J Occup Health 2007; 49: 305Ð310

Case Study 4th day after the cessation of 4 days’ exposure to DMT. Clinical Features and Laboratory Findings A Case of Acute Organotin The patient showed blood pressure of 110/70 mmHg,

Cheol In YOO1, Yangho KIM1, Kyoung Sook JEONG1, pulse rate of 85 per min, respiratory rate of 19 per min, Chang Sun SIM1, Nari CHOY1, Jongchul KIM2, Jun Bum EUM3, and body temperature of 36.3°C with drowsy Yoshiaki NAKAJIMA4, Yoko ENDO4 and Yu Jung KIM1 consciousness in the emergency room. The pupils were symmetric with a pupil size of approximately 3 mm. The 1Department of Occupational and Environmental Medicine, light reflex, corneal reflex, and muscle power were within 2Department of Neurology, 3Department of Internal Medicine, the normal range. The past medical history and family Ulsan University Hospital, University of Ulsan College of history were non-contributable. Posterior anterior chest Medicine, South Korea and 4Research Center for Occupational X-rays showed normal findings. All the clinical Poisoning, Tokyo Rosai Hospital, Japan procedures were performed with the patient’s/patient’s family’s informed consent. The serum level of aspartate Key words: Dimethyl , Trimethyl tin, Neurotoxicity, aminotransferase (AST) and alanine aminotransferase Leukoencephalopathy (ALT) were 81 and 46 IU/l, respectively. The result of spinal tapping was negative on the 4th day of admission. Alkyl compounds of tin chlorides are widely used for On the fourth day of hospital admission, the patient the production of plastics in the chemical industry. They deteriorated into a state of coma, and he was placed on inhibit the dissociation of hydrochloric acid from mechanical ventilation. He also showed metabolic polyvinyl chloride (PVC) and in combination with PVC acidosis in arterial blood gas analysis (ABGA) (pH 7.178, they are not toxic. However, as free molecules, organic pO2 71.5 mmHg, pCO2 25.1 mmHg, HCO3 9.1 mmol/l, tin compounds are highly toxic in contrast to inorganic + SaO2 93.2%) along with severe hypokalemia (K 1.6 tin compounds1). The toxic components are dimethyltin mmol/l), and difficulty in respiration. Electrocardiogram chloride and trimethyltin chloride. Previous studies have showed ST depression and T-wave flattening due to reported that dimethyltin chloride is toxic to the liver hypokalemia. The patient showed signs of acute renal and kidneys, whereas trimethyltin chloride damages the failure (from BUN 58.3 mg/dl and Cr 1.32 mg/dl, to BUN central nervous system2Ð4). The neurotoxicity of dialkyltin 67.6 mg/dl and Cr 2.35 mg/dl) the next day. or trialkyltin compounds has been recognized in animal On day 7, the patient’s blood test showed WBC count studies, but only a few descriptions of their human of 9,360 per mm3, hemoglobin of 11.2 g/dl, platelet count have been reported1, 5Ð14). Especially, reports of human of 185,000 per mm3, AST of 351 IU/l, ALT of 119 IU/l, dimethyltin intoxication are very rare15). We report here BUN of 78.3 mg/dl, Cr of 3.07 mg/dl, LDH of 1,030 IU/ a case with neurological manifestations similar to l, CPK of 9,686 IU/l, CK-MB of 38.29 IU/l, compatible trialkyltin encephalopathy from the exposure to with acute renal failure and rhabdomyolysis. From dimethyltin compounds. hospital day 7, British-anti-Lewisite (BAL) was injected intramuscularly at a dose of 2.5 mg/kg four times daily Case Presentation for two days, and twice a day for the two next days, and A 43-yr-old male with disorientation and behavioral then once a day for four consecutive days. On day 9, change was admitted to our hospital. He had been liver function improved, and hypokalemia was corrected working as a tank cleaner for several different companies (K+ 4.2 mmol/l) with the conservative treatment, however, in the previous 8 yr, and a week before admission he had metabolic acidosis persisted. cleaned a tank which had contained dimethyltin (DMT) The fluid-attenuated inversion recovery (FLAIR) brain for 4 d. A day after finishing the job, he suffered from MR imaging taken on day 12, showed extensive, dizziness, disorientation, hallucination, irritability and symmetric high signal lesions of white matter in the decreased memory. The behavioral changes did not subcortical and deep white matter of bilateral cerebral improve and mental deterioration progressed. Brain hemispheres, posterior rim of the internal capsule, corpus magnetic resonance image (MRI) taken at another clinic callosum, cerebral peduncle, corticospinal track, and did not explain his condition, and he was transferred to middle cerebellar peduncle (Fig. 1AÐD). Therapeutically, the emergency room of Ulsan University Hospital on the dexamethasone was administered in attempt to treat the cerebral edema. Metabolic acidosis was corrected on Received Feb 22, 2007; Accepted Apr 12, 2007 day 14. An electroencephalogram test suggested a Correspondence to: Y. Kim, Department of Occupational and moderate diffuse cerebral dysfunction. From day 20, the Environmental Medicine, Ulsan University Hospital, University patient’s consciousness gradually improved and he of Ulsan College of Medicine, #290-3 Cheonha-Dong, Dong-Gu, responded to verbal commands. However, he continued Ulsan 682-060, South Korea (e-mail:[email protected].) to show disorientation, retrograde amnesia, and severe 306 J Occup Health, Vol. 49, 2007

Fig. 1. Axial fluid-attenuated inversion recovery brain MRI at the hospital on day 12 of hospitalization showed extensive, symmetric high signal lesions in the subcortical and deep white matter of bilateral cerebral hemispheres (A), posterior rim of the internal capsule and corpus callosum (B), cerebral peduncle (C), middle cerebellar peduncle (D). MRI on day 90 (E through H) showed no parenchymal lesion.

Table 1. Clinical course and laboratory findings

HD Laboratory findings

+ Clinical course Treatment K BUN Cr AST ALT LDH CPK HCO3

(mmol/l) (mg/dl) (mg/dl) (IU/l) (IU/l) (IU/l) (IU/l) (mmol/l)

1 Drowsy Conservative Tx 3.5 21.5 1.14 81 46 355 298 4 Comatous, intubation Conservative Tx 1.6 58.3 1.32 61 36 418 110 9.5 7 Ventilator care Chelation started 4.1 78.3 3.07 351 119 1,030 9,686 10.0 9 Fever, ventilator care Chelation 4.2 44.5 2.19 218 94 1,170 4,576 8.9 12 Ventilator care Chelation 3.7 32.0 1.37 117 74 1,162 1,879 13.7 14 Ventilator weaning Chelation stopped 4.8 35.0 1.23 104 69 1,126 1,573 15.4 20 Drowsy Conservative Tx 3.9 28.9 1.07 54 118 626 198 21.4 23 Alert Conservative Tx 3.7 24.7 1.02 32 80 538 118 26.9 163 Discharged 3.9 19.5 0.99 23 23 255 75

HD: hospital days, HD 1 is the 4th day after the cessation of 4 days’ exposure to DMT. Tx: treatment. BUN: blood urea . Cr: serum creatinine. AST: aspartate aminotransferase. ALT: alanine aminotransferase. LDH: lactic dehydrogenase. CPK: creatinine phosphokinase.

motor ataxia. MRI on day 90 (Fig. 1EÐH) showed no moderate motor ataxia, memory loss, disorientation, and parenchymal lesion on FLAIR imaging. Nerve speech difficulty (Table 1). conduction velocity test showed that the sensory potentials of both superficial peroneal nerves and the Occupational History compound muscle action potential (CAMP) of the deep The patient’s had been an office worker at an insurance peroneal nerve were not evoked. The test suggested both company until 8 yr ago. He had then worked as a tank peroneal neuropathy of axonal type. The patient was cleaner for several different companies in the previous 8 discharged on the day 163 from the hospital, still showing yr, and also performed the same cleaning job for 8 d last Cheol In YOO, et al.: Acute Organotin Poisoning 307

Fig. 2. Chromatogram of inorganic tin (In-Sn), monomethyltin (MMT), dimethyltin (DMT), trimethyltin (TMT) in urine, blood and standard samples. Blood and urine samples were obtained on days 6 and 9 of hospitalization, respectively.

year without any problem. One week before admission, the mobile phase (5.0 mM HNO3, 6.0 mM NH4NO3, 1.5 he had cleaned a tank used in the manufacture of mM pyridine dicarbonic acid) at a flow rate of 1 ml/min. dimethyltin dichloride (DMTC) for 4 d. The size of the ICP-MS was used for the determination of tin and 1 mg/ tank was 2.25 m × 2.25 m × 3.4 m. The DMTC was l of germanium solution was used as the internal standard. made from inorganic tin and methyl chloride under 4.5 The ICP-MS detection mass was set to m/z 118 (118Tin+) atmospheric pressure at 170°C. An engineer at the and m/z 72 (72Ge+). Detection limits for In-Sn, MMT, company said that less than 0.3% of trimethyltin chloride DMT and TMT were 0.1, 0.1, 0.05, and 0.5 µg Sn/l, (TMTC) was produced as a by-product in the reaction. respectively. The chromatograms of tin compounds in The patient had worked inside the tank, while three other standard solution, urine and blood of the patient are shown workers assisted him outside the tank. Before the tank in Fig. 2. was opened, it was washed with and water DMT and TMT concentrations in blood and urine several times for several weeks. He had to remove the collected during hospitalization are shown in Table 2. remainder of the inorganic tin accumulated at the bottom TMT concentrations were higher than DMT of the tank with an air drill. He wore personal protective concentrations in all blood samples. The highest DMT clothes and an air supplied mask. concentration in blood was found on the 3rd day of BAL treatment, but TMT was highest at the first sampling on DMT and TMT in Blood and Urine the 3rd day of hospitalization. The highest urinary Speciation analysis of alkyltin in urine and blood were concentrations of DMT and TMT were found on the 3rd performed using a combination of high performance and 5th day of BAL treatment, respectively. During liquid chromatography (HPLC, Model HP-1100, Agilent, chelation therapy, urinary DMT and TMT concentrations USA) and inductively coupled plasma-mass spectrometry were elevated. A trace amount of urinary DMT was (ICP-MS, Model HP4500, Agilent, USA). detected on the 27th day after discharge, but TMT was Urine was diluted 5 times with ultra-pure water, tap not detected in the urine. water purified through Milli-Q-ICP-MS (Millipore Japan, Tokyo, Japan). Blood was diluted 10 times with ultra- Discussion pure water and filtrated through Microcon (YM-10, We diagnozed the present case as alkyltin intoxication Millipore, MA, USA). Fifty microliters of the sample for the following reasons. First, the clinical features in were injected into the HPLC. Inorganic tin (In-Sn), MMT, the present case are compatible with those of trialkyltin DMT, and TMT were separated by HPLC using a cation- encephalopathy6, 10, 16, 17). Second, the worker was exposed exchange column (RSpak NN-614, Shodex, Japan), and to alkyltin for 4 d, and high DMT and TMT concentrations 308 J Occup Health, Vol. 49, 2007

Table 2. Analysis of organotin species in urine and blood

HD MMT-U DMT-U TMT-U DMT-B* TMT-B** (µg/ g Cr) (µg/ g Cr) (µg/ g Cr) (µg/l)(µg/l)

3ÐÐÐ39.6 327.5

6ND262.2 598.4 43.1 266.9 8ÐÐÐ45.7 208.3 9ND779.4 336.5 47.6 168.6 10 Ð Ð Ð 40.9 144.4 11 ND 656.2 946.3 47.4 134.8 14 ND 514.0 578.9 Ð Ð 17 ND 611.1 607.0 Ð Ð 19 ND 515.2 597.8 Ð Ð 24 ND 293.0 459.1 Ð Ð 31 ND 94.3 97.8 5.3 30.5 38 ND 39.0 74.6 5.4 10.9 27th day after discharge Ð 0.2(µg/l)Ð Ð Ð

HD: hospital days, HD 1 is the 4th day after the cessation of 4 days’ exposure to DMT. MMT-U: urinary monomethyltin. DMT-U: urinary dimethyltin. TMT-U: urinary trimethyltin. DMT-B: blood dimethyltin. TMT-B: blood trimethyltin. ND: non detectable. *: The concentration is corrected by the mean recovery rate of 48.8% using 5 blood samples spiked with DMT at 50 µg/l. **: The concentration is corrected by the mean recovery rate of 75.0% using 5 blood samples spiked with TMT at 50 µg/l. †On 27th day after discharge, MMT-U and TMT-U were not checked. DMT-U concentration is not adjusted with creatinine (reference value was under detection limit).

in urine and blood were detected. Third, other cerebral the white matter caused by trialkyl tin has been reported diseases such as brain tumor, cerebrovascular disease, in human and animal studies. An experiment on rats and and encephalitis were ruled out by clinical features, brain dogs showed that triethyl tins produced edema confined MRI and spinal tapping. Fourth, the extensive, symmetric to the white matter, but no vascular damage was found20). high signal lesions throughout the white matter of the More than 100 deaths and over 200 cases of illness brain in MRI support the diagnosis of alkyltin occurred in France in 1954 due to the ingestion of a encephalopathy. preparation containing diethyltin diiodide and triethyltin The first symptoms occurred on the day following 4 monoiodide. A pronounced edema of the white matter days’ exposure in the present case. The latent period in of the brain was seen in the fatal cases16). Triethyltin- the present case is compatible with that (1Ð3 d) reported treated rats showed edema of the white matter in the in another study1). central nervous system without neuronal damage8). Our The present case had neurologic sequelae such as motor case is the first to show leukoencephalopathy induced by ataxia, memory loss, disorientation, and speech difficulty alkyltin using MRI. even after the urinary alkyltin level returned to the normal In the present case, BAL treatment was performed and range. Previous studies have also reported various the patient recovered from coma. Rey et al.1) reported neurologic sequelae9, 10, 17). that the excretion rate of total tin in the urine correlated Our case showed severe hypokalemia. This finding with the severity of the intoxication by DMTC and TMTC was previously reported several times1, 10, 18, 19). Tang et and a patient with more than 1 mg/l of tin excretion al.13) induced hypokalemia in Sprague-Dawley rats by showed severe neurological defect. The highest urinary exposure to TMT. They suggested TMT could induce level of total tin in the present patient was 860 µg/g Cr acute renal leakage of potassium. and this level was consistent with his severe condition, In the present study, the first MRI taken before coma. It was reported that plasma separation or D- admission showed normal findings, and the second penicillamine therapy had no effect on urinary excretion FLAIR MR imaging taken on day 12 of hospitalization, or clinical condition, but BAL treatment was effective, showed the extensive, symmetric high signal lesions as in the present case. throughout the white matter of the brain (Fig. 1). MRI TMT is a by-product of DMTC manufacture7). A on day 90 of hospitalization showed no parenchymal previous report showed that 8% of TMT was produced lesion on FLAIR imaging (Fig. 1). Edema confined to as a by-product of DMTC10). Although many cases of Cheol In YOO, et al.: Acute Organotin Poisoning 309 alkyltin-induced encephalopathy have been caused by Reference exposures to mixtures of DMT and TMT1, 6, 9, 10, 16), those reports suggested that TMT was responsible for the 1) Rey C, Reinecke HJ and Besser R: Methyltin encephalopathy, because previous studies have shown that intoxication in six men: toxicologic and clinical aspect. trimethyltins are more neurotoxic than dimethyltin Vet Hum Toxicol 26, 121Ð122 (1984) 2) Alajouanine T, Derobert L and Thieffry S: compounds21Ð23), and because organotin compounds are Comprehensive clinical study of 210 cases of poisoning said to undergo biotransformation by dealkylation in in by organic salts of tin. Rev Neurol (Paris) 98, 85Ð96 24, 25) vitro and in vivo experimental studies . However, (1958) species analysis of organotin was not performed in those 3) Brown AW, Aldridge WN, Street BW and Verschoyle studies, so they could not identify the type of organotin. RD: The behavioral and neuropathologic sequelae of More than 1,000 people were poisoned by misusing intoxication by trimethyltin compounds in the rat. Am organotin contaminated industrial lard as cooking oil in J Pathol 97, 59Ð82 (1979) southeast China in 199915, 18). The contaminated lards 4) Stoner HB, Barnes JM and Duff JI: Studies on the mostly contained DMT compounds, but the contents of toxicity of alkyltin compounds. Br J Pharmacol 10, 16 trimethyltins in urine and blood were much higher than (1955) that in the lards, thus, Jiang et al.15) suggested that DMT 5) Grunner JE: Damage to the central nervous system after ingestion of an ethyl tin compound (Stalinon). Rev was absorbed and could be methylated to TMT in vivo. 14) Neurol (Paris) 98, 109Ð116 (1958) Jenkins et al. also pointed out the need to investigate 6) Fortemps E, Amand G, Bomboir A, Lauwerts R and DMT neurotoxicity in humans. In the present study, a Laterre EC: Trimethyltin poisoning report of two cases. worker who was exposed to DMT compounds showed Int Arch Occup Environ Health 41, 1Ð6 (1978) neurologic manifestations similar to those of trialkyltin 7) Brown AW, Verschoyle RD, Street BW and Aldridge encephalopathy along with high levels of both DMT and WN: The neurotoxicity of trimethyltin chloride in TMT in the urine and blood. Whether TMT compounds hamsters, gerbils and marmosets. J Appl Toxicol 4, 12Ð detected in the urine and blood are due to exposure to 21 (1984) TMT as a by-product of DMT production or from 8) Squibb RE, Carmichael NG and Tilson HA: Behavioral methylation of DMT in vivo remains to be solved. and neuromorphological effects of triethyl tin bromide The patient wore personal protective clothes and an in adult rats. Toxicol Appl Pharmacol 55, 188Ð197 (1980) air-supplied mask. However, the severe clinical features 9) Ross WD, Emmett EA and Steiner J: Neurotoxic effect suggest that he might have been exposed to rather high of occupational exposure to organotins. Am J concentrations of alkyltins. We assume that the personal Psychiatry 138, 1092Ð1094 (1981) protective devices were inappropriate, and significant 10) Besser R, Kramer G, Thumler R, Bohl J, Gutmann L exposure might have occurred via inhalation and skin and Hopf HC: Acute trimethyltin limbic-cerebellar absorption. The present case shows the importance of syndrome. Neurology 37, 940Ð950 (1987) workplace risk assessment of organotin compounds and 11) Kreyberg S, Torvik A and Bjorneboe A: Trimethyltin strict observance of preventive measures against acute poisoning: report of a case with postmortem poisoning, especially, when working in a confined space. examination. Clin Neuropathol 11, 256Ð259 (1992) The present study has the following limitations. We 12) Perretta G, Righi FR and Gozzo S: Neuropathological were not able to simulate the cleaning process that had and behavioral of trimethyltin exposure. Ann Ist Super Sanita 29, 167Ð174 (1993) taken place inside the tank, so we could not determine 13) Tang XJ, Lai GC, Huang JX, Li LY, Deng YY, Yue F how much DMT or TMT was produced in the working and Zhang Q: Studies on hypokalemia induced by environment, and what the exact exposure route was trimethyltin chloride. Biomed Environ Sci 15, 16Ð24 during the cleaning job. (2002) In conclusion, the patient appeared to have been 14) Jenkins SM, Ehman K and Barone S Jr: Structure- intoxicated from acute exposure to a high level of activity comparison of organotin species: dibutyltin is organotin while cleaning a tank. a developmental neurotoxicant in vitro and in vivo. Brain Res Dev Brain Res 151, 1Ð12 (2004) Acknowledgment: The present case was published in 15) Jiang GB, Zhou QF and He B: Tin compounds and the Korean language in Korean J Occup Environ Med major trace elements in organotin poisoned (2006;18:255-262), and is secondarily published in patient’s urine and blood measured by gas chromatography flame photometric detector and English in J Occup Health with additional findings. inductively coupled plasma mass spectrometry. Bull This work was partly supported by “Research and Environ Contam Toxicol 65, 277Ð284 (2000) development project on the 12 fields of occupational 16) Barnes JM and Stoner HB: The toxicology of tin injuries and illness of the Japan Labour, Health, and compounds. Pharmacol Rev 11, 211Ð231 (1959) Welfare Organization”. 17) Feldman RC, White RF and Eriator II: Trimethyltin encephalopathy. Arch Neurol 50, 1320Ð1324 (1993) 310 J Occup Health, Vol. 49, 2007

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