Seveso (July 10, 1976 [1])
A cloud containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affected ~37,000 residents, causing acute chloracne skin lesions and long-term carcinogenic, cardiovascular and endocrine effects. The accident was caused by malfunction in the production of 2,4, 5 – trichlorophenol (TCP), and TCDD was formed because of high temperature generated by the runaway reaction [
6]. Surface-soil-measured TCDD yielded three different areas of contamination at increasing distances from the plant: zone A (736 residents exposed to > 50 μg/m
2); Zone B (4700 residents exposed to 5–50 μg/m
2); and a ‘reference’ zone, ‘R’ (31,800 residents exposed to < 5 μg/m
2). Approximately 200 children developed different types of chloracne (starting in September 1976) with spontaneous recovery [
7]. Serum TCDD concentrations in approximately 3000 of the 35,000 samples collected in 1976 and 1977 were 5–3000 times higher than the background level of 10 ppt [
8]. Epidemiological follow-up of 900 women showed pre-menarche TCDD exposure to be associated with a prolongation of the menstrual cycle of 0.93 days [
9]; a reduced risk for leiomyoma, consistent with the anti-estrogenic activity of TCDD [
10]; and no increased risk for endometriosis for serum TCDD levels less than 100 ppt [
11]. A significantly lowered offspring sex ratio was shown in 450 local families, related to exposure to paternal TCDD which was approximately 20 times higher than current reference levels [
12,
13] (exposure to TCDD during infancy can also reduce sperm concentration and motility [
14,
15]). Excess mortality has been observed for cardiovascular and respiratory diseases, diabetes, and lymphatic and hematopoietic tissue neoplasms [
16]. The Seveso Women’s Health Study has shown elevated rates for all cancers combined after 30 years [
17]. Although the health surveillance program is no longer active, follow up research is still ongoing. The Seveso accident prompted better legislative control of industrial emission
via the EU “Seveso” Directive 82/501/EEC of 1982 [
18].
Three Mile Island (March 28, 1979)
After two nuclear accidents in military installations in Kyshtym (Russia [then USSR], 1957) and Windscale Piles (UK, 1957), the first major civilian nuclear accident occurred at the Three Mile Island Nuclear Generating station in Dauphin County near Harrisburg, Pennsylvania. Defined as a partial nuclear meltdown, it was due to critical human factors and problems in the control system’s user interface. Although evacuation of pregnant women and preschool children was extended to 20 miles radius of the facility, more than a half of the 663,500 population remained in the area and 98% of the evacuees returned to their homes within 3 weeks [
19]. No effective plan was in place for hospital and nursing care facility evacuation [
20]. The Maximum effective dose was 40 mSv for the emergency worker) and 0 · 015 mSv (average); 0 · 85 mSv (maximum) for the residents living within 80 km radius [
21]. These levels were lower compared to those measured for the later nuclear accidents of Chernobyl and Fukushima. Small elevation was noted in risk for cancer of the bronchus, trachea, and lung, and for leukemia [
2]. Although thyroid cancer incidence is greater than expected in the counties analyzed when compared to local and national population growth, a direct correlation to the accident remains uncertain [
22]. Studies by the Behavioral Taskforce of the President’s Commission [
23] concluded that the most relevant public health effect was on mental health, including symptoms of psychological distress in mothers of young children and emergency workers [
24].
Chernobyl (April, 26, 1986 [4])
Evacuation of Pripyat, the city closest to the nuclear power plant (NPP) was ordered within hours; 10-km-radius evacuation the next day; and 30-km-radius evacuation on May 2nd. In all, 164,700 residents were ordered to evacuate.
Workers (176) and firefighters (250) were at the NPP immediately after the accident and a total of 600 were acutely exposed to high doses of radiation (whole-body γ, skin γ and β, ανδ vapor-phase radionuclide inhalation); the products of melting and burning graphite, bitumen and plastics; dust and debris from building collapses; and the sulfate-spirit bards, hydrochloric acid, formaldehyde, and oxalic acid from tens of thousands of tons of paper waste used for dust suppression. Polymeric foaming compositions based on urea resins and polyvinyl dispersed mixture were also used in large amounts for dust suppression. During 1986–1987 approximately 230,000 civil and military personnel worked as “liquidators”, cleaning up fallout within the 30 km radius. The number of liquidators ultimately reached 600,000 and they received an average absorbed dose of 9 cGy in 1987 and 5 cGy during 1988–1990.
Annual monitoring and specialized treatment for liquidators and residents are conducted in six regional centers and in specialized departments in 89 regions of the Russian Federation. Exposure data are collected into the Russian State Medical Radiation Monitoring Registry (RSMRMR) and, for health outcomes, the National Radiation and Epidemiological Registry (NRER: implemented and linked to the RSMRMR in 1993 and linked to registries in Belarus and Ukraine). As of January 1, 2016, a cohort of 762,721 individuals is registered in the NRER, including liquidators, residents and their children. Although not implemented at the time of the accident, these registries have monitored health status, yielding prediction-model-based physical and mental health treatment programs and the assessment of the relationship between the radiation exposure and the stochastic effects thereof (e.g., leukemia, solid tumors and thyroid cancer).
The Russian liquidators suffered increased leukemia incidence (145 cases) which peaked from 1992 to 1995 and which was similar to the incidence rate among the atomic bomb survivors. The excess risk for leukemia decreased ~9% per year after 1995, approaching the ‘background’ Russian level in 2012 [
25]. The registries in Belarus and Ukraine showed a similar trend. Thyroid cancer also increased among the liquidators [
26] but the highest incidence was observed among children residing in the Bryansk region of Russia which was affected by radiation-contaminated sediment [
27]. A retrospective study of cancer incidence among the emergency workers from 1992 to 2009 showed a statistically significant elevation in cancer incidence rate, but not in mortality from all cancers, relative to the total cancer incidence rate for men in Russia [
28].
The State Register of Ukraine, established in 1991, includes 2,646,106 residents, as of January 1, 2014, which is estimated to be 93% of the people exposed. Medical surveillance from 1987 to 2005 recorded 504,117 deaths (497,348 adults and adolescents – 34,499 of whom were emergency workers – and 6769 children [
29]). Emergency worker mortality from tumors was three times higher than in similar age groups in the general population in 2007 [
29].
The Belorussian National Register (825,703 subjects) and the Joint Chernobyl Register of Russia and Belarus (309,000 subjects), were established in 1993 and are still active. Belarus annually surveys 1,527,188 people, of which 54,468 are liquidators. New medical facilities, institutes, specialized clinics and centers were opened in Belarus for this program. Research and medical follow-up showed, in 1996, an elevated incidence of thyroid cancer among subjects exposed to iodine radionuclides during childhood and adolescence [
30,
31]. In a study involving children who lived within the Gomel region near Chernobyl, 244 of the 251 children born between 1986 and 1993 developed thyroid cancer [
32]. The papillary thyroid cancer incidence among the 99,693 liquidators in the National Register is currently comparable to the average national level and does not appear to be increasing in either men or women.
Bhopal (December 2, 1984 [3])
In Bhopal, more than 500,000 workers and residents were exposed to methyl isocyanate gas and other toxins [
33]. Fatalities were seen immediately with bodies and animal corpses piling around the area within hours. Hospitals were overwhelmed and neither reinforcements nor epidemiological expertise were available. Estimates of the number of people killed in the first few days by the plume from the plant range up to 10,000, and 15,000–20,000 premature deaths have reportedly occurred in the subsequent two decades [
34]. Immediate primary causes of death suggest effects of severe toxicity: choking, reflexogenic circulatory collapse, and pulmonary edema, cerebral edema, tubular necrosis of the kidneys and fatty degeneration of the liver and necrotizing enteritis. In addition, spontaneous abortions occurred in approximately half of the women in their first trimester at the time [
35]: the stillbirth rate tripled and neonatal mortality doubled [
36].
Early reports of health effects were descriptive and no immediate exposure assessment was accomplished due to lack of planning, organization, and expertise. The knowledge of the long-term health effects of the exposure has also been limited by the absence of a structured longitudinal health surveillance program. A high proportion of the exposed population fled when the plant was restarted to burn the residual methyl isocyanate, without returning. This exodus resulted in a major limitation for the implementation of epidemiological health surveillance. Two years after the incident, the Indian Council of Medical Research (ICMR) established a cohort of civilians and workers affected by the disaster [
37] but operational problems included inadequate staffing and equipment (20 research assistants to monitor a cohort of more than 95,000 persons) [
38]. The ICMR ceased follow-up before 1993 and concluded its investigations by 1994. The Centre for Rehabilitation Studies of the Bhopal Gas Tragedy Relief and Rehabilitation Department – under the administrative control of the Madhya Pradesh state government – subsequently took over, restarting epidemiological assessment in 1996. Neither research group was able to collect data on maternal health or mental health services. Furthermore, local mental health services were inadequate with regard to the provision of long-term mental health care to all who needed it, and did not link of primary health care with mental health care. Public mental health education to prevent adverse long-term health consequences, self-care instructions and psycho-social interventions were also all inadequate. In addition, poor coordination with voluntary organizations resulted in mistrust and many residents moved. By 2010, the researchers had lost 79% of the cohort [
39] and in 2011, the cohort was handed back to ICMR and the National Institute for Research in Environmental Health (NIREH) in Bhopal.
World Trade Center (WTC, September 11th, 2001–9/11)
In addition to the 2966 killed (2.606 in the WTC and surrounding areas, 125 at the Pentagon and 265 on the four planes), an estimated number of 90,000 workers and responders from every US state, and ~400,000 residents/vicinity-workers (hereafter ‘survivors’,
per their Health Program name),, were affected by the events at the WTC [
40]. The Fire Department of New York (FDNY) soon after the attack reported respiratory effects in firefighters and emergency medical technicians (EMTs) and Mount Sinai and collaborating occupational health centers worked on a proposal to the federal government to provide screening exams for the non-firefighter (hereafter ‘general’) responders who started presenting within a few days. The WTC Worker and Volunteer Medical Screening Program was established with funding provided by the Centers for Disease Control and Prevention (CDC)/National Institute for Occupational Safety and Health (NIOSH) and the first screening examinations occurred in July 2002. The National Institute for Environmental Health Sciences (NIEHS) also provided initial funding for research. A similar program had been established by the CDC for New York City firefighters in 2001–2002. General responders who provided rescue, recovery, demolition, debris cleanup or restoration of services received a one-time medical evaluation. Physical and mental health treatment services were provided with support from philanthropic sources. In 2004, NIOSH provided funding for additional initial medical evaluations and monitoring examinations every 18 months for what became the General Responder Cohort (GRC), and continued funding for the FDNY to provide the same services to the firefighters. In 2006, NIOSH provided funding for treatment of both physical and mental health conditions, renaming the program the WTC Medical Monitoring and Treatment Program (MMTP). Local community and academic efforts resulted in the first organized surveillance program for community members with an initial CDC-funded study of the local residents by New York University and Bellevue Hospital working with the New York State Department of Health [
41,
42]. This was followed by the development of the New York City Department of Health and Mental Hygiene (NYCDOHMH) WTC Health Registry (WTCHR) [
43]. In contrast to the WTC MMTP, the community programs did not provide health surveillance and clinical examinations. Small programs (initially self-funded pilot programs that received support from philanthropic sources in 2005, the City of New York in 2006, and the federal government in 2008) were developed for the treatment of WTC-related illnesses in the local community. With the passing of the James Zadroga 9/11 Health and Compensation Act of 2010, the WTC Health Program (WTCHP) was established which provided five more years of medical monitoring and treatment for both responders and the community, until July 2016.
Periodic health assessments provided to the GRC are standardized and include a medical questionnaire on WTC-related symptoms and conditions; a one-time exposure assessment questionnaire to capture exposures related to 9/11 and occupational exposures; and physician examination. Because the main exposure route for the caustic WTC dust was
via inhalation, pulmonary function tests (PFTs) are conducted and chest x-rays are taken. Routine blood work and urine analysis are also included [
44]. In addition, a self-administered mental health screening questionnaire identifies general psychiatric symptoms; possible cases of Post-Traumatic Stress Disorder (PTSD); symptoms of panic, generalized anxiety and depression; alcohol dependence and abuse; functioning at home and work; and suicidal ideation. The questionnaire is scored during the same visit, allowing prompt referral for further mental health evaluation and treatment (immediate, if necessary) among those who score above pre-validated thresholds for various mental health conditions, and for those who acknowledge suicidal ideation or substantial disability, irrespective of score. Community members are provided with WTCHP treatment and surveillance,
via the WTC Environmental Health Center (WTC EHC), if they have physical or mental health symptoms (general health surveillance is not provided). Those that do undergo a standardized protocol that includes a self-accessed exposure history and physical and mental health questionnaires and testing. The exposure history captures information on both acute exposure (from the dust clouds created by the buildings’ collapse) and chronic exposure (from re-suspended dust that had settled in homes, streets and workplaces) [
45]. As of 31 March 2014, the WTCHP included 37,281 subjects for the GRC, ~15,000 firefighters and ~5000 survivors [
46].
Certification for treatment requires attestation from a WTCHP medical professional that exposures present during the WTC effort (
e.g., airborne toxins, heavy lifting or repetitive strains on muscles and joints from work performed on the WTC effort, viewing falling bodies or body parts) played a significant role in aggravating, contributing to, or causing the physical or mental health condition. As of March 31
st, 2014, 46% (15,133 of the 33,076) of the GRC were certified for at least one WTC-related condition, whereas, by definition, 100% of the over 8600 enrolled community members have a certification [
47]. Participants in the WTCHP can also receive Workers’ Compensation and benefits from other disability programs and are eligible to receive compensation for physical harm, including death, from the Victims Compensation Fund, which was included in the federal legislation.
More than 20% of the GRC is suffering persistent physical and mental health problems: the cumulative incidence rates of asthma, sinusitis and abnormal spirometry have been reported to be 27.6, 42.3 and 41.8%, respectively [
45], for example. These rates cannot differentiate the diseases diagnosed before 9/11, because of the lack of baseline data, except for the FDNY portion of the responders’ cohort. Multiple comorbidities have been frequently observed: a syndrome of asthma, Gastro Esophageal Reflux Disease (GERD) and sinusitis has been observed in approximately 10% of the GRC. The incidence rate of sarcoid-like granulomatous pulmonary disease has been estimated to be 32
per 100,000 person-years, a rate that is elevated compared to published background rates [
48]. The cumulative incidences for depression, PTSD, and panic disorder in the non-police responders are 27.5, 31.9 and 21.2%, respectively, and approximately 6% of the cohort suffers from all three [
45]. Analyses have shown elevated standardized incidence ratios for all-cancer-sites-combined (SIR = 1.15; 95% CI: 1.06, 1.25), thyroid (SIR = 2.39; 95% CI: 1.70, 3.27), prostate (SIR = 1.21; 95% CI: 1.01, 1.44), soft tissue (SIR = 2.26; 95% CI: 1.13, 4.05), and combined hematopoietic cancer (SIR = 1.36; 95% CI: 1.07, 1.71) [
49,
50]. There is also some indication of an elevation in multiple myeloma [
51]. In contrast to the GRC (and FDNY), nearly 50% of the patients in the WTC EHC are women (most were local workers). As seen in the GRC, most WTC EHC patients suffer from aerodigestive disorders [
52], and rates of screening are positive for PTSD, anxiety and depression. An increasing number of patients are enrolling in the EHC with cancers, including breast, hematopoietic, thyroid and prostate cancer [
44]. Incidence rates cannot be determined from the EHC. The WTCHP provides screening for cervical, breast, colon and lung cancer for both GRC and EHC (
www.cdc.gov/wtc/cancerfactsheets.html).
Fukushima (March 11th, 2011 – 3/11 [5])
Two months after the event, the Nuclear Emergency Response Headquarters of Japan published the “Roadmap for Immediate Actions for the Assistance of Nuclear Sufferers” which outlined the need to track the emergency workers long-term, including after retirement, and implement long-term health care activities. In October 2011, the Japanese Ministry of Health, Labour and Welfare (MHLW) established an expert panel on the long-term health care of the workers and published ministerial guidelines [
53], based on the Industrial Safety and Health Act, to: (1) establish size-appropriate health management and surveillance at each workplace; (2) conduct annual surveillance, for those who participated in the emergency work, consisting of cancer screening, an eye examination for cataracts with a slit-lamp for those with an effective dose greater than 5 cGy, and thyroid tests for individuals with an effective dose greater than 10 cGy; and (3) provide health guidance to the emergency workers. Employers are required to provide the long-term health care, including health surveillance, for their employees. The government provides the long-term health care for the unemployed, for workers who have changed occupations since the accident, and for those employed by some small-to-medium size companies not directly engaged in radiation work. The MHLW also established a Data Center for the radiation dose and health surveillance data [
54].
The MHLW also published an (MHLW-convened) expert panel report which included projections, for emergency workers who worked during the period (March 14 to December 16, 2011) when the effective dose limit was 25 cGy (instead of 10 cGy), that the expected health effects include solid cancers, leukemia, non-cancer diseases, and psychological distress. At the end of 2014, experts in epidemiology, radiation medicine and occupational health were again convened by the MHLW and a cohort study covering all ~20,000 emergency workers was launched [
55]. In addition, Fukushima prefecture, is implementing the “Health Survey of Prefectural Residents (Kenmin Kenkou Chosa)” to assess the levels of exposure to radiation and the health status of their residents, with a view to the early detection, prevention and treatment of potential diseases. The baseline survey (Kihon Chosa) was open to everyone residing in the prefecture since 3/11 and estimated individual exposure levels. Data are collected in a database for long-term follow-up, which includes thyroid ultrasound examination for residents who were ≤18 years old on 3/11 and a general health assessment for all residents, regardless of age. Differential leukocyte counts is also obtained for residents of the evacuation areas, as well as examination of mental health status. For pregnant women, specific questionnaires were added to a maternal and child health handbook. Preliminary findings of the surveys [
56‐
58] have not been officially acknowledged by the government at the time of writing.