1) Autopsies of victims found severe pulmonary edema and a "cherry red" discoloration of the lungs. Microscopic analysis showed damage to the trachea and lungs, including thickened alveolar septa and fluid-filled alveoli.
2) Further autopsies over subsequent years found progressive pulmonary fibrosis and right heart failure. Later autopsies showed more organized fibrosis in the lungs.
3) The study resolved several issues around the progression of injuries from the gas leak and confirmed exposure to multiple toxic chemicals including methyl isocyanate and hydrogen cyanide.
This document summarizes research on the use of hyperbaric oxygen therapy (HBO2) in orthopedic conditions. It discusses how HBO2 has been used in Japan since the 1960s to treat conditions like decompression illness, carbon monoxide poisoning, and crush injuries. The author's hospital has treated over 4,000 patients with 145,700 HBO2 treatments since 1981 for various orthopedic issues like osteomyelitis, crush injuries, and refractory ulcers. HBO2 is believed to help reduce edema, improve oxygen delivery to tissues, and boost the immune system's ability to fight infection.
This study examined cellular immune activation in Gulf War veterans by measuring cytokine production in CD4 T cells. The study compared symptomatic Gulf War veterans (sGWV) to well Gulf War veterans (wGWV) and symptomatic veterans who served in Bosnia or were nondeployed military personnel from the same era (sBEV). The key findings were:
1) sGWV showed evidence of ongoing Th1-type immune activation with elevated levels of IFN-γ and IL-2 producing CD4+ cells compared to wGWV.
2) sGWV also had elevated levels of IL-10 producing memory CD4 cells after polyclonal activation compared to other groups.
3) There was a trend of reduced IFN
Ambush marketing is the unauthorized association of a business with a sponsored event to gain marketing benefits without paying licensing fees. It has a long history, including at the Olympics where Nike famously ambushed sponsor Adidas. Forms include suggestive advertising, blocking sponsor logos, and stunts. It raises ethical issues by confusing consumers and undermining official sponsors. Events now have stricter rules to limit ambush marketing tactics.
Gamification techniques are being applied to learning management systems (LMS) to increase student engagement and motivation. Game elements like points, levels, challenges, and leaderboards are added to traditional LMS to inspire competition and make learning feel more like play. These gamified LMS aim to improve learner retention and performance through intrinsic and extrinsic motivators.
This document summarizes an initiative called ".Asia" that promotes adopting affordable cloud-based ICT solutions to help small and medium enterprises (SMEs) in Malaysia increase profits and reduce costs. It discusses how SMEs are important to Malaysia's economy and why ICT adoption is crucial for their competitiveness. The document also provides examples of cloud-based solutions and addresses common questions about security, uptime, internet requirements, industries, and training. Next steps mentioned are holding business workshops and providing a reseller portal to access ICT solutions on the cloud.
This document discusses blended learning and provides examples of how organizations have implemented blended learning programs. It defines blended learning as combining formal and informal learning strategies by integrating online and in-person learning experiences. The document outlines how to increase the success of blended learning programs through the use of a blended learning portal, and provides two examples of organizations that achieved cost savings and increased completion rates using blended learning portals for self-study and virtual classroom programs. Participant feedback on blended learning programs is also presented.
The document discusses how failure is viewed differently in Silicon Valley compared to Europe. In Silicon Valley, failure is seen as a normal part of innovating and entrepreneurs are encouraged to "fail fast and fail often." Failure is more of a badge of honor and learning experience. In contrast, failure carries a much greater stigma in Europe where bankruptcy can be more punitive and seen as a personal tragedy. This difference in culture influences the level of risk-taking and entrepreneurship.
Here are some potential discussion questions I might ask after watching the Leaders vs. Managers video:
- How do you see the roles of leaders and managers playing out in your own organization? Have you observed examples of both effective leadership and management?
- What are some challenges you've faced in transitioning from a manager role to a leadership role (or vice versa)? How can individuals strengthen their abilities in the other domain?
- The video suggests leaders are focused more on change and the future while managers focus on stability and efficiency. Do you agree with this characterization? Why or why not?
- What additional skills or mindsets do you think are important for individuals to develop to be successful as both leaders and managers? How
This document summarizes research on the use of hyperbaric oxygen therapy (HBO2) in orthopedic conditions. It discusses how HBO2 has been used in Japan since the 1960s to treat conditions like decompression illness, carbon monoxide poisoning, and crush injuries. The author's hospital has treated over 4,000 patients with 145,700 HBO2 treatments since 1981 for various orthopedic issues like osteomyelitis, crush injuries, and refractory ulcers. HBO2 is believed to help reduce edema, improve oxygen delivery to tissues, and boost the immune system's ability to fight infection.
This study examined cellular immune activation in Gulf War veterans by measuring cytokine production in CD4 T cells. The study compared symptomatic Gulf War veterans (sGWV) to well Gulf War veterans (wGWV) and symptomatic veterans who served in Bosnia or were nondeployed military personnel from the same era (sBEV). The key findings were:
1) sGWV showed evidence of ongoing Th1-type immune activation with elevated levels of IFN-γ and IL-2 producing CD4+ cells compared to wGWV.
2) sGWV also had elevated levels of IL-10 producing memory CD4 cells after polyclonal activation compared to other groups.
3) There was a trend of reduced IFN
Ambush marketing is the unauthorized association of a business with a sponsored event to gain marketing benefits without paying licensing fees. It has a long history, including at the Olympics where Nike famously ambushed sponsor Adidas. Forms include suggestive advertising, blocking sponsor logos, and stunts. It raises ethical issues by confusing consumers and undermining official sponsors. Events now have stricter rules to limit ambush marketing tactics.
Gamification techniques are being applied to learning management systems (LMS) to increase student engagement and motivation. Game elements like points, levels, challenges, and leaderboards are added to traditional LMS to inspire competition and make learning feel more like play. These gamified LMS aim to improve learner retention and performance through intrinsic and extrinsic motivators.
This document summarizes an initiative called ".Asia" that promotes adopting affordable cloud-based ICT solutions to help small and medium enterprises (SMEs) in Malaysia increase profits and reduce costs. It discusses how SMEs are important to Malaysia's economy and why ICT adoption is crucial for their competitiveness. The document also provides examples of cloud-based solutions and addresses common questions about security, uptime, internet requirements, industries, and training. Next steps mentioned are holding business workshops and providing a reseller portal to access ICT solutions on the cloud.
This document discusses blended learning and provides examples of how organizations have implemented blended learning programs. It defines blended learning as combining formal and informal learning strategies by integrating online and in-person learning experiences. The document outlines how to increase the success of blended learning programs through the use of a blended learning portal, and provides two examples of organizations that achieved cost savings and increased completion rates using blended learning portals for self-study and virtual classroom programs. Participant feedback on blended learning programs is also presented.
The document discusses how failure is viewed differently in Silicon Valley compared to Europe. In Silicon Valley, failure is seen as a normal part of innovating and entrepreneurs are encouraged to "fail fast and fail often." Failure is more of a badge of honor and learning experience. In contrast, failure carries a much greater stigma in Europe where bankruptcy can be more punitive and seen as a personal tragedy. This difference in culture influences the level of risk-taking and entrepreneurship.
Here are some potential discussion questions I might ask after watching the Leaders vs. Managers video:
- How do you see the roles of leaders and managers playing out in your own organization? Have you observed examples of both effective leadership and management?
- What are some challenges you've faced in transitioning from a manager role to a leadership role (or vice versa)? How can individuals strengthen their abilities in the other domain?
- The video suggests leaders are focused more on change and the future while managers focus on stability and efficiency. Do you agree with this characterization? Why or why not?
- What additional skills or mindsets do you think are important for individuals to develop to be successful as both leaders and managers? How
Reporte coordinacion municipal de atencion a la juventud comajuveevilchucky
El documento resume las actividades realizadas por la Coordinación Municipal de Atención a la Juventud en Apizaco, incluyendo la realización de un concurso de cartas a los padres, el inicio de un programa de rescate de espacios públicos, una feria de salud y derechos para adolescentes, jornadas de limpieza, y cursos de primeros auxilios, así como la promoción de eventos juveniles durante la feria patronal.
The document provides an overview for starting your own eLearning business, including why you should start one, who should start one, what it takes to get started, how to find and retain clients, pricing, project execution, and considerations for the future. It discusses traits of successful entrepreneurs, developing a business plan and legal/financial setup, marketing strategies like networking and blogging, managing client expectations, pricing models, and common myths and reasons businesses can fail. The presentation ends with encouraging questions and contact information for following up.
The document provides an investor information summary for S.C. Pangiran Budi Service S.R.L. It includes details about the principal such as name, nationality, passport information, date of birth, occupation, business details, and contact information. It also lists bank drafts totaling USD 440 million and affirms that the information provided is true and accurate and that the funds comply with anti-money laundering policies.
Bob Brown was born in 1944 and graduated from Sydney University with a degree in medicine. He became an environmental activist and director of the Wilderness Society, being jailed twice for organizing protests against dams and logging. Brown was elected as the first Green party member of the Tasmanian Parliament and later the Australian Senate. As a senator, he introduced bills regarding climate change, wildlife protection, and other environmental and social issues. Brown received the Australian Peace Prize in 2009 for his commitment to peace, non-violence, and global justice.
The document is an invitation to attend a Commercialisation Lab hosted by AIM, a Malaysian government agency, to facilitate the commercialization of 43 innovations. The 3-day lab will involve presentations about the innovations to interested businesses. Those interested can then commit to further stages to license the innovations with support from AIM to overcome challenges in bringing the products to market. Attendees are encouraged to find new opportunities to grow their businesses and generate revenue through commercializing the innovations.
C:\fakepath\Impact of tsunami on soil propertiessekaran
The document discusses the impact of tsunamis on soil properties based on various research studies. It describes how tsunami waves can deposit mud and sediments on top of soils, increasing salinity and changing the soil profile. Research findings showed that salts in affected soils were quickly leached due to rainfall but nutrient imbalances from high sodium and low calcium levels remained, affecting crop growth. Studies analyzed changes in soil physical and chemical properties from tsunami deposits and found that while salinity reduced over time, issues like low fertility and compaction persisted in some areas.
The document discusses two topics related to studying consumer reviews: when reviews adequately portray a product or service, and seeing consumer relationships from an ecosystem perspective. Regarding the first topic, the document notes that more reviews generally converge on an assessment, but some products are polarizing. It also discusses how review sites indicate helpfulness and how this may signal when sufficient reviews have been reached. The second topic discusses how consumers connect businesses through their patronage, rather than just competition, and how analyzing these ecosystems can provide a richer understanding to help businesses with search advertising.
The document discusses a video email automation platform called Video Email that creates and delivers multiple optimized versions of a marketer's video to ensure compatibility with different email clients. It generates various video file formats like MP4, OGV, GIF, PNG, and FLV from an uploaded source video. When a recipient opens the email, the appropriate video file is rendered based on the capabilities of their mail client or browser to provide the best viewing experience.
This document provides information about an exhibition at the Virginia Museum of Fine Arts titled "Picasso: Masterpieces from the Musée National Picasso, Paris". The exhibition features over 170 works from Picasso's career spanning eight decades. It allows viewers to trace Picasso's life and the evolution of modern art in the 20th century. The works are from the largest collection of Picasso's work in the world. The exhibition provides insight into Picasso's artistic processes and explores his relationships and depictions of women throughout his career.
The document discusses the benefits of exercise for mental health. Regular physical activity can help reduce anxiety and depression and improve mood and cognitive functioning. Exercise causes chemical changes in the brain that may help protect against mental illness and improve symptoms.
The document contains periodic measurements of Rat%, Rat#, and Shr% between 23:43 and 24:28. Rat% ranges from around 3.2% to 6.1%, Rat# ranges from around 48.3 to 92.6, and Shr% ranges from around 13.8% to 24.4% over the course of the measurements.
This document provides a course plan for a subject called "Computer Application in Biotechnology" with 38 total lectures over 10 weeks. It includes the lecture content, assignments, and test dates. The lectures cover topics such as introductions to computers and biotechnology, hardware, software, memory, storage, input/output devices, the internet for biologists, databases, sequence analysis, and protein structure prediction. There are 3 assignments and 4 tests scheduled throughout the course.
Digital collaboration can increase student learning in several ways. It allows students to work jointly with others on intellectual endeavors using technology. This fits in all learning environments, whether face-to-face, blended, or virtual classrooms. Specific digital tools for collaboration include storytelling, polling, wikis, blogs, and collaborative questing. When used effectively, these tools engage students and help them move up Bloom's taxonomy of learning from lower to higher order thinking.
The document discusses the cosmic conflict between God and Satan that has been ongoing throughout history. It describes some of the major events in this conflict from the creation of the universe to Jesus' crucifixion and resurrection. The document also discusses how God has validated the Bible through the canonization process and archaeological evidence, and how lives have been transformed through reading it. It outlines a class that will discuss engaging with Muslims and call them to faith by comparing Christianity and Islam.
This chapter provides an introduction and overview of operating systems. It defines an operating system as a program that manages computer hardware and software resources and provides common services for computer programs. It describes the components of a computer system including hardware, operating system, application programs, and users. It then discusses the structure and functions of operating systems, including process management, memory management, storage management, protection and security, and distributed systems. It provides examples of different computing environments like traditional, client-server, peer-to-peer, and web-based computing.
Medical coding started as a way to track causes of death during outbreaks of the Black Death plague in the 14th century. Over time, standardized coding systems were developed to classify causes of mortality and morbidity. The current system used in the United States is ICD-10, an international standard endorsed by the World Health Organization in 1990. ICD-10 expanded the number of codes and added specificity compared to the previous ICD-9 system. ICD-10-CM is used for medical diagnoses and ICD-10-PCS for inpatient medical procedures.
Below is the minimum amount of material you should submit as an outl.docxaman341480
Below is the minimum amount of material you should submit as an outline. This one (from another course) received a grade of B and could have been improved by having more text in the outline describing the sections and more precise citations (that included page numbers). Lloyd
----------------------------
STUDENT NAME
HIST 285
Winter 2017
Health and Medicine During the Black Death, 1325-1350
Thesis: What were the roles of plague doctors during the Black Death in the fourteenth century?
Introduction: The Black Death was one of the largest pandemics in history. Today, it is known as the Black Plague or the bubonic plague. Medieval people called it “the blue sickness,”
La pest
(“the Pestilence”) and “the Great Mortality.” The word
bubonic
comes from the Latin word
bubo
or the Italian
bilbo,
meaning a pustule or swelling. It led to the deaths of 75 to 200 million people, peaking in Europe in the years 1346-53. Most of the victims died within three or four days of developing symptoms, while others died after two weeks. The plague spread throughout the Mediterranean and Europe, killing an estimated 30-60% of Europe’s total population. Most scholars believe the Black Plague was a bacterial strain of
Yersinia pestis
. Medieval doctors had no idea of what caused the Plague, and antibiotics were not available during this era. There were different types of doctors during this time period, and challenges came from a lack of fully qualified physicians to treat the number of patients. This paper will examine the reactions of physicians to the Black Death during the fourteenth century.
Part 1: Medical education and medical practices
Hippocrates and Galen
Education, physician vs surgeon
Untrained/unlicensed practitioners that emerged during the Plague
Part 2: Doctors acted as public servants (Wray)
Tasks included recording the deaths due to the plague
Plague doctors were requested to perform autopsies to help determine the cause of death
Plague doctors gave advice to their patients about their conduct before death. The relationship between doctor and patient was governed by a complex ethical code.
Part 3: What doctors believed caused the Black Death
Punishment from God
Miasmatic vapors, bad air
Improper balance of the four Humours (Slavicek)
Part 4: Methods (Cantor)
Doctors practiced bloodletting, putting frogs or leeches
Dung and urine and bad smells
Drinking vinegar, eating crushed minerals, arsenic, mercury
Conclusion: How search for cure led to scientific thinking during the Enlightenment
Bibliography
Primary Sources:
George
Deaux,
The Black Death 1347
. New York: Weybright and Talley, 1969. Chapter IV, pp. 75ff.
Secondary Sources:
Cantor, N. F. (2001).
In the wake of the plague: the Black Death and the world it made
. Simon and Schuster.
Siraisi, N. G. (2009).
Medieval and early Renaissance medicine: an introduction to knowledge and practice
. University of Chicago Press.
Slavicek, Louise Chipley.
The Black Death
. New York: Chelsea House, ...
Reporte coordinacion municipal de atencion a la juventud comajuveevilchucky
El documento resume las actividades realizadas por la Coordinación Municipal de Atención a la Juventud en Apizaco, incluyendo la realización de un concurso de cartas a los padres, el inicio de un programa de rescate de espacios públicos, una feria de salud y derechos para adolescentes, jornadas de limpieza, y cursos de primeros auxilios, así como la promoción de eventos juveniles durante la feria patronal.
The document provides an overview for starting your own eLearning business, including why you should start one, who should start one, what it takes to get started, how to find and retain clients, pricing, project execution, and considerations for the future. It discusses traits of successful entrepreneurs, developing a business plan and legal/financial setup, marketing strategies like networking and blogging, managing client expectations, pricing models, and common myths and reasons businesses can fail. The presentation ends with encouraging questions and contact information for following up.
The document provides an investor information summary for S.C. Pangiran Budi Service S.R.L. It includes details about the principal such as name, nationality, passport information, date of birth, occupation, business details, and contact information. It also lists bank drafts totaling USD 440 million and affirms that the information provided is true and accurate and that the funds comply with anti-money laundering policies.
Bob Brown was born in 1944 and graduated from Sydney University with a degree in medicine. He became an environmental activist and director of the Wilderness Society, being jailed twice for organizing protests against dams and logging. Brown was elected as the first Green party member of the Tasmanian Parliament and later the Australian Senate. As a senator, he introduced bills regarding climate change, wildlife protection, and other environmental and social issues. Brown received the Australian Peace Prize in 2009 for his commitment to peace, non-violence, and global justice.
The document is an invitation to attend a Commercialisation Lab hosted by AIM, a Malaysian government agency, to facilitate the commercialization of 43 innovations. The 3-day lab will involve presentations about the innovations to interested businesses. Those interested can then commit to further stages to license the innovations with support from AIM to overcome challenges in bringing the products to market. Attendees are encouraged to find new opportunities to grow their businesses and generate revenue through commercializing the innovations.
C:\fakepath\Impact of tsunami on soil propertiessekaran
The document discusses the impact of tsunamis on soil properties based on various research studies. It describes how tsunami waves can deposit mud and sediments on top of soils, increasing salinity and changing the soil profile. Research findings showed that salts in affected soils were quickly leached due to rainfall but nutrient imbalances from high sodium and low calcium levels remained, affecting crop growth. Studies analyzed changes in soil physical and chemical properties from tsunami deposits and found that while salinity reduced over time, issues like low fertility and compaction persisted in some areas.
The document discusses two topics related to studying consumer reviews: when reviews adequately portray a product or service, and seeing consumer relationships from an ecosystem perspective. Regarding the first topic, the document notes that more reviews generally converge on an assessment, but some products are polarizing. It also discusses how review sites indicate helpfulness and how this may signal when sufficient reviews have been reached. The second topic discusses how consumers connect businesses through their patronage, rather than just competition, and how analyzing these ecosystems can provide a richer understanding to help businesses with search advertising.
The document discusses a video email automation platform called Video Email that creates and delivers multiple optimized versions of a marketer's video to ensure compatibility with different email clients. It generates various video file formats like MP4, OGV, GIF, PNG, and FLV from an uploaded source video. When a recipient opens the email, the appropriate video file is rendered based on the capabilities of their mail client or browser to provide the best viewing experience.
This document provides information about an exhibition at the Virginia Museum of Fine Arts titled "Picasso: Masterpieces from the Musée National Picasso, Paris". The exhibition features over 170 works from Picasso's career spanning eight decades. It allows viewers to trace Picasso's life and the evolution of modern art in the 20th century. The works are from the largest collection of Picasso's work in the world. The exhibition provides insight into Picasso's artistic processes and explores his relationships and depictions of women throughout his career.
The document discusses the benefits of exercise for mental health. Regular physical activity can help reduce anxiety and depression and improve mood and cognitive functioning. Exercise causes chemical changes in the brain that may help protect against mental illness and improve symptoms.
The document contains periodic measurements of Rat%, Rat#, and Shr% between 23:43 and 24:28. Rat% ranges from around 3.2% to 6.1%, Rat# ranges from around 48.3 to 92.6, and Shr% ranges from around 13.8% to 24.4% over the course of the measurements.
This document provides a course plan for a subject called "Computer Application in Biotechnology" with 38 total lectures over 10 weeks. It includes the lecture content, assignments, and test dates. The lectures cover topics such as introductions to computers and biotechnology, hardware, software, memory, storage, input/output devices, the internet for biologists, databases, sequence analysis, and protein structure prediction. There are 3 assignments and 4 tests scheduled throughout the course.
Digital collaboration can increase student learning in several ways. It allows students to work jointly with others on intellectual endeavors using technology. This fits in all learning environments, whether face-to-face, blended, or virtual classrooms. Specific digital tools for collaboration include storytelling, polling, wikis, blogs, and collaborative questing. When used effectively, these tools engage students and help them move up Bloom's taxonomy of learning from lower to higher order thinking.
The document discusses the cosmic conflict between God and Satan that has been ongoing throughout history. It describes some of the major events in this conflict from the creation of the universe to Jesus' crucifixion and resurrection. The document also discusses how God has validated the Bible through the canonization process and archaeological evidence, and how lives have been transformed through reading it. It outlines a class that will discuss engaging with Muslims and call them to faith by comparing Christianity and Islam.
This chapter provides an introduction and overview of operating systems. It defines an operating system as a program that manages computer hardware and software resources and provides common services for computer programs. It describes the components of a computer system including hardware, operating system, application programs, and users. It then discusses the structure and functions of operating systems, including process management, memory management, storage management, protection and security, and distributed systems. It provides examples of different computing environments like traditional, client-server, peer-to-peer, and web-based computing.
Medical coding started as a way to track causes of death during outbreaks of the Black Death plague in the 14th century. Over time, standardized coding systems were developed to classify causes of mortality and morbidity. The current system used in the United States is ICD-10, an international standard endorsed by the World Health Organization in 1990. ICD-10 expanded the number of codes and added specificity compared to the previous ICD-9 system. ICD-10-CM is used for medical diagnoses and ICD-10-PCS for inpatient medical procedures.
Below is the minimum amount of material you should submit as an outl.docxaman341480
Below is the minimum amount of material you should submit as an outline. This one (from another course) received a grade of B and could have been improved by having more text in the outline describing the sections and more precise citations (that included page numbers). Lloyd
----------------------------
STUDENT NAME
HIST 285
Winter 2017
Health and Medicine During the Black Death, 1325-1350
Thesis: What were the roles of plague doctors during the Black Death in the fourteenth century?
Introduction: The Black Death was one of the largest pandemics in history. Today, it is known as the Black Plague or the bubonic plague. Medieval people called it “the blue sickness,”
La pest
(“the Pestilence”) and “the Great Mortality.” The word
bubonic
comes from the Latin word
bubo
or the Italian
bilbo,
meaning a pustule or swelling. It led to the deaths of 75 to 200 million people, peaking in Europe in the years 1346-53. Most of the victims died within three or four days of developing symptoms, while others died after two weeks. The plague spread throughout the Mediterranean and Europe, killing an estimated 30-60% of Europe’s total population. Most scholars believe the Black Plague was a bacterial strain of
Yersinia pestis
. Medieval doctors had no idea of what caused the Plague, and antibiotics were not available during this era. There were different types of doctors during this time period, and challenges came from a lack of fully qualified physicians to treat the number of patients. This paper will examine the reactions of physicians to the Black Death during the fourteenth century.
Part 1: Medical education and medical practices
Hippocrates and Galen
Education, physician vs surgeon
Untrained/unlicensed practitioners that emerged during the Plague
Part 2: Doctors acted as public servants (Wray)
Tasks included recording the deaths due to the plague
Plague doctors were requested to perform autopsies to help determine the cause of death
Plague doctors gave advice to their patients about their conduct before death. The relationship between doctor and patient was governed by a complex ethical code.
Part 3: What doctors believed caused the Black Death
Punishment from God
Miasmatic vapors, bad air
Improper balance of the four Humours (Slavicek)
Part 4: Methods (Cantor)
Doctors practiced bloodletting, putting frogs or leeches
Dung and urine and bad smells
Drinking vinegar, eating crushed minerals, arsenic, mercury
Conclusion: How search for cure led to scientific thinking during the Enlightenment
Bibliography
Primary Sources:
George
Deaux,
The Black Death 1347
. New York: Weybright and Talley, 1969. Chapter IV, pp. 75ff.
Secondary Sources:
Cantor, N. F. (2001).
In the wake of the plague: the Black Death and the world it made
. Simon and Schuster.
Siraisi, N. G. (2009).
Medieval and early Renaissance medicine: an introduction to knowledge and practice
. University of Chicago Press.
Slavicek, Louise Chipley.
The Black Death
. New York: Chelsea House, ...
CPT classification system Assignment 4.pdfsdfghj21
The CPT classification system has six main sections that provide coding guidelines for different services. CPT codes describe medical, surgical, and diagnostic services and are used primarily for billing purposes. HCPCS codes are also used for some services not covered by CPT codes. ICD procedure codes describe medical procedures for data collection but are not used for reimbursement like CPT codes.
The Goiânia accident was a radioactive contamination event in 1987 in Brazil caused when an unsecured radiotherapy source was stolen from an abandoned hospital. It was mishandled by several people, resulting in 4 deaths. Over 100,000 people were examined and 249 were found to be contaminated. Responses included medical treatment, decontamination of areas and vehicles, waste disposal, and long-term environmental monitoring and health screening. It demonstrated the need for strict regulation and security of radioactive materials.
Epidemiology is the study of the distribution and determinants of health-related states or events in specified populations, and the application of this study to control health problems. This document discusses epidemiology and provides details on cholera, including its history and causes. It describes how John Snow used epidemiology to discover that cholera is spread through contaminated water by tracing a cholera outbreak in London back to a contaminated water pump. It also discusses the "miasma theory" of disease transmission via air that was previously widely accepted, as well as the scientists who first discovered the cholera bacteria and advocated for improved sanitation to prevent disease.
Pathophysiology is the study of abnormal functions or breakdown of homeostasis in diseases. It examines the mechanisms by which lesions are produced and their functional implications. Key events in the history of pathophysiology include Hippocrates introducing ethical medicine, Galen proposing the humoral theory, and advances in microscopy and staining techniques in the 19th century enabling the study of cells and microorganisms. Major developments in the 20th century included identifying DNA as the genetic material, cloning animals, and completing the Human Genome Project to sequence the entire human genome.
Unit 731 was a covert biological and chemical warfare research unit of the Imperial Japanese Army located in Harbin, China. Over 10,000 people, mostly Chinese and Korean civilians, were imprisoned and experimented on without anesthesia, resulting in around 200,000-580,000 deaths. Experiments included vivisection, weapons testing, and developing biological weapons such as the plague-infected flea bomb. After the war, members of Unit 731 received immunity from the U.S. in exchange for their data, avoiding prosecution for their horrific human experimentation and crimes against humanity.
This document summarizes the changing views of hysteria from the late 19th century to the early work of Sigmund Freud. It discusses how the adoption of germ theory fundamentally changed concepts of disease by identifying specific microorganisms as the cause of sets of symptoms. It then discusses how in the 1880s, hysteria was consistently viewed as a functional nervous disorder without observable organic causes. Freud's early work on hysteria needs to be understood in the context of these prevailing views of hysteria as a functional disorder without identifiable organic lesions.
Reconstructing Exposures From The Uk Chemical Warfare Agent Human Research Pr...guest971b1073
This document discusses reconstructing exposures from the UK's chemical warfare agent human research program from World War 1 through 1989 at Porton Down, Wiltshire. The authors assessed exposure data for 150 veterans to determine if records were complete and identifiable for a cohort study on long-term health effects. The records included sufficient identifying information and quantitative exposure data for vesicants and nerve agents. Based on their review, the authors concluded that the Porton Down records provide a unique resource for reconstructing exposures and the cohort study has potential to provide information on long-term health impacts of chemical warfare agent exposure.
Evolution of nuclear science in venezuela iomarcuratolo
1) Nuclear science in Venezuela began in the late 1940s and early 1950s with the use of radioactive isotopes for medical research. This led to the formation of organizations like the Venezuelan Association for the Advancement of Science.
2) In the following decades, nuclear science research grew with the establishment of institutes like the Venezuelan Institute for Neurobiology and Brain Research and the Venezuelan Institute for Scientific Research. However, research output fluctuated due to political and economic events.
3) In the 21st century, nuclear science research has declined in Venezuela due to an exodus of scientists and a struggling economy, though some resilience and international collaboration has been seen. The legacy of over 70 years of nuclear science
Clinical microbiology and molecular techniquesIndhra Yogaesh
Molecular biology is the science of biomolecules. Even though the term “biomolecules” includes all molecules such as proteins, fatty acids etc, it is refers to nucleic acid these days.
The application of molecular technology in medicine is almost endless, some of the applications of molecular methods are:
1. Classification of organism based on genetic relatedness (genotyping)
2. Identification and confirmation of isolate obtained from culture
3. Early detection of pathogens in clinical specimen
4. Rapid detection of antibiotic resistance
5. Detection of mutations
6. Differentiation of toxigenic from non-toxigenic strains
7. Detection of microorganisms that lose viability during transport, impossible, dangerous and costly
to culture, grow slowly or present in extremely small numbers in clinical specimen
8. Apart from their role in microbiology, these techniques can also be used in identifying
abnormalities in human and forensic medicine.
1) The earliest reports of coronaviruses date back to the late 1920s when an respiratory disease affected chickens in North America. 2) The first human coronaviruses were discovered in the 1960s in the UK and US through two different techniques. 3) By 1967, the structures of IBV, B814 and 229E were analyzed using electron microscopy and shown to be morphologically similar, having club-like spikes, establishing them as a new family of viruses called coronaviruses.
At the end of this presentation the attendant is expected to:
Define Epidemiology.
Identify the main issues in the definition.
Discuss the uses of Epidemiology.
This editorial discusses two dimensions of epidemics - their bio-demographic burden and their psychological impact through fear. It notes that epidemics trigger social perceptions of panic, blame and need for authority response beyond just quantifiable disease impacts. Decision-making for epidemic control aims to balance both dimensions but is complicated by fear, uncertainty and time pressure, often resulting in overreaction. Managing public perception of risk and feeling of control is important for effective and efficient epidemic response.
The document summarizes the key events related to the 1984 Bhopal gas tragedy in India. It describes how the Union Carbide India Limited (UCIL) plant was built in 1969 to produce pesticides using methyl isocyanate (MIC). There were earlier leaks at the plant in the 1970s and 1980s. On the night of December 2, 1984, water is believed to have entered an MIC storage tank, causing a catastrophic release of MIC gas that killed thousands immediately and exposed over 500,000 people. The leak had long-term health impacts on the surrounding population. The legal proceedings and settlements resulting from the disaster are also summarized.
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1. GENERAL ARTICLE
The Bhopal gas tragedy: An environmental disaster
S. Sriramachari
The multi-disciplinary study of histopathology and toxicology of Bhopal gas tragedy resolved seve-
ral issues. First, the progression of severe pulmonary oedema to chronic fibrosis was confirmed
experimentally, following a single exposure to MIC. Analysis of the residue in Tank 610 revealed
over 21 chemicals. Apart from MIC and HCN, some of them were tracked down to the blood and
viscera of dead and living ‘exposees’. The rationale of NaTS therapy was substantiated by elevated
urinary NaSCN levels in Double Blind Clinical Trials as well as patients. Apart from cyanide, the
‘cherry red’ discolouration was also shown to result from binding of MIC to end-terminal valine
residues of Hb, as shown by changes in 2–3DPG levels and blood gas profiles. The finding of N-
carbamoylation of several other end-terminal amino acids of tissue proteins confirmed the distribu-
tion of MIC within the body, although the underlying mechanism is not yet fully understood. Possibly,
the much faster S-carbamoylated compounds of the blood like glutathione and other sulphydryl-
containing enzymes like rhodanese could be responsible for re-circulation of MIC and protracted
cyanide toxicity. It is hoped that eventually the enigma of the ‘Bio-chemical Lesion’ of MIC toxicity
will be unraveled.
BY all accounts the Bhopal gas leak on the night of 2–3 The MLI continued to perform autopsies on gas-affected
December 1984, is the worst chemical disaster in history. victims in subsequent years.
It took a heavy toll of human lives. People started dying
within hours and more than 2000 lives were lost in the first
Brief clinical manifestations
few days. Late Heeresh Chandra, the man who had to
deal with it first-hand, presented the forensic aspects at
According to Dureja and Saxena1, one of the earliest of the
the Third Indo-Pacific Congress on Legal Medicine held
‘Rescue Teams’ to reach Bhopal when panic was at its
at Madras in December 1989, followed by Sriramachari
peak at major hospitals of the city, the patients could be
on the histopathology and toxicological studies. Accord-
graded symptomatically into four categories: (i) Minor
ing to Ivor Doney who reviewed the proceedings, ‘A silent
eye ailments, throat irritation and cough, (ii) Severe con-
stunned audience listened with awe the terrible story of
junctivitis, keratitis, acute bronchitis and drowsiness, (iii)
1984, when on one tragic day poisonous fumes killed
Severe pulmonary oedema leading to cardio-respiratory
hundreds of people or maimed thousands of them in the
distress, and (iv) Convulsions, followed by cardio-respi-
ensuing months’. He likened this tragedy to ‘Pompeii sud-
ratory arrest. Intense fatigue and muscular weakness was
denly engulfed in the dust of Vesuvius, or Hiroshima
another common feature. Another early and comprehen-
when the atom bomb was dropped’. He concludes ‘that the
sive report is by Kamat et al.2. Soon thereafter, other cli-
story should be told at some future international forensic
nicians like N. P. Misra3, P. S. Narayanan, and S. K. Jain
meetings again and again and again’.
had encountered similar patterns, with minor variations.
By 7.00 AM, 70 people were dead, by 9.00 AM 260 were
Several thousands survived with a variety of morbidity
dead and thereafter the figures continued to rise. Though not
and permanent disabilities. According to the recent press
all dead bodies were brought to the Medico-Legal Institute
reports, there are a large numbers of survivors, with lin-
(MLI), 311 bodies were received on 3.12.1984, followed by
gering ailments and incapacity to work.
another 250 on 4.12.1984. Thereafter, the rate declined.
Non-availability of any information about the toxicity
A total of 731 bodies were received in December 1984
of even the parent compound, MIC (methyl isocyanate),
alone, 103 in 1985; 90 in 1986 and 44 and 22 respec-
was a great impediment to institute ‘detoxication measures’
tively in 1987 and 1988. These figures from the morgue
and lay down guidelines for therapeutic intervention and
may not account for all the deaths in the city of Bhopal.
management of the victims. Hence, there was an urgent
need to generate de novo, authentic scientific evidence
and information. The ICMR rushed to the scene and tried
S. Sriramachari is at the Institute of Pathology – ICMR, New Delhi 110 029,
India. to fill the void. It funded, amongst 24 other projects, two
e-mail: ssriramachari@hotmail.com comprehensive studies on toxicology and a collateral pro-
CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004 905
2. GENERAL ARTICLE
ject on PFT (pulmonary function tests)/blood gas analy- While elevation of pressure and temperature inside the
ses. Both these projects rapidly transformed themselves closed tank or container in Bhopal was widely recogni-
into ‘multidisciplinary and multi-institutional investiga- zed, the liberation of hydrogen cyanide (HCN) became
tions’ (Tables 1 and 2). one of the most contentious issues. In retrospect, it is amus-
ing that the Union Carbide Corporation (UCC) decried
cyanogensis and let loose a campaign of misinformation.
Nature of the toxic gases in Bhopal There were sufficient indications to that effect even in
UCC’s earlier reports9. And it was amply confirmed in
Public attention to the high reactivity of MIC was drawn
the publication of Blake and Ijadi-Maghsoodi10, about
by Devkumar and Mukherjee4. It was followed by more
two years prior to the Bhopal disaster. While there is no
authoritative accounts in the Varadarajan Committee Re-
doubt about the decomposition of MIC, it was suppressed
port5. According to the report, there was a massive leak
on puerile grounds, due to uncertainty of the temperature
of MIC stored for a long period in the incriminated Tank
attained within Tank 610 and in the absence of consensus
610 of the Pesticide Plant of Union Carbide of India Ltd
as to the quantity of HCN liberated at specific tempera-
(UCIL). Several hypotheses attributed for this disaster
tures, say 200°C, 300°C and 420°C! Further, it was known,
include, ‘prolonged bulk storage of 42 tons of MIC, non-
ever since 1927, that apart from other nitrile compounds,
functioning refrigeration system, failure of safety mea-
HCN forms an ‘adduct with MIC’ itself11. Depending on
sures and malfunctioning of neutralization facilities’. One
the reactions, theoretically it is even possible for the more
or more of these factors might have contributed to the
lethal ‘cyanogen’ to be formed. It is proposed to discuss
accidental and uncontrolled runaway reaction. From all
later several issues related to confirmation of ‘cyanide
accounts, quite unlike leakage of a single chemical like
toxicity in Bhopal’.
ammonia, sulphuric acid, phosgene or hydro cyanic acid,
the gas release in Bhopal is not due to mere leakage of
cold MIC. The presence of an array of multiple chemicals
was demonstrated5–7. Careful re-examination by the toxi- Critical human autopsy studies
cology project of the ICMR, revealed the presence of as
many as 21 chemical constituents, including 9 or 10 addi- Heeresh Chandra and his colleagues started performing
tional unidentified compounds8. However, the toxicity was autopsies within 72 h of the disaster. It was noticed that
NOT known about any of the compounds, including MIC. the usual post-mortem lividity or cyanosis was not pre-
sent; instead, there was a pinkish discolouration over all
parts of the body.
Table 1. Multidisciplinary studies undertaken
The most important findings were in the lungs. There
Human autopsies was a gross increase in the weight of nearly 2 ½– 3 times
Histopathology the normal. The entire respiratory tract showed a series of
Electron microscopy
Experimental studies pathological changes. The lungs were heavily water log-
Pulmonary function tests (PFT) ged and had a distinctive cherry-red colour (Figure 1 a).
Elevated levels of haemoglobin (Hb) The mucosa was intensely congested. The trachea and the
Alterations in blood gases
Elevated 2–3 DPG (di-phospho-glycerate) levels major divisions of the bronchi revealed necrotizing or
Evidence of acute and chronic cyanide toxicity ulcerative changes. The following striking microscopic
Therapeutic response to detoxification by NaTS findings were noticed. Severe tracheitis and bronchitis
Forensic toxicology
Proof of direct binding of MIC to Hb and with denudation of the epithelium was seen in some sec-
tissue proteins through N-carbamoylation tions (Figure 1 b). There was marked congestion and thic-
Faster and reversible S-carbamoylation kening of the alveolar septa (Figure 1 c). The alveoli were
(attempted but not successful)
filled with eosinophilic albuminous fluid (Figure 2 a).
Table 2. Trans-institutional collaboration
Institutions Collaborators
Medico-Legal Institute, M.G.M. College, Bhopal Heeresh Chandra, Satapathi, colleagues and scientific project staff
Department of Pathology, M.G.M. College, Bhopal B. S. Darbari and S. Kanhere
Institute of Pathology-ICMR, S.J. Hospital, New Delhi S. Sriramachari and H. M. K. Saxena, Ashok Mukherjee and A K Jain
G.B. Pant Hospital, New Delhi P. S. Narayanan
AIIMS, New Delhi A. Ramaiah and Roman Reddy
DRDE, Gwalior P. K. Ramachandran and colleagues, K. Jeevaratnam
INMAS, New Delhi N. Lakshmipathi, S. K. Sharma and Pant
DIPAS, New Delhi K. Sridharan and A. C. Patil
IIT, Madras D. V. Ramana
IICT, Hyderabad M. Vairamani
906 CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004
3. GENERAL ARTICLE
Intra-alveolar hyaline membranes were seen frequently. More or less similar features were observed in a large
Many sections of the lung showed extensive emphysema- number of autopsies carried out in the second week fol-
tous areas (Figure 2 b). There was very little evidence of lowing the gas leak. Both grossly and microscopically, the
secondary infection. In some places there was necrotizing lungs continued to be the seat of primary change. The
bronchiolotis (Figure 2 c). Polymorpho-nuclear cellular lung parenchyma showed varying degrees of bronchioli-
infiltrates were not very prominent. Instead, cellular res- tis, bronchopneumonic changes and infiltration of the
ponse in the lung was largely one of proliferation of the alveolar spaces by polymorpho-nuclear cells, around and
alveolar macrophages. within the lumen of bronchioles (Figure 3 a). There was a
Figure 2 a–c. Early autopsy findings. a, Photomicrograph showing
Figure 1 a–c. Early autopsy findings. a, Gross picture of lung shows terminal and respiratory tubules, interstitial congestion and intra-alveo-
typical cherry red discolouration; b, Low power photomicrograph lar oedema and some emphysema; b, Photomicrograph of sections of lung
showing marked congestion and epithelial denudation of trachea; c, with bullous emphysema showing destruction of alveolar septa and
Photomicrograph of lung parenchyma showing marked congestion and coalescence; c, Photomicrograph shows peribronchial and intraluminal
thickening of alveolar septa. bronchiolitis suggestive of necrotizing bronchiolitis.
CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004 907
4. GENERAL ARTICLE
gradual transition in the pathological changes. There was or secondary to severe shifts in the intra and extra-cel-
persistence of acute desquamative changes in the trachea lular fluid, apparently associated with outpouring of fluid
and the main divisions of the bronchi. The alveolar into the pulmonary parenchyma. A noteworthy feature in
spaces also showed a variable degree of infiltration by the earlier series of autopsies was the marked distension
inflammatory cells. of the gall bladder with excess of fluid. Curiously enough,
In the acute phase, the other viscera showed gross analogues increased excretion of bile and water content
appearance of oedema of the brain and congestion of of excreta has been reported12 in chicks fed ‘cassava rich
the leptomeninges. In a few cases, the liver showed mild in cyanide’ content.
degree of fatty change, which might be either incidental
Continuing autopsy studies
Excluding the initial lot of 22 cases studied in 1984, the
Institute of Pathology received during 1985–88, represen-
tative tissue samples from over 170 autopsies. Approxi-
mately there were 90 cases in 1985; 18 in 1986; 17 in 1987
and 47 in 1988, although there is a possibility of some
overlap in the dates.
In 1985 the earlier picture of pulmonary oedema, bron-
chopneumonia and bronchiolitis seems to be gradually
replaced by a picture of diffuse interstitial pneumonitis, but
without any significant fibrosis. There was progressive
decrease of oedematous fluid accompanied by well-defi-
ned interstitial mononuclear cellular reaction, histiocyto-
sis and macrophages. At this stage, no significant changes
indicative of passive venous congestion were present.
The autopsy material obtained in 1986–87 showed a pic-
ture of interstitial pneumonitis with thickening oedema
and increased cellularity of the alveolar septae progress-
ing to more organized fibrosis. Apart from the presence
of ‘bronchiolotis obliterans’ in an occasional field (Fig-
ure 3 b), there was evidence of ‘desquamatative intersti-
tial pneumonitis’ (DIP) (Figure 3 c). An occasional case
showed evidence of ‘giant cell interstitial pneumonitis’
(GIP) (Figure 4 a) of the usual or giant cell type. A uni-
que autopsy case of a young doctor exposed to toxic gases
on 3.12.1984 who died in the middle of 1987, revealed
significant findings. Multiple sections of the lung showed
broncho-pneumonic changes, superimposed with a pic-
ture of desquamatative alveolitis with large collections of
macrophages. (Figure 4 b). Normal or functional alveoli
were scarcely seen in most of the sections. There was
evidence of atelectasis with intervening pulmonary fibro-
sis. The findings were suggestive of marked interstitial
fibrosis or ‘fibrosing alveolitis’ (Figure 4 c). Yet another
significant observation in 1986–87 is the picture of chro-
nic passive venous congestion of the liver with charac-
teristic features of congestion, necrosis and pigmentary
changes indicative of right heart failure.
The material received in 1988 showed a similar picture,
but of a more organized nature. There was greater fibrosis
of alveolar septae and patchy fibrosis of lung parenchyma.
Figure 3 a–c. Progression of autopsy findings in the lung. a, Photo-
Histopathological changes in other organs
micrograph showing picture of early bronchopneumonic consolidation; The brain, in general, showed in the acute phase hallmarks
b, Photomicrograph showing atypical picture of bronchiolitis oblite-
rans; c, A later autopsy shows a picture of congestion and interstitial of gross oedema and congestion of the leptomeninges. In
pneumonitis with intra-alveolar macrophages. a few cases there was obvious evidence of sub-arachnoid
908 CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004
5. GENERAL ARTICLE
and intra-ventricular haemorrhages (Figure 5 a). Occa- degeneration of Nissl was seen in a scattered manner in
sional cases also showed grossly cortical and sub-cortical the dentate nucleus (Figure 6 b). However, there was no
ring haemorrhages (Figure 5 b). Miscrospically distinct indication of satellitosis or neuronophagia. Selective neu-
pericapillary and ‘focal flame haemorrhages’ were seen ronal damage of Purkinje cells was seen in the cerebellar
in the cortex as well as the white matter (Figure 5 c). The folia (Figure 6 c).
brains in general showed evidence of generalized peri- The liver showed a picture with normal appearance in
cellular and peri-capillary oedema. It was more apparent most of the cases, with some degree of moderate fatty
in the paraffin sections (Figure 6 a). The same was also change in a few cases and necrosis and disorganization of
confirmed in the celloidin sections. Focal acute nerve cell the liver cell cords occasionally.
Figure 4 a–c. Late autopsy findings. a, Photomicrograph showing an Figure 5 a–c. Autopsy findings in other organs. a, Gross appearance
occasional picture of giant cell interstitial pneumonitis; b, Photomicro- in early autopsy with marked sub-arachnoid congestion and intraven-
graph showing a picture of bronchopneumonia superimposed by des- tricular haemorrhages; b, Cortical and sub-cortical haemorrhages in
quamative alveolitis; c, Photomicrograph of the same case showing gross sections of the brain seen occasionally; c, Photomicrograph of the
extensive atalectasis and fibrosing alveolitis (Masson Trichrome Stain). brain showing peri-capillary flame haemorrhages.
CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004 909
6. GENERAL ARTICLE
The kidney showed in a few cases acute tubular necro- the lungs showed a consistent picture of thickening of the
sis, particularly of the proximal tubules. The medulla in alveolar membrane. Although there was a marked reduc-
such case showed congestion and presence of tubular tion of the epithelial lining or Type-I pneumonocytes (Fig-
casts in the collecting ducts. ure 7 a), it is significant that Type-II pneumonocytes were
present in large numbers as electron-dense whorl-like mate-
Ultrastructural changes rial (Figure 7 b). This probably represents an attempt at
The study indicated certain interesting changes, which enhanced synthesis of the surfactant material phosphati-
supported the light microscopic findings. The alveoli of dyl ethanolamine. There was no evidence of acute myo-
cardial infarction or myolysis except for the presence of
oedema. Electron microscopic examination of heart mus-
cle tissue revealed the presence of degenerated mitochon-
Figure 6 a–c. Autopsy findings in the brain. a, Photomicrograph
showing peri-cellular and peri-capillary oedema suggestive of cerebral Figure 7 a–c. Early ultra structural changes. a, Alveolar septa showing
anoxia; b, Photomicrograph showing focal acute nerve cell degenera- reduction of type I pneumonocytes; b, Electron micrograph showing in-
tion of dentate nucleus of cerebellum suggestive of selective neuronal crease of type II pneumonocytes with whorl-like electron dense material
damage due to anoxia; c, Photomicrograph of typical anoxic changes suggestive of increased production of surfactant; c, Electron micrograph of
with the partial loss of Purkinje cells of cerebellar folia. mitochondria of cardiac tissue showing floccular degeneration.
910 CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004
7. GENERAL ARTICLE
dria with floccular masses (Figure 7 c). However, it is to cytic processes abutting on the pericapillary gliovascular
be pointed out that these ultra-structural findings were membranes (Figure 8 b). Interestingly, some of the eryth-
seen sparsely. rocytes within the capillaries were electron lucent (Figure
Electron microscopy of the brain tissue also confirmed 8 c). This is suggestive of leaching out of some lipid sub-
the enlargement of pericapillary Virchow–Robin spaces stances of the erythrocyte membrane, possibly due to loss
(Figure 8 a) and swollen oligodendroglial cells and astro- of carbamoylated glutathione.
Experimental studies
As pointed out earlier, practically nothing was known
about the toxicity of MIC, except for some acute experi-
ments conducted by UCC in the Bushy Run Laboratories.
In the aftermath of the Bhopal gas leak, several experi-
mental studies were undertaken in different parts of the
world. But most of them dealt with the study of its irri-
tant effects on repeated exposures. Only Nemery et al.13
attempted to study the effects of single exposure, although
confined only to the acute phase. Further, it was consid-
ered desirable to know about the toxic effects of not only
pure MIC, but also its aqueous derivatives, methyl amine
and di-methyl urea with a view to simulating the in vivo
situation. Hence, the pathological effects of a single expo-
sure of rats to the above three constituents were also
studied. Apart from the lethal damage, the sub-lethal
effects were also studied. In addition to the inhalation
route with single or two LC50 doses, the toxic chemicals
were administered subcutaneously at one LD50 dosage.
Only surviving animals, sacrificed at various time inter-
vals, extending from one day to ten weeks, were submit-
ted to histopathology. Care was taken to discard the dead
animals, with attendant autolytic changes. In all, lungs
from over 240 animals were available for study. With the
help of this experiment, it was possible to reproduce the
full spectrum of histopathology of lung, seen in the human
victims. Some of the B&W illustrations published14,15 have
since been reproduced as colour photomicrographs. Initi-
ally, at the end of 24 h there was an overwhelming bland
oedematous fluid filling up of the alveoli and eosino-
philic necrosis of the bronchial epithelium (Figure 9 a at
one LC50 and Figure 9 b at two LC50 dosages). Even when
administered subcutaneously at a dosage of one LD50, the
lung was found to be the target organ with intense inter-
stitial pneumonitis although without any noticeable oedema
(Figure 9 c). This is in consonance with the so-called
‘special vulnerability’ with alveolar membrane by the inha-
lational route as shown earlier in the case of ‘phosgene’
(cited by Cohen and Oppenheimer16). At subsequent
periods, the sequaelae of intra-alveolar oedema and inter-
stitial pneumonitis, and bronchitis and even fibrosis were
observed by the end of one week (Figure 10 a and b) and
Figure 8 a–c. Early ultra structural changes. a, Electron micrograph
showing enlargement of Virchow–Robin pericapillary spaces indicative with both the routes of administration. Even diffuse pul-
of extensive oedema; b, Electron micrograph of another area showing monary fibrosis could be demonstrated by the end of ten
capillary packed with erythrocytes and oedematous changes in the glio- weeks (Figure 10 c). Thereby, it has been possible to
vascular membrane in astrocytic processes and oligodendroglia; c, Elec-
tron micrograph of a capillary structure in the brain showing electron establish experimentally MIC toxicity. It is noteworthy,
lucent erythrocytes suggestive of loss of some material. that methyl amine produced similar lesions, albeit less
CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004 911
8. GENERAL ARTICLE
severe than MIC itself. DMU caused still milder and tran- priate antidotes on an emergency basis. Thus the observa-
sient changes14,15. tion of the cherry red colour of lung and viscera assumed
great importance, and even overshadowed all other factors.
Toxicological studies Issue of cyanide toxicity
The main purpose of toxicological studies was detection On the basis of autopsy findings, Heeresh Chandra postu-
of the possible toxic substance(s) and to determine appro- lated cyanide toxicity as a causative factor. Max Daunde-
Figure 9 a–c. Early stages of experimental studies in rats. a, 24 h picture
of lung exposed to one LC50 dose of MIC showing eosinophilic necrosis
of bronchiolar epithelium and lobular distribution of intra alveolar oedema; Figure 10 a–c. Late stages of experimental studies. a, Photomicrograph
b, Similarly exposed to two LC50 doses of MIC showing more exten- of lung at the end of one week showing extensive pulmonary interstitial
sive pulmonary damage as in the above; c, Exposed to one LD50 dose of oedema; b, Photomicrograph at the 4 week showing a picture of mild
MIC subcutaneously; still the lung is the target with marked interstitial oedema, bronchiolitis and interstitial pneumonitis; c, Photomicrograph at
pneumonitis. the end of 10 weeks showing a picture of diffuse pulmonary fibrosis.
912 CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004
9. GENERAL ARTICLE
rer, a German toxicologist, who came to Bhopal in the first Preliminary therapeutic trials with NaTS and
week after the accident, also reiterated this fact. Based on enhanced urinary SCN response
his perception of possible cyanide toxicity, Daunderer
brought diagnostic kits and ample supplies of the anti- Attempts to repeat the experiments of Daunderer met with
dote, sodium thiosulphate. These developments spurred variable results. Twenty very ill patients unrelieved after
vigorous research into the possible causes of the ‘cherry six weeks of adequate conventional treatment with bron-
red’ discolouration. A series of pathophysiological and toxi- chodilators, etc. were subjected to NaTS therapy. Twelve
cological studies were undertaken on an emergency basis. were fully cured but with residual tachycardia. Two had
Certain preliminary investigations, with positive or nega- no relief while six were continued on treatment. How-
tive results at each stage, paved the way for subsequent ever, in view of the reported dramatic response to injec-
studies. ‘Direct vision spectroscopy’ and spectrophoto- tions of sodium thiosulphate, Sriramachari postulated the
metry of blood were initiated as early as 14.12.1984, i.e. need to routinely monitor the urinary thiocyanate levels
second week after the disaster. However, none of the sam- of the survivors. On the analogy of studies on smokers, it
ples examined showed evidence of carboxy-haemoglobin was considered worthwhile to monitor routinely survi-
or cyan-methaemoglobin. In all samples of all the vic- vors and exposees for urinary thiocyanate levels (NaSCN),
tims, only the twin absorption bands characteristic of oxy- both before and after the administration of NaTS. Sur-
haemoglobin were seen. prisingly enough, they were elevated three to four times
Table 3. First Double Blind Clinical Trial With NaTS. Urinary thiocyanate
levels (in mg%) after injection of glucose or NaTS
Post-glucose Post NaTS
Name Resting injection % Change injection % Change
Sita 0.90 0.8 – 11 1.60 + 100
Sakita 1.25 1.75 + 40 2.80 + 60
Azazuddin 1.00 1.35 + 35 1.20 – 11
Satia Ban 0.50 0.30 – 40 3.00 + 900
Devi Singh 1.50 0.80 – 46 1.20 + 50
Sumet Lal 1.00 1.80 + 80 0.80 – 55
Anna Malai 0.40 0.70 + 75 1.60 + 128
Rama Ji 1.40 0.60 – 57 1.40 + 133
Prem Chand 2.00 0.60 – 70 0.70 + 16
Zetru Nisa 1.80 0.80 – 55 1.20 + 50
Mira Bai 0.50 1.20 + 140 0.50 – 58
Raju Bagga 1.00 1.40 + 40 1.60 + 15
Kannaria 0.80 1.00 + 20 1.70 + 70
KS Pawara 0.80 1.00 + 20 1.00 0
Beck Lal 0.70 3.15 + 320
Puri 0.35 0.85 + 157
Increase ≥ 50% 3 10
Total cases 14 16
Fischer’s exact test: P = 0.031.
Table 4. Follow-up study of urinary thiocyanate
Group n 1985–86 1986–87 t value Significance
A. Males – Below 40 years 44 Mean 1.2354 Mean 0.8931 4.5197 99.9%
SD ± 0.5446 SD ± 4054
B. Females – Below 40 years 41 Mean 1.2178 Mean 0.7066 5.4961 99.9%
SD ± 0.5446 SD ± 0.3817
C. Males – Above 40 years 36 Mean 1.27083 Mean 0.82297 3.4645 99%
SD ± 0.7574 SD ± 0.3755
D. Females – Above 40 years 12 Mean 1.0341 Mean 0.7166 2.0631 ns
SD ± 0.4508 SD ± 0.2525
E. Previous values of more than 1 mg 88 Mean 1.4538 Mean 0.8364 11.2143 99.99%
SD ± 0.3760 SD ± 0.4040
F. Previous value of less than 1 mg 45 Mean 0.66272 Mean 0.7134 0.1929 ns
SD ± 0.2174 SD ± 0.3549
CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004 913
10. GENERAL ARTICLE
the normal. These findings supported a prima facie case had a ‘clinical relapse’ with increased pulse and respiratory
of ‘cyanide exposure’. In view of raging controversies rates, out of proportion to the degree of pulmonary dam-
prevailing at that time, abundant precautions were taken age or pulmonary function tests. Raised urinary NaSCN
to ensure that the estimations were double-checked in some levels often accompanied such episodes. The patients res-
of the laboratories. Accordingly, the Institute of Nuclear ponded well to repeated doses of NaTS, thereby confirm-
Medicine and Allied Sciences (INMAS) was chosen. ing that the underlying changes were not merely subjective,
It was found that in comparison with the normals the but supported by objective scientific evidence.
affected population had twice or thrice-elevated levels,
even after accounting for smoking habits, use of Brassica
species of vegetables (cabbage and cauliflower). Several
Blood and tissue cyanide levels
investigations on urinary thiocyanate were undertaken by
There were initial hurdles in the matter of HCN estima-
the two toxicology projects.
tions on blood and viscera with conventional methods.
With the help of Head Space Analyser on a HPLC sys-
Controlled double blind clinical trials tem, it was shown that HCN levels of the blood of victims
or ‘exposees’, were more than double compared with living
However, pitted against divided medical opinion, it was or normal autopsy samples (Table 5). Thus it was estab-
considered desirable to carry out controlled double blind lished that there was some degree of ‘cyanide toxicity’.
clinical trials (CDBTs). With adequate precautions and
statistical appraisal, it was established that NaTS was bene-
ficial in relieving the symptomatology of the victims and
Studies on Hb, 2–3 DPG and blood gases
was also accompanied by elevation of NaSCN (Table 3).
The possibility of ‘cyanate’ being directly responsible for
This work was carried out by late Narayanan and
the cherry red discolouration was simultaneously pursued
Ramaiah, ably assisted by the local team of doctors, led
in other directions. Patients admitted to the 30-bed J.L.N.
by Abha Jain. The phenomenal improvement of the vic-
Hospital showed ‘recurrent respiratory problems’, due to
tims, including the relief of muscular weakness, was
excessive muscle weakness. Surprisingly, their pulmonary
accompanied by further elevation of NaSCN. The CDBTs
status and functions were reasonably satisfactory. But a
enabled a major policy decision of ICMR advocating wide-
majority of them exhibited abnormal changes in certain
spread use of NaTS as a therapeutic measure.
parameters of the blood such as Hb levels. The residents
of J.J. Colonies seem to have consistently elevated Hb,
Follow-up studies which persisted for nearly 1–1½ years (Table 6).
Many of the victims also had abnormally high 2–3 DPG
Regular clinical trials on large cohorts of patients, both levels which were more than double the normal, of 1.0 µ
adults and children, were carried out for one and a half mole/ml, as if they had been at a high altitude of 14,000 ft,
years. Serial observations on a large cohort of 300 pati- for over two–three weeks. It took nearly a year for 2–3
ents clearly established the beneficial role of thiosulphate DPG levels to return to normal.
in the earlier period, in different categories of patients.
The results are given in Table 4. Table 5. Blood cyanide levels (µg%) in controls and exposees
Monitoring of the urinary thiocyanate levels became an
accepted norm. The total study involving 19,122 samples Group n Range Average
of urine including 1079 controls, added further confi- Control Live 15 5–30 20
dence to the validity of the hypothesis of ‘disturbance in Post-mortem 31 10–50 25
cyanide metabolism’. Thus, one of the primary objectives Gas exposed Live 34 50–110 70
of the toxicological studies was vindicated as early as Post-mortem 43 60–360 150
February 1985. When declining trends were confirmed
Even after two months of preservation, autopsy samples (one sample
from the end of 1985, the treatment was tapered off. Out from each group) on re-examination revealed no deviation from initial
of 143 gas-exposed subjects studied in December 1984, values.
46.15% showed thiocyanate excretion of > 1.00 mg%. In
the following years 1985–87, it came down to 41.05% Table 6. Haemoglobin levels of 14 g and
out of 7752 subjects in 1985, 38.67% out of 5698 sub- above in the victims
jects in 1986 and 29.9% out of 4450 individuals in 1987.
Time of examination n Percentage
Relapses and recurrences February 1985 8/20 40
June 1985 17/38 44
However, therapeutic success of detoxification was not September 1985 49/120 37.5
March 1987 45/121 23.6
unqualified. A large proportion (nearly 30%) of patients
914 CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004
11. GENERAL ARTICLE
In view of the abnormal levels of Hb and 2–3 DPG of the alpha and beta chains of the haemoglobin mole-
levels, it was considered worthwhile to investigate the ‘gas cule. Ever since the occurrence of the Bhopal episode and
carriage and utilization mechanisms’ of the victims. Fur- the description of the cherry red discolouration of blood
ther, it was also decided to study these parameters, before and lungs by Heeresh Chandra, several alternative hypo-
and after administration of NaTS and correlate the changes theses were entertained, even within the ICMR Toxicology
with the clinical improvement and alterations in the blood Project. Towards the end of December 1984 itself,
gases. Blood gas studies of arterial and venous oxygen Sriramachari postulated that there could be several fac-
and carbon dioxide were undertaken with ABL-3 Blood tors that can cause cherry red discolouration. Although
Gas Analyser and Oxymeter. Out of 26 patients, 14 pati- the role of carbon monoxide and cyanide is well known,
ents had a PaO2 less than 85 mm of mercury (range 47.3 there are other lesser-known factors, such as aliphatic and
to 85.6 mm). Out of a batch of 14 untreated patients expo- aromatic nitriles and organic thiocyanates contributing to-
sed to MIC, eight had PaCO2 below 35 mm mercury, wards the ‘cyanogen pool’. Isocyanate itself, directly by
which is the accepted lower limit of PaCO2. Out of the carbamoylation of the end-terminal amino acids of the
four treated patients, one had PaCO2 of 35.6 mm and all alpha, and beta chains of the Hb molecule can modify the
the rest had between 40 and 45 mm. oxygen affinity of blood. This could result in ‘left shift of
On the venous side, peripheral samples from the ante- the Bohr effect’. Failure of deoxygenation or inability to
cubital vein, only two out of the 23 patients investigated, shed oxygen due to reduction of CO2-carrying capacity
had Hb less than 10 g%. Others ranged from 10 to 16 g%. could be the possible cause. The work of Cohen and Op-
Three out of 17 patients investigated had venous PvCO2 penheimer16 supports such possibilities. These aspects
of below 40 mm of mercury; while nine out of 14 had were verified from January 1985 onwards.
values above 46 mm of mercury of PvCO2, i.e. above the
upper limit. It is concluded that the patients had low Reduction of free amino groups. Reduction in the ‘free-
PaO2, low PaCO2 and low PvO2 values, and normal or amino groups’ of the samples of blood from Bhopal was
high PvCO2 values at rest, which did not increase on assessed. It was soon established that there was a 20–
exercise. Also, the values in general could not be corre- 40% reduction of ‘free amino groups’, by the tri-nitro
lated on Hb basis. benzene sulphonic acid, TNBS Technique (Ramaiah et al.,
Apart from clinical improvement after NaTS treatment, unpublished data). It was not certain whether all the
subjective or objective, the blood gases showed the fol- reduction was due to N-carbamoylation, since its greater
lowing changes: There was no significant change in PvO2 interaction with SH groups of glutathione etc. could not
which continued to remain low, indicating that the Hb be excluded17.
showed some alterations in the oxygen-carrying capacity.
Patients treated with thiosulphate had PaO2 ranging from Carbamoylation of Hb. Further investigations confirmed
85 mm Hg upward and O2 concentration of 96%. More the presence of ‘carbamoylated end-terminal valine resi-
importantly, there was a demonstrable increase in PvCO2 dues’ of the Hb molecules, both in experimental and cli-
at rest, which was further increased after exercise. The nical material from Bhopal18. Out of a batch of 60 samples
‘peripheral as well as central’ catheterized venous CO2 of blood, 19 were found positive for N-carbamoylated
concentration was equally elevated. This increase in PvCO2 methyl valine hydantoin (HVH)19. The scope of this work
pari passu, with definite clinical improvement, suggests was enlarged at MLI, Bhopal, with the acquisition of HPLC
the relief from ‘chronic recurrent cyanide poisoning’. Typi- and GCMS equipment20. Figure 11 shows the possible
cal cases showing increase in the PvCO2 values after NaTS stages in the interaction of MIC with end-terminal valine
therapy are shown in Table 7. residues of Hb chains. Mass spectrometric evidence of N-
carbamoylated valine agreed with Finnegan Matt Spectro-
meter Library Reference data (Figure 12). Increasingly, a
Studies on carbamoylation large number of cases were shown to be positive for
MVH19 and occasionally ‘non-methylated valine hydantoin’
The issue of alterations in the oxygen-carrying capacity
(VH)21, suggesting the possibilities of break-up of MIC into
led to further investigations on possible carbamoylation
HNCO, either in the atmosphere or demethylation proces-
ses in the human victims. Indeed, carbamoylation of Hb
Table 7. Therapeutic reversal after sodium was proof of the MIC crossing the ‘alveolar-capillary bar-
thiosulphate rier’ and spreading throughout the body, contrary to the
Name Status PvO2 PvCO2 initial statements of the Union Carbide from December
1984 onwards.
Azazuddin Pre 25.4 47.3
Post 34.0 53.5
Tissue carbamoylation. Due to non-availability of proper
Wahid Pre 35.0 44.8 reference standards, Heeresh Chandra and colleagues pre-
Post 28.6 51.1
pared a set of N-methyl carbamoylated hydantoins. First,
CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004 915
12. GENERAL ARTICLE
the five amino acids, glycine, valine, phenyl alanine, methio- Group felt that it could be due to transport across the tis-
nine and threonine were used. Later, another batch of five sues of the much faster and reversible S-carbamoylated
amino acids, viz. serine, glutamic acid, glutamine, ala- glutathione.
nine and histidine were included. Unfortunately, the results
with cysteine were not satisfactory. All the hydantoins were Possible role of S-carbamoylation. Unfortunately, due to
counter-checked with mass spectrometric data available the lack of access to appropriate CI (Chemical Ionisation),
with reference library. Chloroform extracts of preserved GCMS, the problem could not be pursued further. How-
samples of autopsy tissues from exposees as well as con- ever, Bailie and Slatter23 had demonstrated experimentally
trols, were screened for the presence of N-carbamoylated that glutathione undergoes S-carbamoylation and functions
end-terminal amino acids of tissue proteins. A summary as an exchange pool or a reservoir of the isocyanate in
of the studies is given in Figure 13. Perhaps in the history the body. For want of further evidence, perhaps it can only
of chemical disasters these findings are a unique example be surmised that reversible S-carbamoylation of acetyl cho-
of tracing the offending chemicals to the blood and tis- line esterase and aldolase may account for repeated episo-
sues of the victims. des of muscle weakness, experienced by the Bhopal victims.
As pointed by Heinrickson24, the enzyme rhodanese
Limitation of N-carbamoylation. However, the results of can be selectively inactivated by phenyl glyoxal, com-
N-carbamoylation did not fully answer the issues of re- bined with cyanide, at any of the two-cysteinyl residues
currence and repeated episodes of illness in the patients. at 247, 254 and 263 positions in the ‘catalytic apparatus’
It was observed that, on the analogy of some information of its B-domain. It is possible that in the Bhopal victims
generated in the ITRC, there was a reduction in the gluta- S-carbamoylated rhodanese is continually and reversibly
thione content of the blood22. The ICMR Toxicology inactivated under conditions of in vivo build-up of endo-
genous cyanide in the body. In all probability, the meta-
bolic block of the ‘catalytic apparatus’ is corrected by
STAGES IN VALINE - MIC INTERACTION repeated exposure to ‘sulphane–sulphur’ of NaTS. It is
VALINE Methyl Isocyanate ( MIC ) hoped that the dilemma will be resolved about ‘recurrent
H3 C CH 3 R1 endogenous chronic cyanide toxicity’ following exposure
+ to MIC. However it must be admitted that in our studies,
CH 3 N C O
CH
R2 as of then, we failed to demonstrate S-carbamoylation.
H O C N CH 3
H C N
H Tank residue studies
HOOC
H3 C CH 3
+H2O Attention has already been drawn to the reports on the
CH O generation of a large array of chemicals in the course of
R2
H pyrolysis of MIC in Bhopal. The ICMR Toxicology pro-
H C N C N CH 3
gramme confirmed and enlarged the findings. Mass spec-
H H trometric analysis of chloroform residue confirmed and
HOOC N- Carbamoylation
enlarged the range of chemicals that could be detected25
(Figure 14 a, b). Apart from the presence of known che-
H3 C CH 3 N- Methyl Carbamoyl Valine micals like MIC trimers, some of the unidentified com-
OR
CH N- Methylated Valine Hydantoic Acid pounds could be demonstrated in the autopsy samples of
R2 blood and tissues26,27. Although the toxic effects of such
H C NH
compounds remain an enigma, they are certainly of foren-
HCL
HO O C C sic evidentiary value.
-H2O
H N O
CH 3 Discussion
H3 C CH 3
The moment the Bhopal gas disaster took place, the Union
CH + HO- H Carbide Company adopted a policy of suppressio vary
R2
and suggestio falsi. Concerted efforts were made to spread
H C NH
the message of disinformation. Invoking the rapid clear-
N- Methyl Valine Hydantoin
C C ing of ocular changes, it was suggested that, on contact
O N O with aqueous surfaces, MIC is rapidly broken down to the
CH 3 relatively innocuous methyl amine and that MIC as such
does not cross the alveolar-capillary barrier. No cogni-
Figure 11. Chemical pathways of N-carbamoylation. sance was taken about the high reactivity and chemical
916 CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004
13. GENERAL ARTICLE
binding of MIC to end-terminal amino acids of blood and corrected and the fluid reabsorbed. Strangely enough,
tissue proteins as discussed by Cohen and Oppenheimer16. ignoring the adverse effects of a highly reactive chemi-
Secondly, it was suggested that acute anoxia and pul- cal, even Indian scientists echoed similar sentiments. In
monary oedema are transient and they would soon be his Presidential oration of the January 1985 Session of
Figure 12. Comparison of mass spectrometric data of N-carbamoylation of valine residues of Hb of a victim compared with
that of library reference standard.
Studies on carbamoylation
In paranthesis are the number samples showing chromatographic evidence of carbamoylation with reference to five
In parenthesis are the number of of samples showing chromatographic evidence of carbamoylation with refe-
rence to five amino acids; **Samples confirmed on GC-ITD; T, Total; C, Control; E, Exposed.
amino acids; **Samples confirmed on GC-ITD; T, Total; C, Control; E, Exposed.
Figure 13. Summary table of N-carbamoylation of clinical and autopsy samples of blood and tissues.
CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004 917
14. GENERAL ARTICLE
the Indian Science Congress, Paintal28 suggested that the matter of satisfaction that in the teeth of opposition, the
oedema would disappear by itself, on the analogy of High toxicology projects by ICMR were able to generate viable
Altitude Pulmonary Oedema (HAPO). evidence on some of these issues.
Thirdly, the issue of ‘cyanide toxicity’ was hotly con- In the projects relating to toxicology, an attempt was
tested29. The Union Carbide mobilized international sci- made to describe the series of pathological and biochemi-
entific opinion to belittle the ongoing toxicological studies cal alterations. These studies were by no means exhaustive.
in the wake of the Bhopal disaster (Ballantyne 1995, pers. In fact there are a few other studies which dealt with dif-
commun.). The rapid binding or adduct formation of HCN ferent aspects of clinical and laboratory studies, including
with MIC was ignored or missed by both Indian and for- immunological and chromosomal aspects30. However, it
eign media and the scientific community. It is indeed a is not clear to what extent some of them are incidental
changes unrelated to the pathogenesis of the lesions.
Therefore in our studies an attempt was made to interpret
a the significance of the changes, which have a bearing on
the patho-physiology or toxicity of MIC or its breakdown
products.
As stated earlier, the Bhopal disaster cannot be attri-
buted to exposure to a single chemical like MIC, at nor-
mal temperature. Instead, it is the combined effect of
‘cold MIC’ super-added with its pyrolytic products, fol-
lowing the powerful exothermic reaction in a closed stain-
less container or tank. Indeed, the complex and variegated
clinical manifestations can be explained by correlating
the adverse effects of several compounds (MIC, etc.).
MIC toxicity in human beings in Bhopal can be broadly
classified into two categories, viz. MIC itself and ‘pro-
b ducts of its pyrolysis’. It is impossible to distinguish the
overlapping time sequences of each one of the compo-
nents and in terms of any logical sequence of events.
Within these limitations an attempt was made to interpret
the findings.
Effects of pyrolysed MIC
Products of pyrolysed MIC, like carbon monoxide, ammonia
and HCN could result in formation carboxy-haemoglo-
bin, methaemoglobin and cyan-methaemoglobin. Theore-
tically, the last two can contribute towards the cherry red
c discolouration of blood and viscera. However, in the light
of the negative spectroscopic findings, they do not seem
to be present in significant amounts. But the permanent
cherry red colour could be the result of damage of cyto-
chrome oxidase system and damage to the respiratory cen-
tres, causing instantaneous death of many victims. The
subsequent alterations in the blood gases such as fairly
high PaO2 but low PaCO2 and high PvO2 and low PvCO2
resulting in cherry red colour, are strongly suggestive of
‘acute cyanide toxicity’. Increased plasma and urinary
thiocyanate and prompt response to NaTS gave further
credence to acute cyanide toxicity. These findings
were initially challenged as speculative. The elevated
Figure 14 a–c. Mass spectrometric analysis. a, Total ion chromatogram levels of blood and tissue cyanide in the Bhopal exposees
of chloroform-extract of the residue from MIC-Tank E-610; b, Chro- provided further confirmatory evidence. Bhattacharya
matogram and mass spectrum of unidentified compound, U.I. x 11, et al.31 demonstrated that MIC pyrolysed at high tempera-
Corresponding to Peak-16 of the above; c, Ion chromatogram with MS
analysis of two unidentified compounds detected in the blood sample tures caused inhibition of ‘cytochrome oxidase activity’ of
from PM 489/84. brain tissues.
918 CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004
15. GENERAL ARTICLE
However, the subsequent features of reversibility and Conclusions
recurrence do not support the cyanide hypothesis. Also,
the elevated Hb and 2-3 DPG levels need to be explained, The two ICMR projects on histopathology and toxicology
apart from the cyanide issue. have more than fulfilled the initial hopes and expecta-
tions. The sequence of pathological changes in the acute,
Direct effects of MIC sub-acute and chronic stages have been clearly deline-
ated. Structurally, continuing respiratory impairment in a
The sudden physiological changes, following the exo- proportion of cases resulted in progressive pulmonary
thermic reaction of MIC on the cellular and vascular com- damage, including desquamative pneumonitis or fibrosing
ponents, can be attributed only to MIC. The flooding of alveolitis or its variants, like DIPF and GIPF. Experimen-
the respiratory tract and ‘massive pulmonary oedema’ are tal studies with MIC and its aqueous derivatives have con-
perhaps responsible for acute anoxic anoxia, rapid stimu- firmed the pathogenesis and pulmonary changes after
lation of the ‘respiratory centres’, cerebral oedema and ‘single exposure’ are comparable to human autopsy findings.
subarachnoid haemorrhage and eventual death. While these The possibility cannot be excluded, at least initially,
features by themselves, cannot explain the cherry red col- that some degree of ‘exogenous HCN’, due to thermal de-
our, the changes in blood gases, such as lowered PO2, low- composition of MIC might have contributed to some
ered arterial and venous O2 and CO2 levels can readily degree of ‘acute cyanide toxicity’ and irreversible dam-
explain the increase in 2-3 DPG levels and increase of Hb age to cardio-respiratory and medullary centres of the vic-
levels and ‘compensatory erythropoesis’. The experimen- tims. Perhaps in the survivors, the ‘threshold limit values’
tal study following a single exposure to MIC, MA or DMU, were not reached, and thereby death was avoided. How-
also confirms the sequence of transudative and exudative ever, there was no escape from severe pulmonary oedema
changes demonstrated in the experimental studies closely and extreme muscular weakness.
simulating the human autopsy findings. The ‘cherry red discolouration’ could be the immediate
The available information about the high reactivity and effect of HCN. In the long run, it would appear that N-
binding of MIC end-terminal amino acids of blood and carbamoylation, which persists through the 120-day life
tissue proteins was virtually ignored. However, the uni- cycle of erythrocytes, accounted for a greater part of the
queness of MIC toxicity became apparent with the rapid phenomenon. In Bhopal the question of repeated expo-
development of chemical binding of MIC to end-terminal sure to HCN is extremely unlikely, but ‘endogenous libe-
amino and SH groups. The successful demonstration of ration of cyanide’ due to partial impairment of rhodenese
N-carbamoylation of blood within the first 120 day life- and S-transferases seems plausible. This may account for
cycle, clearly provided an alternate explanation for the the raised or elevated respiratory pulse rates and muscle
cherry red discolouration, elevation of Hb and 2–3 DPG weakness and protracted excretion of urinary thiocyanate.
levels as well as the characteristic alterations in the blood While N-carbamoylation cannot be undone, it would
gases, especially the lowering of PvCO2 values. The sub- appear that sulphydryl radicals contained in acetyl-choline
sequent restoration of the latter, both in the peripheral esterase (ACE), aldolase and especially rhodanese are
and central venous pool, provides an explanation for the periodically reactivated and ‘chronic cyanide metabolism’
dynamic changes in the blood gases. However, the clini- corrected. Normalcy is attained only when the MIC sto-
cal phenomenon of recurrence and reversibility by NaTS red in the body is fully depleted. But, in the exigencies of
provided a clue to the much faster S-carbamoylation, rather an alarming human disaster, it has not been possible to
than recurrent exposure to cyanide. In all probability, this try other potent sulphane donors described by Cohen and
is due to rapid reversible S-carbamoylation of sulphydryl Oppenheimer16. It seems that the ‘Biochemical Lesion’ of
groups of key enzymes like rhodanese, esterase, etc. Bhopal disaster may lie between the interplay of N- and
None of these features could be explained by mere accu- S-carbamoylation.
mulation of cyanide. It would appear that S-carbamoy-
lation is probably responsible for the secondary chronic 1. Dureja, G. P. and Saxena, R. S., The methyl isocyanate (MIC) gas
cyanide toxicity due to accumulation of endogenous tragedy in Bhopal (India). Indian J. Anaesth., 1987, 35, 264–268.
metabolic products. It would appear that S-carbamoyla- 2. Kamat, S. R. et al., Early observations of pulmonary changes and
clinical morbidity due to isocyanate gas leak at Bhopal. Postgrad.
tion effects a ‘labile’ circulating component like gluta-
Med., 1985, 31, 63–72.
thione and ‘fixed’ sulphydryl-specific functional enzymes. 3. Misra, N. P. et al., Clinical profile of gas leak victims in acute phase
It is only when the reservoirs of S-carbamoylated MIC after Bhopal episode. Indian J. Med. Res. (Suppl.), 1987, 86 11–19.
are exhausted, the secondary cyanide toxicity in general, 4. Devkumar, C. and Mukerjee, S. K., Methyl isocyanate: Profile of
and MIC toxicity in particular, is corrected. These mecha- a killer gas. Science Today, January 1985, 10, 11 and 16.
5. Varadarajan, S. et al., Report of Scientific studies on the factors
nisms seem to be accelerated by periodic exposure to
related to Bhopal Taxic gas Leakage, December 1985.
‘sulphane sulphur’ in the form of NaTS. The effects of 6. UCC (Union Carbide Corporation), Danbury, Connecticut. Bhopal
exposure to pyrolysed MIC in Bhopal appear to be a sci- Methyl Isocyanate incident investigation team report, March
entific challenge, which needs further elucidation. 1985.
CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004 919
16. GENERAL ARTICLE
7. D’Silva, T. D. J., Lopes Anibal, Jones, R. L., Singhawangcha, S. 24. Heinrickson, R. L., Structure–function relationship in hepatic rho-
and John, K. C., Studies of methyl isocyanate chemistry in the daneses, In Frontiers in Bio-chemical and Biophysical Studies of
Bhopal incident. J. Org. Chem., 1986, 51, 3781–3788. Proteins and Membranes (eds Liu et al.), Elsevier, 1983, pp. 163–
8. Rao, G. J. et al., Bhopal gas disaster: Unidentified compounds in 192.
the residue of the MIC Tank-610. J. Indian Acad. For. Sci., 1991, 25. Chandra, H., Rao, G. J., Saraf, A. K., Sharma, V. K., Jadhav, R. K.
30, 13–18. and Sriramachari, S., GC-MS identification of MIC trimer: A con-
9. Reactive and Hazardous Chemicals Manual, UCC (Union Carbide stituent of tank residue in preserved autopsy blood of Bhopal gas
Corporation), 1967. victims. Med. Sci. Law, 1991, 31, 194–198.
10. Blake, P. G. and Ijadi-Maghsoodi, S., Kinetics and mechanism 26. Saraf, A. K., Rao, G. J. and Chandra, H., GC-MS evidence of di-
of the thermal decomposition of methyl isocyanate. Int. J. Chem. methyl isocyanurate and 2,4 dione of methyl isocyanate in the vis-
Kinet., 1982, 14, 945–952. cera of Bhopal victims. Curr. Sci., 1995, 68, 500–501.
11. Slotta, K. H. and Tshesche, R., Berichte, 1927, 60, 1021 cited by 27. Chandra, H., Saraf, A. K. Jadhav, R. K., Rao, G. J., Sharma V. K.,
Blake and Maghsoodi. Sriramachari, S. and Vairamani, M., Isolation of an unknown com-
12. Panigrahi, S., A review of the potential for using cassava root meal in pound, from both blood of Bhopal aerosol disaster victims and
poultry diets. In Tropical Tuber Crops (eds G. T. Kurup et al.), residue of Tank E-610 of Union Carbide India Limited-chemical
Oxford and IBH, New Delhi, 1996, pp. 416–428. characterization of the structure. Med. Sci. Law, 1994, 34, 106–110.
13. Nemery, B., Dinsdaale, D., Sparrow, S. and Ray, D. E., Effects of 28. Lepkowski, W., Methyl isocyanate: Debate persists over mecha-
methyl isocyanate on the respiratory tract of rats. Br. J. Ind. Med., nism of its toxicity. Chem. Engl. News, 1986, pp. 17–20.
1985, 42, 799–805. 29. Paintal, A. S., ‘High altitude studies: Mountain preservation and
14. Jeevaratnam, K. and Sriramachari, S., Comparative toxicity of methyl prosperity’ Presidential Address, 72nd Indian Science Congress,
iscocyanate and its hydrolytic derivatives in rat: I pulmonary histo- Lucknow, 1985.
pathology in the acute phase. Arch. Toxicol., 1994, 781, 1–6. 30. Deo, M. G. et al., Immunological, mutagenic and genotoxic investi-
15. Sriramachari, S. and Jeevaratnam, K., Comparative toxicity of gations in gas exposed population of Bhopal. Indian J. Med. Res.
methylocyanate and its hydrolytic derivatives in rats: I-Pulmonary (Suppl.), 1987, 86, 63–76.
histopathology in the subacute and chronic phase. Arch. Toxicol., 31. Bhattacharya, B. K., Malhotra, R. C. and Chattopadhyay, D. P.,
1994, 787, 1–7. Inhibition of rat brain cytochrome oxidase activity by pyrolysed
16. Cohen, S. and Oppenheimer, E., Biological Formation and Reac- products of methyl isocyanate. Toxicol. Lett., 1987, 3, 131–134.
tions of Cyanates; The Chemistry of Cyanates and their Thio Deri-
vatives (ed. Patai S.), John Wiley, New York, 1977, Part 2, Ch. 20,
pp. 923–967. ACKNOWLEDGEMENTS. This article is dedicated to the memory
of the several thousands of people who perished in the aftermath of the
17. Torchinsky, Yu. M., Properties of -SH groups, sulfhydryl reagents.
In Sulfur in Proteins. Pergamon Press, Oxford, 1991. Bhopal gas disaster and the survivors who continue to remain crippled
18. Ramachandran, P. K. et al., Gas chromatograph studies of the car- for the remaining part of their lives. My special tribute to the following
departed souls who had contributed largely to our joint research endea-
bamoylation of haemoglobin by methyl isocyanate in rats and rab-
bits. J. Chromatogr., 1988, 426, 239–247. vours in Bhopal: Prof. P. S. Narayanan, Prof. Heeresh Chandra, Dr M.
19. Sriramachari, S., Rao, G. J., Sharma,V. K. Jadhav, R. K., Saraf, A. P. Dwivedi, Dr C. R. Ramachandran, Prof. V. Ramalingaswami and Dr
C. R. Krishnamurthi.
K. and Chandra, H., GC-NPD and GC-MS analysis of preserved
tissue of Bhopal gas disaster: Evidence of methyl carbamoylation Starting my research career as a ‘Lady Tata Memorial Scholar’ 50
in post-mortem blood. Med. Sci. Law, 1991, 31, 289–293. years ago, I deem it as fortuitous to be associated with the symposium
in honour of Sir Dorabji Tata at the Centre for Tropical Diseases. I thank
20. Sharma, V. K., Rao, G. J., Jadhav, R. K. Chandra, H. and Srirama-
chari, S., High performance liquid chromatographic estimation of Raghunath who has given me an opportunity to present a comprehen-
carbamoylated amino acids. Curr. Sci., 1990, 59, 528–529. sive scientific re-appraisal of the Environmental Disaster of Bhopal,
long after the dust and din have settled down. My special thanks are
21. Sharma, V. K., Rao, G. J., Jadhav, R. K., Saraf, A. K., Chandra,
H. and Sriramachari, S., Demonstration of methyl valine hydan- due to Shri Pushp Raj, Ms Seema and Dr A. K. Jain of IOP for render-
toin (MVH) and valine hydantoin (HV) in blood samples in Bho- ing all possible help in my attempts at restoration of the colour and
clarity of the old illustrations.
pal. Proceedings of 14th Meeting of International Association of
Forensic Sciences (IAFS), Tokyo, 1996. More than a score of individual scientists had participated in the
22. Srivastava, R. C. et al., Effect of exposure to toxic gas on the multi-disciplinary and multi-institutional ICMR projects on toxicologi-
cal studies in Bhopal. Special thanks are due to Prof. N. K. Ganguly,
population of Bhopal: Part III – Assessment of toxic manifesta-
tions in humans – Haematological and biochemical studies. Indian Dr S. Varadarajan and Dr V. S. Arunachalam, for all help from the
J. Exp. Biol., 1988, 26, 165–172. several establishments of DRDO.
23. Bailie, T. A. and Slatter, G., Glutathione: A vehicle for the transport
of chemically reactive metabolite in vivo. Acc. Chem. Res., 1991,
24, 264–270. Received 10 December 2003; accepted 6 February 2004
920 CURRENT SCIENCE, VOL. 86, NO. 7, 10 APRIL 2004