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REVIEW ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 3  |  Page : 117-128

The styrene gas disaster – lessons to learn and the way forward


1 Indian Institute of Public Health, Hyderabad, Telangana, India
2 Chief of Medical Oncology, KIMS-ICON Hospital, Sheelanagar, Visakhapatnam, Andhra Pradesh, India
3 Endocrine and Diabetes Centre, Visakhapatnam, Andhra Pradesh, India
4 Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA

Date of Submission14-Mar-2021
Date of Acceptance14-Mar-2021
Date of Web Publication17-Mar-2022

Correspondence Address:
Prof. Raghunadharao Digumarti
208 Green City Heights, Green City, Yadava Jaggaraju Peta, SEZ Post Office, Visakhapatnam, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdrntruhs.jdrntruhs_32_21

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  Abstract 


The incident: A large amount of styrene gas was accidentally released from the LG Polymers India plant in Visakhapatnam, India, on 7 May 2020. The release resulted in 12 deaths and hundreds of injured persons in the nearby communities. This article reviews the potential causes and consequences of the accident on the people and the surrounding environment.
Health Effects: The chemistry, toxicology, and exposure pathways of styrene are discussed to facilitate understanding the health effects on the exposed population. Lessons from the Bhopal disaster are discussed with a view to investigating and preventing future industrial disasters.
The way forward: Using the experience of experts from the Bhopal Gas Tragedy, we propose the requisite methodology to monitor the exposed population using epidemiological research protocols that incorporate risk stratification and clinical investigation of the victims exposed to styrene.

Keywords: Epidemiology, industrial disaster, LG Polymer, Visakhapatnam, styrene, toxicology


How to cite this article:
Dhara V R, Digumarti R, Sridhar G R, Gassert TH. The styrene gas disaster – lessons to learn and the way forward. J NTR Univ Health Sci 2021;10:117-28

How to cite this URL:
Dhara V R, Digumarti R, Sridhar G R, Gassert TH. The styrene gas disaster – lessons to learn and the way forward. J NTR Univ Health Sci [serial online] 2021 [cited 2022 Nov 30];10:117-28. Available from: https://www.jdrntruhs.org/text.asp?2021/10/3/117/339805




  Introduction Top


In the predawn hours of May 7, 2020, people asleep in the densely populated Gopalapatnam and four other nearby villages of Visakhapatnam, Andhra Pradesh, India (hereafter “Vizag”) were exposed to a highly concentrated cloud of styrene vapour that wafted through their neighborhood and homes as it escaped from the nearby LG Polymers chemical plant.[1] The extent of gas spread was up to 3 km downwind. Workers were reopening the plant process after it had been closed due to a COVID-19 pandemic lockdown. Twelve residents, including two children, died acutely and nearly six hundred others were hospitalized with breathing and vision complaints. Three additional deaths occurred in subsequent weeks, which are linked to the accident. Overall, more than 1000 had suffered illnesses. It is evident that the chemical must have escaped in extremely high concentrations.

The Vizag event, an industrial disaster resulting in gas exposure of sleeping residents, although far less deadly, was reminiscent of the horrific methyl isocyanate disaster in Bhopal, India, almost 36 years ago in 1984, because sequential factors leading up to and resulting in these chemical accidents were so similar, and both were preventable. Indeed, prior to and since these two accidental exposures, Indian workers and citizens have regularly been victims of industrial chemical plant releases, fires, and explosions. Notably, the Vizag and Bhopal chemical plants were foreign ventures of well-endowed corporations from South Korea (LG Polymers) and USA (Union Carbide, since subsumed by Dow Chemical Corp.). The polymer plant in Vizag was originally established in 1961, and then subsequently bought in 1997 by LG Chem, now the tenth largest chemical company in the world. The plant in Vizag uses styrene monomer to produce polystyrene (PS) plastics and expandable PS (EPS) foam products, as well as styrene copolymers, all requiring multiple chemical additives. Interestingly, “Styrofoam” is a trademark of Dow Chemical, but EPS products are widely made by many companies. PS and EPS products are essentially not biodegradable and eventually end up as permanent waste in water bodies, oceans, and landfills, and are mistakenly consumed by animals and sea life. There are safer alternatives from an environmental perspective.

Styrene is particularly toxic to the brain and lungs. As a monomer, it is a highly reactive aromatic chemical, a colorless oily liquid derivative of benzene that easily evaporates if not stored below 22°C (IUPAC preferred name is ethenylbenzene; CAS# 100-42-5) thus posing a contact and inhalation hazard. It is estimated that an overheated storage tank (M6) released about 800 tonnes of styrene, possibly with other trace chemicals, around 02:30 to 03:00 that morning in very high concentration from the Vizag plant, and being slightly denser than air, it permeated in ambient air currents through streets, alleys, and open windows for a long distance.

The Andhra Pradesh High Powered Committee (HPC) described in its report the runaway reaction as follows: “....the uncontrolled release of Styrene vapour from M6 Tank was due to the high increase in temperatures in the M6 Tank.[2] The increase in temperatures led to polymerization and the heat generated due to polymerisation finally led to runaway reactions. Increase in temperature to the boiling point of Styrene monomer viz 145°C led to the boiling of the liquid Styrene, leading to uncontrolled vapour formation. Further increase in temperature led to increase in the pressure of the vapour which led to the uncontrolled release of vapour from the vents into the atmosphere.” [Page 306].

The HPC report defined the root cause as follows: “In the light of the above, the Committee is of the view that the root causes of the accident in the Styrene storage M6 Tank can be attributed to poor design of tank, inadequate refrigeration and cooling system, absence of circulation of mixing systems, inadequate measurement parameters, poor safety protocol, poor safety awareness, inadequate risk assessment and response, poor process safety management systems, slackness of management, insufficient knowledge amongst staff, insufficient knowledge of the chemical properties of Styrene, especially during storage under idle conditions and total breakdown of the emergency response procedures.” [Pages 308–9].

The release resulted in significant water and soil pollution. The least contaminated water sample from a dug well in the community contained styrene levels 87 times higher than the WHO guideline, and the least contaminated soil sample from the Narava Kota Reservoir violated Canadian standards for agricultural land by more than 1000-fold. A search did not reveal standards established in India. The HPC report noted that the tank that released styrene (M6) was more than 50-year old and designed to store molasses, not a toxic chemical. The HPC noted that “The M6 tank is inferior in design in all respects for storing styrene.” LG manually operated the critical styrene tank cooling system only from 8 am to 5 pm. The HPC criticized this practice calling it “unscientific, human error oriented and unacceptable in terms of process safety.” The HPC condemned LG's disregard for safety, stating that, “LG Polymers does not have any process safety management system.” The committee concluded that the “handling of emergency response by LG Polymers was inept.” The company not only failed to alert the community of the deadly release but also did not perform any rescue and evacuation operations. “Any reasonable person of ordinary prudence would have blown the Emergency Siren to save the life of residents in the neighbourhood.” At a webinar organized by the Asian Network for the Rights of Occupational and Environmental Victims, the HPC report was nevertheless faulted for uncritical acceptance of information provided by LG Polymers, that its interpretations were based on faulty data, that the styrene vapor dispersion model results are unreliable, and that victims were neglected in the analysis. [3,4]

A reliable timeline of the accident is available from the International Pollutants Elimination Network at https://ipen.org/news/timeline-lg-tragedy-india.


  Reported Health Effects and Gas Exposure Characteristics Top


By all accounts, over 1000 villagers sought medical care when exposed to the toxic styrene vapor cloud, and 12 died including 2 children. About 585 persons of all ages required hospitalization, with women and children particularly affected. The local hospitals and clinics were unprepared for the nighttime mass incident and were overwhelmed.

Acute exposure by inhalation was likely enhanced by increased respiratory rates as people exerted themselves in panic running through the gas cloud to escape. Observations in the inhalation exposed population included neurological symptoms of giddiness, a feeling of drunkenness, nausea, and vomiting, changes in color vision, tiredness, confusion, slowed reaction time, as well as concentration and balance problems. Studies have shown that physical exertion, when exposed to the chemical, leads to higher blood levels of styrene when compared to being at rest.[5] Gas inhalation also caused upper airway irritation of the nose and throat, and lung symptoms of cough, shortness of breath, and eventual fluid in the lungs of some. Direct contact of the skin and mucous membranes caused irritation and blistering. Eye contact resulted in burning sensation, and a few complained of loss of vision. A review of medical records from government and private health facilities showed the following acute symptoms: headache, vomiting, drowsiness, altered sensorium, headache, and difficulty breathing.[6] The exposed victims were treated symptomatically with intravenous fluids, oxygen, painkillers, and multivitamins.

The causes of death were thought to be due to central nervous system depression in those who died shortly after exposure, and asphyxia due to pulmonary edema from chemical inflammation in those who died later. Information from autopsy studies are not available yet but should throw more light on probable causes of death.

The effects on animals of all sizes and plants were noteworthy. About 32 animals, including cattle, dogs, and a cat died. One hundred and ninety-nine animals were treated, mostly for breathlessness.[7] Poultry birds were also noted to have died.[8] Stretches of greenery were noted to have turned pale brown in Venkatapuram village.[9]

The toxicology of styrene is well-known to occupational physicians and hygienists and is extensively documented in medical and safety literature, but the safety measures were apparently not taken seriously by the LGPI owners, managers, and parent company LG Chem, and the information was not disseminated to the surrounding Vizag residential communities by the company and the local health authorities. The lessons of the Bhopal tragedy and the May 2019 Hanwha Total styrene gas release accident in South Korea, and subsequent regulatory reforms for chemical industry disaster prevention were apparently not implemented at LGPI, resulting in the occurrence of an entirely preventable disaster. [1,10] While styrene was the main substance emitted, a detailed chemical analysis of the exposures of the Vizag accident is needed to determine if there were by-products and decomposition products also present in the gas plume that could have enhanced the adverse health outcomes.

The minimal risk level (MRL) for acute inhalation exposure to the general population is 5 ppm daily over no more than a 14-day period. This level is much lower than that allowed for workers.[11] The MRL is an estimate of daily human exposure that is likely to be tolerated without appreciable noncancerous health effects. The MRL are established for noncancer effects, and used for public health advisory purposes and are not regulatory levels. Cancer risk is estimated using cancer potency of a chemical.

The International Agency for Research on Cancer (IARC) has determined that styrene is a possible carcinogen.[12] The United States Environmental Protection Agency's USEPA's human carcinogen potency factor (q1*) for styrene is 2.47 × 10–2 (mg/kg/day).[13] The occupational permissible exposure level mandated by the US Occupational Safety and Health Administration is 100 ppm for an adult worker averaged over an 8-h work shift, 40 h per week; 200 ppm not to be exceeded at any time; and 600 ppm as the 5-min maximum peak, which should never be exceeded in any 3-h work period.[14] The Immediately Dangerous to Life and Health exposure level for an adult worker is 700 ppm.[15] The styrene air concentration data in the air during and after the incident were not measured but some of these levels might have been severely exceeded as indicated by the number of deaths and injured villagers. Accounts of any health effects experienced by the Vizag LG Chem workers are not available.

A preliminary gas plume dispersion model has estimated exposure concentrations up to 312,000 ppm at 0.1 km to 975 ppm at 2.5 km downwind of the plant[16] [Figure 1]. The results of the modeling were mapped onto a Google map as Red, Orange, and Yellow zones based on the US Environmental Protection Agency's Acute Exposure Guideline Levels for exposure to airborne styrene monomer.[17] In the Red zone, exposure for up to 60 min to such concentrations may have life-threatening health effects or may cause death; in the Orange zone, exposed persons could experience serious adverse health effects or an impaired ability to escape in a 60 min exposure period; in the Yellow zone, persons may experience notable discomfort, irritation, or certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of a 60-min exposure to these concentrations. The modeling results show that the Red zone was 0.1–1.0 km from the source with most concentrations >1100 ppm; the Orange zone was 1.1–2.5 km from the source with concentrations ranging from 792–114 ppm; and the Yellow zone was 2.6–6.3 km from the source, with concentrations ranging from 110–20 ppm.
Figure 1: A preliminary gas plume dispersion model. Dhara S. Visakhapatnam gas leak incident: A preliminary modelling study. May 15, 2020. https://ecologise.in/2020/05/15/visakhapatnam-gas-leak-accident-a-preliminary-modelling-study/

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Conditions impacting exposure include quantity and rate of styrene release, wind speed and direction, topography and terrain, microenvironmental conditions, and height of the gas plume. It is expected that the plume dispersion model will be further refined as more information on the above factors becomes available.


  Styrene Chemistry and Toxicology Top


Styrene is naturally occurring in certain food plants in very low concentrations: e.g., roasted filberts, dried legumes, peanuts, cinnamon, wheat, oats, nectarines, strawberries, and peaches, and may also enter food from manmade styrene-derived containers and packaging and from contaminated soil and groundwater. By far, it is a manmade synthetic chemical produced since the 1950s in ever-increasing vast quantities by the chemical industry globally, and in this regard poses an increased exposure potential for toxic effects on humans and animals who are directly exposed, and for environmental harm from its polymer products.[11]

Styrene is known by several names, including ethenylbenzene, phenylbenzene, and vinylbenzene. It is a colorless to slightly yellowish oily liquid at 20°C that evaporates easily, and when pure smells sweet. The monomer evaporates from shallow soils and surface water and can be broken down in the air within 1–2 days by certain microorganisms. It can polymerize when heated and its polymerized forms (PS, EPS, XPS or extruded PS, and copolymers) are essentially nonbiodegradable.[11]

Styrene monomer is a highly flammable and explosive substance with a lower explosive limit of 0.9% v/v in air, and an upper explosive limit of 6.8% v/v. Styrene reacts with oxygen above 40°C to form heat-sensitive explosive peroxide. While maximum temperatures in the Vizag area have rarely exceeded 35°C in the past, future temperature rises likely due to climate change may have implications for the manufacture and storage of styrene. Thus, styrene requires strict controls on containment, temperature, transport, and handling due to its toxicity and volatility.

Human exposures generally occur through inhalation and to a lesser extent through the skin, because of its lipid solubility.[18] Urban air often contains higher concentrations than rural or suburban air. Indoor air often contains higher levels (0.07–11.5 parts per billion (ppb)) than outdoor air (0.06–4.6 ppb). Workers involved in styrene polymerization, rubber manufacturing, and styrene-polyester resin facilities and workers at photocopy centers may be exposed to styrene.

Toxicological studies of animals, mostly rodents, and reports of human exposures have demonstrated that, depending upon route of exposure, there is a strong irritant effect on eyes, skin, mucous membranes, and the linings of the respiratory and gastrointestinal tracts.[11] Once absorbed into the bloodstream through any of these routes, styrene is primarily metabolized via oxidation of the vinyl group to styrene-7,8-oxide (SO), which is subsequently biotransformed to several other metabolites, including mandelic acid (MA) and phenyl glyoxylic acid (PGA). Both of these metabolites are detectable in the urine of styrene-exposed rodents and humans if sampled proximal to the exposure.

Studies of worker inhalation exposures to styrene vapor have demonstrated nervous system effects, including changes in color vision, tiredness, slow reaction time, concentration, and balance (vestibular) problems. Styrene concentrations that cause these effects are more than 1000 times higher than the levels normally found in the environment [Table 1]. Animal studies have shown hearing loss, changes in the lining of the nose, and liver damage following styrene inhalation. Guinea pigs, upon exposure to styrene for 7–8 h a day five days a week for six months, died of toxicity; they developed acute inflammation, edema, and hemorrhage of the lungs.[19]
Table 1: Examples of Health Effects of Acute Inhalation Exposure to Styrene in Humans and Mice

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  Biotransformation, Elimination, and Biomarkers of Styrene Exposure Top


Styrene is rapidly absorbed, 60%–70%, through the respiratory tract in humans and steady-state levels are achieved in blood in about an hour.[20],[21],[22] The elimination of styrene from blood is biphasic, with a half-time (T1/2) of 1 min for the rapid distribution phase and 40.8 min for the elimination phase. Styrene is rapidly distributed throughout the body with the highest concentrations found in adipose (fat) tissue. In rats, styrene concentration in adipose tissue is approximately 50-fold higher than in muscle. The biological T1/2 is 6.3 h in adipose tissue and 2.0–2.4 h in the blood, liver, kidney, spleen, muscle, and brain.[23]

Another human inhalation study determined that between 59% and 66% of inhaled styrene (50–200 ppm) was retained after a 4–8 h exposure.[24] Urinary elimination of MA was biphasic with a half-life for the first phase of 4 h and for the second phase 25 h. The half-life of urinary elimination of PGA was determined to be 11 h. This was regarded by the authors as being the first phase of elimination since MA is a precursor of PGA.

The elimination of styrene via expired air may be used to identify exposure to styrene. [25,26] Only a small percentage of unchanged styrene is expired after cessation of exposure. There are no adequate studies correlating postexposure exhaled styrene with previous exposure levels. The presence of styrene metabolites in urine within 24 h have been used as biomarkers and can be used to estimate actual exposure level, however they cannot be used to predict the kind of health effects that might develop from that exposure. In humans, styrene is primarily excreted in the urine as MA and PGA. The half-lives in the urine are 2.2–4.2 h for MA and 3.5–13.9 h for PGA following a 2-h exposure to 50 ppm styrene.[22]

Assessment of occupational exposure involving measurement of unchanged styrene in urine has been reported.[27] In this study of workers, the styrene air concentrations were 3.8–14 ppm and the urinary concentrations of styrene were 0.7–4.1 μg/L. Urinary mutagenic activity was also evaluated in this study and was not a good indication of exposure to styrene. Only a small fraction of unchanged styrene is recovered in the urine. However, measurement of styrene in urine is a reliable indicator of styrene exposure if the exposure is recent. [25,27]

Analysis of unchanged styrene in blood may be used as a qualitative indicator of styrene exposure.[28] In one study, styrene was detected in the blood of humans exposed to 80 ppm.[29] The maximum blood concentration at the end of exposure was 0.92–0.26 μg/mL. The half-life values for rapid and slow clearance curves were 0.58 and 13 h, respectively. In another study, the concentration of styrene in blood (0.2–3.7 mg/L) increased with the level and duration of styrene exposure.[30]

The presence of styrene in adipose tissue is also an indicator of exposure. The concentration of styrene in the adipose tissue of two workers exposed to 7.5–20 ppm of styrene during a work week suggested a half-life of 5.2 days for one worker and 2.8 days for the other worker. The elimination time was estimated to be five weeks.[31]

Given these data, it is estimated that blood and urine sampling for styrene exposure is best done within 48 h, as it takes five half-lives to eliminate about 99% of styrene and its metabolites. Assuming that the Vizag gas victims were exposed to extremely high concentrations, styrene and/or its MA and PGA metabolites would be detectable by biological sampling of blood and urine. It is not known yet if any the hundreds of hospitalized Vizag victims underwent blood or urine sampling for styrene and its metabolites in the first two days after the May 7th gas exposure incident. Nor are there reports of postmortem toxicological studies for styrene and its metabolites. Adipose sampling by needle aspiration in survivors, or on postmortem for those who died, would be indicated for exposure estimation if acute phase sampling of urine and blood in the first 48 h postexposure was not achieved.

General population exposure to styrene in air and food has been estimated to be 18–54 and 0.2–1.2 μg/person/day, respectively, with a total daily exposure of 18.2–55.2 μg/day or 0.0003– 0.0008 mg/kg/day (assuming a 70-kg reference body weight).[11] This low level of exposure would likely be undetectable and would not confound biological samplings for gas exposure.

The biological exposure index (BEI) is defined as an index chemical that appears in a biological fluid or in expired air following exposure to a workplace chemical, and which serves as a warning of potential or actual overexposure. For styrene, rather than using blood or expired air, the American Conference of Governmental Industrial Hygienists (ACGIH) recommends monitoring the sum of MA and PGA in urine as the preferred indicator of exposure to styrene, and the value of 0.15 g/g creatinine is recommended as the styrene BEI for an adult worker, which corresponds to a TLV-TWA of 20 ppm.[32] The Deutsche Forschungsgemeinschaft (DFG) of Germany recommends a BEI of 0.25 g/g creatinine, which is slightly more lenient than the ACGIH BEI.[33]

Typically, the physician can conduct pre- and postshift urine sampling, or next morning preshift sampling, in a worker, or acute postexposure (as soon as possible within 48 h) of accidental exposures, as was the case with the Vizag incidence. If elevated urine (or other specimen) is found, a convalescent urine specimen can be evaluated to assure elimination of the chemical and can also serve as proof of exposure. In general, civilians who are not styrene workers should have normal studies, so any positive detection in a civilian serves as proof of exposure regardless of quantification, especially if after exposure a convalescent sampling test shows no styrene metabolites.


  Discussion of MRLs, Lowest Observed Adverse Effect Levels (LOAELs), and No Observed Adverse Effect Levels (NOAELs) with Reference to Inhalation and Dermal Exposure to Styrene Top


The principal route of styrene exposure for both workers and the general population is inhalation of contaminated air. However, the general public, including workers after they leave work, are also more likely to be exposed through ingestion of styrene in food packaging and polluted drinking water. The Toxics Release Inventory reported that more than 51 million pounds of styrene was released annually in the United States in the environment, over 90% in air.[34]

Health guidance values (HGVs) are derived by various agencies and organizations to protect general populations and particularly health workers from unintentional exposure to chemicals present in our environment. MRLs are Agency for Toxic Substances and Disease Registry (ATSDR) HGVs used to evaluate the toxicity and risk posed by priority environmental chemicals and are based on the concept that a threshold level of exposure exists, below which no noncancer health effect is likely to occur. For the derivation of MRLs, exhaustive literature searches are conducted to compile the database on the overall toxicity of the chemical of concern. Identified studies are then categorized by route and duration of exposure and organ systems toxicity. Next, the studies that present dose response data are closely reviewed to identify a critical study that includes the data for the most sensitive effect at the lowest dose in humans or animals for the specific route and duration of exposure. Such a study provides point of departure (POD) that is used to derive the MRL. All other appropriate studies identified are used as supporting evidence for the MRL derivation. The POD is divided by uncertainty and modifying factors to calculate the MRL. Depending on the available data, the POD could be the highest NOAEL or the lowest LOAEL or the lower limit of the 95% confidence interval of the benchmark dose level. Sometimes the POD could be determined based on actual external exposure levels, default values, time weighted averages (TWA), through dosimetric adjustments, or even target organ or system specific concentrations using physiologically based pharmacokinetic models.

The acute toxicity of styrene has been studied in humans and various laboratory animal species.[11] Examples of health effects of acute inhalation exposure are given in [Table 1]. The data collectively suggest that the nervous system is the most sensitive target of styrene toxicity in humans following acute-duration inhalation exposure. The lowest LOAEL in humans was 87 ppm for vestibular impairment in human subjects exposed to styrene for 1 h (Ödkvist et al. 1982). A similar LOAEL (80 ppm) was identified for nasal effects in mice exposed to styrene for 3 days.[39]

Also, a large number of occupational exposure studies support the nervous system as the critical target organ of styrene toxicity.[11] Briefly, a variety of neurological effects may occur, ranging from changes in neuropsychological function, disturbed color vision, impaired nerve conduction velocity, and psychiatric disorders. [44,45] Welp et al. published a report whether styrene could lead to chronic central nervous system disorders. They studied a large international historical cohort of 35,443 workers from reinforced plastic industry between 1945 and 1991.[46] The conclusion was that deaths from Central nervous system (CNS) disorders increased with time since first exposure, duration of exposure, average level of exposure, and cumulative exposure to styrene.

An update on the potential health effects following worldwide occupational and environmental exposure to styrene was published in 2019.[47] The evaluation updated health hazard and exposure information developed since the Harvard Center for Risk Analysis risk assessment for styrene was performed in 2002.[48] Inhalation and ingestion are the principal routes by which the chemical enters the human body. Concentration in the surface and ground water is low because it is volatile and rapidly biodegraded as a monomer, whereas polymer products (e.g., polystyrene) persist almost indefinitely. Essentially, the two significant concerns to human health of styrene monomer exposure were related to human cancers and ototoxicity in the earlier report. Nearly 20-year later, they still continue to be areas of concern, although they are much better understood.

Important aspects stand out from the updated report of 2019: first, over the time interval, release of styrene in general is reducing, with lower concentrations in both indoor and outdoor environments. In addition, it diffuses into the surrounding atmosphere, and has a low affinity to remain in the soil. Styrene monomer is degraded and is not persistently seen in any media. Reassuringly, the occupational risks with styrene exposure were similar between the 2002 and 2019 publications despite the long follow-up and exposures to the chemical. Unless high exposure occurs as in fiber-reinforced plastic industries, the update concluded that “styrene is a low concern for human health risk.” However, the 2020 accident in Vizag resulting from substandard industry practices in India coupled with a lack of oversight by multinational corporate safety shows that styrene continues to have the potential for being a major health risk.

Medical Management of Styrene Exposed Victims

A comprehensive account of the toxicology and medical management of styrene is available on the International Program on Chemical Safety peer-reviewed Chemical Safety Poisons Information website.[49] The US National Library of Medicine PubChem (formerly Toxnet) website also provides extensive information on styrene monomer and other substances of the Vizag gas cloud if any are identified (https://pubchem.ncbi.nlm.nih.gov/). As referred to earlier, occupational toxicity results from respiratory and skin routes. The immediate action for medical management consists of rapid removal from exposure and effective decontamination, followed by assessment of vital functions and administration of processes to maintain airway patency, breathing, and circulatory support. Oxygen may be administered if necessary.

When eyes are exposed to styrene, they are irrigated with water or isotonic saline immediately and continuously for 15 min. Skin is flushed with water for 15 min; nonabrasive soap can be used. The victim is moved to a location with access to fresh air.

In the unlikely event of toxicity due to ingestion, vomiting should not be induced because styrene is lipophilic and can enter the lungs causing severe inflammation. When ingestion is massive and recent, gastric lavage can be done with activated charcoal slurry. Intake of fats and oils should be avoided, which can increase the absorption of styrene.

Cancer and Styrene

Cancer in humans: The IARC stated that there is limited evidence in humans for the carcinogenicity of styrene. Positive associations have been observed between exposure to styrene and lymphohematopoietic malignancies. There is inadequate evidence in humans for the carcinogenicity of styrene-7,8-oxide, the major metabolite of styrene. In experimental animals, there is sufficient evidence for the carcinogenicity of styrene and styrene-7,8-oxide. In the overall evaluation, IARC has determined that styrene and styrene-7,8-oxide are probably carcinogenic to humans (Group 2A).[12] In making this overall evaluation, the IARC Working Group took account of the mechanistic and other relevant data that supported the classification of styrene in Group 2A. Styrene-7,8-oxide is an electrophile and there is strong evidence in human systems that it forms DNA adducts and is genotoxic. The human carcinogen potency factor (q1*) for styrene is 2.47 × 10–2 (mg/kg/day) for oral exposure, which can be used to determine lifetime excess cancer risk.[13] The US National Toxicology Program lists styrene as reasonably anticipated of being a human carcinogen.

Epidemiological studies found that styrene workers had increased mortality from hematolymphoid malignancies—leukemias and lymphomas as well as esophageal and pancreatic cancers. A 2010 case-control study in six European countries reported significantly elevated risks for B-cell non-Hodgkin's lymphoma [odds ratio (OR) 51.6; 95% confidence interval (CI) 51.1–2.3] and for follicular lymphoma (OR 5 2.6; 95% CI 5 1.3–5.2) in relation to styrene exposure. Exposure-related trend analyses also demonstrated increased risks (P < 0.05) for lymphomas in relation to increases in styrene exposures.

Genotoxicity of Styrene and Its Derivatives[50]

Styrene is mutagenic. Probably because of an unfavorable activation–inactivation ratio, some mutagenicity assays may fail to detect this. Styrene is converted by microsomal monooxygenases in vivo to styrene-7,8-oxide, which is a well-known mutagen. Only a few derivatives of styrene have been tested for mutagenicity. The results are characterized by difficulties in metabolic activation. Human whole-blood lymphocyte cultures have a peculiar feature, that is, styrene and many of its analogs substituted at the ring or vinyl chain induce sister chromatid exchanges in the cultured cells without exogenous metabolizing systems. This activation is brought about by red blood cells present in the cultures and probably results from the conversion of styrene to styrene-7,8-oxide.

Increased frequencies of chromosome aberrations have been seen in lymphocytes of workers employed in the reinforced plastics industry, mainly in manual laminating jobs, where exposure to styrene is high. Two studies have also reported an increase of micronuclei in the lymphocytes of workers from the reinforced plastics industry

Reproductive Toxicity[51]

Styrene oxide was toxic to both species studied: rat and the rabbit. A significant reduction in corpora lutea was observed postexposure. Significantly fewer mated rats were found to result in pregnancy. This suggested a preimplantation loss of embryos. Fetuses showed evidence of toxicity with all four epoxides. There was no overt teratogenic activity, but a number of minor morphologic aberrations were detected. Aside from these experimental studies, there is no available evidence on the human reproductive toxicity of high dose exposure to styrene vapor, as happened at the LG Polymers and the Hanwha Total factories in Vizag India and in Seosan S. Korea, respectively. Postexposure epidemiological assessment of pregnant female gas victims from these accidents would be very important in understanding human reproductive effects. This might also require dose equivalent assessments, along with hypoxemia, as factors in adverse pregnancy outcomes.

Carcinogenicity of Styrene and Derivatives[52]

Suggestions for a Medical monitoring Strategy for Vizag Styrene Gas Victims

Health monitoring can begin with identification of all (as many as possible of approximately 1000) individuals who sought medical care and their enrollment in a proper medical surveillance epidemiological protocol for baseline and prospective periodic, including perhaps biometric, assessment. Such a monitoring study could be both descriptive and clinical in nature, and would be subject to an institutional review board oversight for international standard protection of human subjects voluntarily taking part, such as with an independent India-based medical center, medical school, medical expert panel, or school of public health. Enrollment in the study would have to be coupled with a referral commitment for prompt medical support for any abnormal findings requiring specialist care or consultation. Also, enrollment would ideally also risk-stratify based upon exposure modeling for individuals in relation to the individual's location proximity and duration of styrene exposure during the gas event of May 7, 2020.

Following enrollment and exposure risk stratification of individual victims, there would be a need to conduct individual interviews or questionnaires to establish normative baselines, which would include review of each victim's medical records immediately postevent. A very important component would be whether biological sampling specimens (of blood and urine) included toxicological testing for styrene exposure, or whether such specimens, even if untested, have been preserved so that they can be tested for styrene exposure in order to ascertain a baseline for styrene exposure in the victim population.[30]

For purposes of determining whether outcomes are directly related to styrene toxicity in the exposed population, various study designs can be considered. A cross-sectional case series report would be the easier but would provide less causal information. Whereas, a case-control or cohort prospective study matching exposed and unexposed persons of similar demographics would provide much stronger evidence for styrene health effects in human victims of the Vizag styrene gas event.

The goal of this study would be to enumerate and evaluate acute, intermediate, and long-term effects—physical as well as psychological. To determine acute health effects, information would need to be collected on the baseline medical assessment records, including laboratory and imaging studies, immediately postexposure when victims were accessing medical care during and in subsequent days following the event. This would involve medical record review and perhaps follow-up standardized personal interviews. Also, it would be important to access autopsy findings on the deceased, and to determine the geographical location of their exposures to styrene on May 7th, 2020. This would be contiguous with the exposure risk stratification of survivors.

A study baseline under an epidemiological protocol would include history questionnaire and, if possible, clinical examination of hospitalized and nonhospitalized enrollees of the entire body including target organs, such as the heart, lungs, skin, eyes, and reproductive and nervous systems, as well as investigations of blood, urine, chest X-ray, brain scans, andpsychological and neurobehavioral testing.

Health effect studies must be guided by exposure stratification of the population by biological monitoring, location, and movement of the individual while exposed to the gas. (See Box)

Cause of death has to be determined by clinical and autopsy information and correlated with each individual's styrene cloud exposure risk stratification. Biological monitoring of blood, urine, and autopsy specimens will have to be performed for the purposes of care, exposure determination, and compensation.
Table 2: Recommendations For Monitoring Exposure and Dose

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The exposed population, including those women who were pregnant or in the reproductive age group, must be systematically monitored for long-term genotoxicity, reproductive loss or incapacity to bear children, teratogenesis in the immediate and subsequent pregnancies, as well as development of cancers or cancer-like conditions (myelodysplasias, etc.).

Intermediate health effects studies for the period from six months to one year would include information from the acute phase focusing on brain, skin, eyes, and lung effects plus other systemic and reproductive systems. The decision on health endpoints to be included can be guided by medical and toxicology studies on human and animals. Pregnancy loss or complication needs to be monitored in those women who are already pregnant as well as those likely to conceive in the next few months to a year. Children born to those mothers who were pregnant must be monitored for teratogenesis amongst the other parameters of normal growth, puberty, and early peaks of chronic illnesses.

Long-term health studies on survivors should include end-points identified from the acute and intermediate phases with a view to determining the spectrum of health effects suffered by the Vizag cohort, focusing on scholastic achievement, endocrine deficiencies, reproductive capabilities, psychosocial effects, and effects on the nervous system and other systems identified from toxicological studies. The information guiding these studies will include questions like the amount and types of toxins released, their emission levels, area of spread of the gas, neighborhoods affected, toxin seepage and persistence in the environment, and how many people were potentially exposed to this toxic gas cloud. These questions can be addressed by detailed accident analysis and modeling the gas plume dispersion.

The exposed population in Vizag would comprise children, pregnant women, older individuals, and people with comorbid conditions like heart, lung, and other ailments which would render them more vulnerable to the toxic effects of styrene. This population would form the cohort for inclusion in the long-term studies. Additional questions like the interaction between infection and the inflammatory effects of the toxic gas cloud on various body systems like the lungs and brain should be included. Health workers providing care to the gas victims should also be studied as they had potential for exposure to the gas breathed out by the patients. This is known as secondary transmission of toxins and was reported by many health workers attending to Bhopal gas victims.
Table 3: Recommendations For Health Effects Monitoring

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Such a monitoring and surveillance program would develop a database and would result in periodic reports on the epidemiological consequences for the Vizag victims, if not just an initial report.

What We Can Still Learn from the Bhopal Gas Disaster

It is essential to establish a permanent health authority at the central government level, with local government commitment, to register industrial accident (including agrochemical) worker and community exposed populations—symptomatic or not. In so doing, the authorization would be immediately to conduct studies of victims and to follow for continuous monitoring, to gain an understanding of the spectrum of health effects which are important for care, compensation, restoration, and rehabilitation of victims, as well as to serve as a guide map for investigation of future disasters. An analysis of the occupational health records of current and former workers will aid in understanding the health risks of styrene exposure at LGPI. While numerous studies were done on Bhopal victims, the syndrome of health effects characterizing the disaster was never properly defined, thus sowing confusion about the care and compensation for the victims. [53,54] Clarification on the causes of the gassing event and methods of prevention would inform why no future gassing events involving the styrene industry should ever again occur, and inform as to safer substitutes. Such findings could guide government regulators and the greater chemical industry, in general, for all industrial practices. India continues to experience severe industrial disasters and 35-year later, the lessons of the worst industrial disaster, Bhopal, are still to be learned and adopted in India and by India's foreign investors in the chemical industries.

The victims of Vizag styrene poisoning fully deserve that their experience, their painful lessons, and the experiences of Bhopal, and of so many other industrial disasters in India and elsewhere, be taken into account in finding them restitution and protection for the future.[55]


  Our Recommendations Top


  1. A multispecialty hospital and/or school of public health must be established with state-of-the-art facilities for the monitoring and specialized treatment of victims. Such an institution can also serve as a specialty centre for the treatment, monitoring, and research in occupational and environmental health. It may be independent or part of an existing academic medical or public health institution and headed by a public/occupational health expert
  2. The gas-related disease categories need to be broadened based on the information gathered by monitoring the population. In other words, there needs to be a styrene exposure risk stratification for individual victims. For an epidemiological study, there are additional considerations, as described in the text above
  3. Health data collected by the relevant authorities should be communicated to the population and submitted for publication in professional journals.
  4. Gas victims to have the right of access to their medical records
  5. Victim organizations should be adequately represented in the committees dealing with the disaster
  6. Criteria for compensation should include medical, economic, and social damage to the victims
  7. Allocation of resources for economic and social rehabilitation of people and their communities should be made.


Acknowledgements

The authors wish to thank Dr. Moiz Mumtaz for his valuable contribution to the Toxicology section; and Drs. Ashish Mittal and Domyung Paek for their valuable comments and critique of the article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Dhara V. Thirty-five years later, Bhopal gas leak failures resurface in Vizag. Hindustan Times. 2020.  Back to cited text no. 1
    
2.
Committee H-P. The Report of the High-Power Committee on the Styrene Vapor Release Accident at M/s LG Polymers India Pvt. Ltd. In: 2020.  Back to cited text no. 2
    
3.
Kalapala BR. Review of High-Powered Committee Report on LG Polymer India Pvt. Ltd. Presented at the Asian Network for Rights of Occupational and Environmental Victims (ANROEV) webinar. 2020.  Back to cited text no. 3
    
4.
Several wrong conclusions drawn in HPC report on Vizag Gas Leak [press release]. New Indian Express, July 25, 2020. 2020.  Back to cited text no. 4
    
5.
Wolff MS. Evidence for existence in human tissues of monomers for plastics and rubber manufacture. Environ Health Perspect 1976;17:183-7.  Back to cited text no. 5
    
6.
Dhara V. Medical records provided by representatives of the Asian Network for the Right of Occupational & Environmental Victims ANROEV. 2020.  Back to cited text no. 6
    
7.
Jaganmohan M. Number of animals affected by styrene gas leak in Visakhapatnam, India as of May 2020. Statista. 2020.  Back to cited text no. 7
    
8.
Apparasu S. Unconscious people, animals turning grey: Scenes outside Vizag plant. The Hindustan Times. 2020.  Back to cited text no. 8
    
9.
Devalla R. LG Polymers gas leak hits Vizag's biodiversity hard. The Hans News Service. 2020.  Back to cited text no. 9
    
10.
Ministry of Environment MoEaL, Chungcheongnam-do, Seosan-si, Korea Environment Corporation, Korea Occupational Safety and Health Agency, Citizen Participation Group. Accident of Hanwha Total's Chemical Leakage [May 17th -18th, 2019] Final report on joint investigation with related Organizations 2019.  Back to cited text no. 10
    
11.
ATSDR. Toxicological Profile for Styrene. In: US Dept. of Health & Human Services; 2010.  Back to cited text no. 11
    
12.
IARC. IARC Monographs Volume 121: Styrene, styrene-7,8-oxide, and quinolone. In. Vol 121: International Agency for Research on Cancer 2019.  Back to cited text no. 12
    
13.
USEPA. Healthand Environmental Effects Profile for Styrene. In.  Back to cited text no. 13
    
14.
USDOL. Permissible Exposure Limits. In. US Dept. of Labor2006.  Back to cited text no. 14
    
15.
NIOSH. Styrene. In. National Institute for Occupational Safety & Health 1994.  Back to cited text no. 15
    
16.
Dhara S BRK. Preliminary modelling of the vapor release from LG Polymers, Visakhapatnam on 7 May 2020.  Back to cited text no. 16
    
17.
USEPA. Styrene. INTERIM ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs). In: 2008.  Back to cited text no. 17
    
18.
Dutkiewicz T, Tyras H. Skin absorption of toluene, styrene, and xylene by man. Br J Ind Med 1968;25:243.  Back to cited text no. 18
    
19.
Spencer H. The response of laboratory animals to monomeric styrene. J Industrial Hyg Toxicol 1942;24:295-301.  Back to cited text no. 19
    
20.
Johanson G, Ernstgård L, Gullstrand E, Löf A, Osterman-Golkar S, Williams CC, et al. Styrene oxide in blood, hemoglobin adducts, and urinary metabolites in human volunteers exposed to (13) C (8)-styrene vapors. Toxicol Appl Pharmacol 2000;168:36-49.  Back to cited text no. 20
    
21.
Maestri L, Imbriani M, Ghittori S, Capodaglio E, Gobba F, Cavalleri A. Excretion of N-acetyl-S-(1-phenyl-2-hydroxyethyl)-cysteine and N-acetyl-S-(2-phenyl-2-hydroxyethyl)-cysteine in workers exposed to styrene. Sci Total Environ 1997;199:13-22.  Back to cited text no. 21
    
22.
Wigaeus E, Löf A, Bjurström R, Nordqvist MB. Exposure to styrene. Uptake, distribution, metabolism and elimination in man. Scand J Work Environ Health 1983;9:479-88.  Back to cited text no. 22
    
23.
IARC. Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene. In. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 822002.  Back to cited text no. 23
    
24.
Guillemin MP, Bauer D. Human exposure to styrene. Int Arch Occup Environ Health 1979;44:249-63.  Back to cited text no. 24
    
25.
Guillemin MP, Berode M. Biological monitoring of styrene: A review. Am Ind Hyg Assoc J 1988;49:497-505.  Back to cited text no. 25
    
26.
Stewart RD, Dodd HC, Baretta ED, Schaffer AW. Human exposure to styrene vapor. Arch Environ Health 1968;16:656-62.  Back to cited text no. 26
    
27.
Dolara P, Caderni G, Lodovici M, Santoni G, Salvadori M, Baroni A. Determination of styrene in the urine of workers manufacturing polystyrene plastics. Ann Occup Hyg 1984;28:195-9.  Back to cited text no. 27
    
28.
Antoine S. Environmentally significant volatile organic pollutants in human blood. United States: N. p. 1986.  Back to cited text no. 28
    
29.
Ramsey JC, Young JD, Karbowski RJ, Chenoweth MB, McCarty LP, Braun WH. Pharmacokinetics of inhaled styrene in human volunteers. Toxicol Appl Pharmacol 1980;53:54-63.  Back to cited text no. 29
    
30.
Baselt R. Styrene. Biological MonitoringMethods for Industrial Chemicals. 2nd ed. PSG Publishing company, Davis, CA; 1988. p. 265-7.  Back to cited text no. 30
    
31.
Engström J, Astrand I, Wigaeus E. Exposure to styrene in a polymerization plant. Uptake in the organism and concentration in subcutaneous adipose tissue. Scand J Work Environ Health 1978;4:324-9.  Back to cited text no. 31
    
32.
ACGIH. Ethyl Benzene. Documentation of the Threshold Limit Values and Biological Exposure Indices. 2014.  Back to cited text no. 32
    
33.
Worksafe New Zealand – Biological Exposure Indices. In: Workplace exposure standards and biological exposure indices 2020.  Back to cited text no. 33
    
34.
USEPA T. TRI explorer: Providing access to EPA's toxics release inventory data. Washington. In. Toxics Release Inventory 2009.  Back to cited text no. 34
    
35.
Odkvist LM, Larsby B, Fredrickson MF, Liedgren SR, Tham R. Vestibular and oculomotor disturbances caused by industrial solvents. J Otolaryngol 1980;9:53-9.  Back to cited text no. 35
    
36.
Seeber A, Blaszkewicz M, Golka K, Hallier E, Kiesswetter E, Schäper M, et al. Neurobehavioral effects of experimental exposures to low levels of styrene. Toxicol Lett 2004;151:183-92.  Back to cited text no. 36
    
37.
Ska B, Vyskocil A, Tardif R, Carrier G, Thuot R, Muray K, et al. Effects of peak concentrations on the neurotoxicity of styrene in volunteers. Hum Exp Toxicol 2003;22:407-15.  Back to cited text no. 37
    
38.
Cruzan G, Cushman JR, Andrews LS, Granville GC, Miller RR, Hardy CJ, et al. Subchronic inhalation studies of styrene in CD rats and CD-1 mice. Fundam Appl Toxicol 1997;35:152-65.  Back to cited text no. 38
    
39.
Cruzan G, Cushman JR, Andrews LS, Granville GC, Johnson KA, Bevan C, et al. Chronic toxicity/oncogenicity study of styrene in CD-1 mice by inhalation exposure for 104 weeks. J Appl Toxicol 2001;21:185-98.  Back to cited text no. 39
    
40.
Green T, Lee R, Toghill A, Meadowcroft S, Lund V, Foster J. The toxicity of styrene to the nasal epithelium of mice and rats: Studies on the mode of action and relevance to humans. Chem Biol Interact 2001;137:185-202.  Back to cited text no. 40
    
41.
De Ceaurriz J, Desiles JP, Bonnet P, Marignac B, Muller J, Guenier JP. Concentration-dependent behavioral changes in mice following short-term inhalation exposure to various industrial solvents. Toxicol Appl Pharmacol 1983;67:383-9.  Back to cited text no. 41
    
42.
Salomaa S. Inactivity of styrene in the mouse sperm morphology test. Toxicol Lett 1985;24:151-5.  Back to cited text no. 42
    
43.
Kankaanpää JTJ, Elovaara E, Hemminki K, Vainio H. The effect of maternally inhaled styrene on embryonal and foetal development in mice and chinese hamsters. Acta Pharmacol Toxicol 1980;47:127-9.  Back to cited text no. 43
    
44.
Misumi J, Nagano M, Zhao W, Aoki K. Neurophysiological changes in rats subchronically treated with styrene or its metabolites. J Occup Health 2000;42:328-35.  Back to cited text no. 44
    
45.
Castillo L, Baldwin M, Sassine MP, Mergler D. Cumulative exposure to styrene and visual functions. Am J Ind Med 2001;39:351-60.  Back to cited text no. 45
    
46.
Welp E, Kogevinas M, Andersen A, Bellander T, Biocca M, Coggon D, et al. Exposure to styrene and mortality from nervous system diseases and mental disorders. Am J Epidemiol 1996;144:623-33.  Back to cited text no. 46
    
47.
Banton MI, Bus JS, Collins JJ, Delzell E, Gelbke HP, Kester JE, et al. Evaluation of potential health effects associated with occupational and environmental exposure to styrene – An update. J Toxicol Environ Health B 2019;22:1-130.  Back to cited text no. 47
    
48.
Cohen JT, Carlson G, Charnley G, Coggon D, Delzell E, Graham JD, et al. A comprehensive evaluation of the potential health risks associated with occupational and environmental exposure to styrene. J Toxicol Environ Health B 2002;5:1-263.  Back to cited text no. 48
    
49.
INCHEM I. Styrene: International Programme on Chemical Safety Poisons Information Monograph 509. In: International Program on Chemical Safety.  Back to cited text no. 49
    
50.
Norppa H, Vainio H. Genetic toxicity of styrene and some of its derivatives. Scand J Work Environ Health 1983;9:108-14.  Back to cited text no. 50
    
51.
Hardin BD, Niemeier RW, Sikov MR, Hackett PL. Reproductive-toxicologic assessment of the epoxides ethylene oxide, propylene oxide, butylene oxide, and styrene oxide. Scand J Work Environ Health 1983;9:94-102.  Back to cited text no. 51
    
52.
Huff J, Infante PF. Styrene exposure and risk of cancer. Mutagenesis 2011;26:583-4.  Back to cited text no. 52
    
53.
Dhara VR, Gassert TH. The Bhopal syndrome: Persistent questions about acute toxicity and management of gas victims. Int J Occup Environ Health 2002;8:380-6.  Back to cited text no. 53
    
54.
Dhara VR. What ails the Bhopal disaster investigations? (And is there a cure?). Int J Occup Environ Health 2002;8:371-9.  Back to cited text no. 54
    
55.
From Bhopal Gas Tragedy to Bombay Docks Explosion: Revisiting major industrial disasters in India. [press release]. may 7, 2020. 2020.  Back to cited text no. 55
    


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