Life-threatening intoxication with methylene bis(thiocyanate): clinical picture and pitfalls. A case report
© Braun et al; licensee BioMed Central Ltd. 2006
Received: 27 June 2005
Accepted: 11 April 2006
Published: 11 April 2006
Methylene bis(thiocyanate) (MBT) is a microbiocidal agent mainly used in industrial water cooling systems and paper mills as an inhibitor of algae, fungi, and bacteria.
We describe the first case of severe intoxication following inhalation of powder in an industrial worker. Profound cyanosis and respiratory failure caused by severe methemoglobinemia developed within several minutes. Despite immediate admission to the intensive care unit, where mechanical ventilation and hemodialysis for toxin elimination were initiated, multi-organ failure involving liver, kidneys, and lungs developed. While liver failure was leading, the patient was successfully treated with the MARS (molecular adsorbent recirculating system) procedure.
Intoxication with MBT is a potentially life-threatening intoxication causing severe methemoglobinemia and multi-organ failure. Extracorporeal liver albumin dialysis (MARS) appears to be an effective treatment to allow recovery of hepatic function.
Extracorporal albumin dialysis using the Molecular Adsorbent Recirculating System (MARS®) is now used in many hospitals to support excretory hepatic function. Main indications are acute-on-chronic liver failure, acute liver failure, primary graft dysfunction after liver transplantation, and liver failure post liver surgery [1–3]. The MARS procedure allows removal of the protein-bound toxins, such as bilirubin, phenols, or "false" neurotransmitters, improvement of hepatorenal syndrome, and the creation of a "bridge" for patients awaiting urgent liver transplantation. Theoretically this treatment is suggestive to be of value in intoxications in which the liver represents the main target organ, either by eliminating protein-bound substances not removed by other extracorporeal procedures, or by supporting excretory hepatic function, thereby allowing spontaneous recovery of the failing liver or transplantation of a suitable graft. Here we report an unusual case of acute liver failure secondary to intoxication with MBT successfully treated with MARS.
Selected Blood Chemistry Before and After Treatment with MARS Albumin Liver Dialysis
At admission (day 0)
Before first MARS session (day 16)
After first MARS session (day 17)
After last MARS session (day 23)
At discharge (day 69)
Prothrombine time (%); [INR]
Chemical Overview of Methylene (Bis)Thiocyanate
Thiocyanic acid, methylene ester
CAS Registry Number:
OPP Chemical Code:
Trade and other names (USA):
Basic manufacturers (USA):
Akzo Chemicals, Inc.
Albright and Wilson, Ltd.
Buckman Laboratories International, Inc.
There is still a data gap for metabolism primarily due to inadequate metabolite idenfication . In rats, up to 99% of [14C]MBT were excreted over a 4-day period. Urine was the primary route of excretion (55–70%), followed by fecal elimination (15–30%) and expired CO2 (10–15%). It is tempting to speculate that fecal elimination is most likely achieved via biliary excretion of MBT and/or toxic metabolites. This would help to explain the cholestatic pattern of acute liver failure observed in our patient. Radiolabeled compounds found in fecal extracts from rats treated with high, but not in those with low, doses were identified as [14C]MBT (Brown L et al., Inveresk Research International, unpublished data). However the data provided on the identification of the metabolites in the urine, feces, expired air, and tissue is incomplete. Total radioactivity in the blood, blood cyanide and plasma thiocyanate exhibited biphasic elimination from the blood. The terminal elimination phase started 1 hour after dosing and had a half-life of 7 hours. The following mechanisms of metabolism were proposed: One is the reaction of alkylmono-thiocyanates with a soluble liver enzyme fraction containing glutathione S-transferase and glutathione. A second reaction involves P-450 isoenzymes. The additional thiocyanate group may make the methylene carbon suitable for oxygen insertion producing the corresponding aldehyde with the release of thiocyanate. Further oxidation of the aldehyde to the corresponding acid followed by decarboxylation would yield CO2. Toxicity of MBT would therefore be due to 1) cyanide release, 2) glutathione depletion, and 3) toxic metabolites other than cyanides and thiocarbamates. Hydrolysis studies indicate that MBT degrades to thiocyanate ion, formic acid, and mercapto-(methylenethiocyanate) depending on the pH of the medium. So far, however, it is not clear whether degradation to cyanide occurs in the working environment. In the present case the latter possibility could be excluded by biochemical analysis of a serum specimen obtained at the time of hospital admission, in which no cyanide could be detected. In addition patients with acute cyanide intoxication typically develop severe lactic acidosis, which was not observed in the present case.
Toxicity studies in rats and mice reported signs and symptoms comparable to those of acute cyanide intoxication and included dyspnea, tremors, and ataxia after MBT doses up to 160 mg/kg body weight . In animals surviving for at least 24 hours, the stomach was identified as the target organ, demonstrating necrotic inflammatory lesions of the mucosal surface. After 13 week administration rats treated with MBT (up to 16 mg/kg) developed mild anemia, and sperm motility was decreased in male rats. No mutagenic properties were observed in S. typhimurium, with or without S9 activation.
Two occupational incidents were reported to the Office of Pesticide Programs Incident Data System . The first involved a man who was exposed to MBT while dipping lumber. He developed swollen eyes, a rash on his cheeks and insomnia. The man was diagnosed lupus erythematodes during follow-up; a causal relationship to the pesticide was considered improbable. In the second incident, a man was exposed to a multiple active ingredient formulation containing 10% MBT through a leaking line. He developed a rash on his arm, shortness of breath and a cough, but fully recovered within 24 hours. Clearly the patient reported here had a much more severe course after inhalational exposure to MBT, exhibiting a biphasic pattern with methemoglobinemia and hemolytic anemia immediately after hospital admission and life-threatening multi-organ failure involving liver, kidneys and lungs in the following days. Although we cannot formally prove a causal relationship on the basis of the present case description, inhalational MBT uptake most likely accounts for the described complications. Glucose-6-phosphate-dehydrogenase deficiency, known to exaggerate methylene blue toxicity and cause acute hemolysis, was excluded later during the hospital stay. The molecular basis of MBT toxicity remains unclear, although it is most probably not related to the production of cyanide, but rather to methemoglobinemia.
This case is, to our best knowledge, the first report of a multi-organ failure secondary to inhalation of methylene-bis-thiocyanate and one of the first reports of the successful use of MARS albumin dialysis in hepatic failure due to intoxication [11–13]. This case underlines the diagnostic and therapeutic dilemma of emergency physicians faced with unusual intoxications. A direct effect of MARS on MBT metabolism or on toxin elimination is very unlikely, as our patient has been treated with MARS only after more than 14 days of extracorporeal renal replacement therapy. MARS albumin dialysis therefore appears to be an effective treatment to allow recovery of liver function after severe intoxication or, in the case of more fulminant liver disease, bridge patients awaiting urgent liver transplantation.
Written consent could not be obtained from the patient or any relative. At the end of treatment, the patient was transferred from our hospital to a reeducation center. He was then lost to follow-up. All efforts were made to trace the patient, without success.
- Mitzner SR, Stange J, Klammt S, Risler T, Erley CM, Bader BD, Berger ED, Lauchart W, Peszynski P, Freytag J, Hickstein H, Loock J, Löhr JM, Liebe S, Emmrich J, Korten G, Schmidt R: Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial. Liver Transpl. 2000, 6: 277-286. 10.1053/lv.2000.6355.View ArticlePubMedGoogle Scholar
- Steiner C, Mitzner S: Experiences with MARS liver support therapy in liver failure: analysis of 176 patients of the International MARS Registry. Liver. 2002, 22 (Suppl 2): 20-25.PubMedGoogle Scholar
- Heemann U, Treichel U, Loock J, Philipp T, Gerken G, Malago M, Klammt S, Loehr M, Liebe S, Mitzner S, Schmidt R, Stange J: Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study. Hepatology. 2002, 36: 949-958.View ArticlePubMedGoogle Scholar
- Jeevaratnam K: Systemic toxicity of methyl isocyanate in mammals. Indian Journal of Pharmacology. 1993, 25: 5-13.Google Scholar
- Mehta PS, Mehta AS, Mehta SJ, Makhijani AB: Bhopal tragedy's health effects. A review of methyl isocyanate toxicity. JAMA. 1990, 264: 2781-2787. 10.1001/jama.264.21.2781.View ArticlePubMedGoogle Scholar
- National Institute for Occupational Safety and Health (NIOSH). International Chemical Safety Cards. [http://www.cdc.gov/niosh/ipcsneng/neng1287.html]
- United States Environmental Protection Agency. Reregistration eligibility decision (RED) methylene bis(thiocyanate). [http://www.epa.gov/oppsrrd1/REDs/2415red.pdf]
- Output Reporting USEPA/OPP Chemical Information: Methylene bis(thiocyanate) active products. [http://www.cdpr.ca.gov/cgi-bin/epa]
- TOXNET National Library of Medicine Specialized Information Services: Methylene bis(thiocyanate). [http://www.toxnet.nlm.nih.gov]
- Burka LT: NTP technical report on the toxicity studies of Methylene Bis (thiocyanate) (CAS No. 6317-18-6) administered by gavage to F344/N rats and B6C3F1 mice. Toxic Rep Ser. 1993, 32: 1-E7.PubMedGoogle Scholar
- McIntyre CW, Fluck RJ, Freeman JG, Lambie SH: Use of albumin dialysis in the treatment of hepatic and renal dysfunction due to paracetamol intoxication. Nephrol Dial Transplant. 2002, 17: 316-317. 10.1093/ndt/17.2.316.View ArticlePubMedGoogle Scholar
- Prokurat S, Grenda R, Lipowski D, Kalicinski P, Migdal M: MARS procedure as a bridge to combined liver-kidney transplantation in severe chromium-copper acute intoxication: a paediatric case report. Liver. 2002, 22 (Suppl 2): 76-77.View ArticlePubMedGoogle Scholar
- Shi Y, He J, Chen S, Zhang L, Yang X, Wang Z, Wang M: MARS: optimistic therapy method in fulminant hepatic failure secondary to cytotoxic mushroom poisoning – a case report. Liver. 2002, 22 (Suppl 2): 78-80.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-227X/6/5/prepub
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