventional cytogenetics, using techniques such as FISH, Immuno-FISH, SKY and SNP analysis, to build up a cytogenetic database of the surviving population.

Epidemiologic methods lessons learned from environmental public health disasters: Chernobyl, the World Trade Center, Bhopal, and Graniteville, South Carolina.

BACKGROUND: Environmental public health disasters involving hazardous contaminants may have devastating effects. While much is known about their immediate devastation, far less is known about long-term impacts of these disasters. Extensive latent and chronic long-term public health effects may occur. Careful evaluation of contaminant exposures and long-term health outcomes within the constraints imposed by limited financial resources is essential. METHODS: Here, we review epidemiologic methods lessons learned from conducting long-term evaluations of four environmental public health disasters involving hazardous contaminants at Chernobyl, the World Trade Center, Bhopal, and Graniteville (South Carolina, USA). FINDINGS: We found several lessons learned which have direct implications for the on-going disaster recovery work following the Fukushima radiation disaster or for future disasters. INTERPRETATION: These lessons should prove useful in understanding and mitigating latent health effects that may result from the nuclear reactor accident in Japan or future environmental public health disasters.

Bhopal atmospheric dispersion revisited.

There is a vital need to understand details of the methylisocyanate (MIC) release that occurred at the 1984 Union Carbide Ltd. pesticide plant in Bhopal, India in order to avoid or respond to such releases in the future. However, we believe there are serious deficiencies in currently available dispersion predictions of the impact of toxic materials on humans and animals downwind of the plant. Specifically, cloud densities have been underestimated due to failure to account for the presence of a liquid/solid aerosol that would have been produced by the chemical reactions that caused the problem. Using data reported in Union Carbide's own investigation of the accident, which included chemical reaction data, we estimated aerosol compositions and cloud densities, then modeled the Bhopal release, simulating potential exposure levels at various locations under a number of wind-condition scenarios. For the worst-case (low wind speed and high aerosol densities), our predicted MIC concentrations at ground level are at least one order of magnitude greater than any previously published estimates. The centerline elevation of the jetting plume released at 33 m elevation is predicted to rise to about 41 m before falling, resulting in a 40 ppm (Immediately Dangerous to Life or Health, IDLH) concentration contour that reaches the ground at about 410 m downwind of the release location. This is consistent with observations that the plant environs were not hard-hit while the public immediately downwind of the plant perimeter was severely exposed. Concentrations on the order of 1000 ppm are predicted at some ground-level locations, which are more consistent than previous estimates with the reported large numbers of deaths and injuries of humans and animals.