CARBOXYHAEMOGLOBIN AND FATAL METHYLENE CHLORIDE POISONING

274 anticonvulsant with no toxic effects on the mother or baby probably cannot be found until the pathology of pre-eclampsia is understood. Effort might be better spent improving doctors’ familiarity with the dosage regimens and side-effects of one drug. Practice in the USA where magnesium sulphate, first used in 1916, has remained the drug of first choice contrasts with that in the UK. Slater and colleagues1 saw no convulsions after initiation of phenytoin therapy but reported only twenty-six patients, of whom seven had a maximum blood pressure of more than 160/110 mm Hg and two others had had convulsions before therapy-too few patients on which to base a change of management policy. We hope that phenytoin will be studied prospectively in a large series before it is widely introduced, and we would welcome collaborators in such a

study. St James’s Hospital, Leeds

D. TUFFNELL P. O’DONOVAN R. J. LILFORD

dependent enzyme activities, may have also occurred. This hypothesis would account for the acidosis and hypercapnia to which respiratory failure due to pulmonary oedema and central-nervoussystem depression may also have contributed. High, but not per se critical, COHb levels appear to be formed after acute exposure to concentrated methylene chloride vapours but the toxicological significance of CO formation in methylene chloride poisoning, however, remains to be clarified. CO concentrations and effects in target tissues, such as brain and heart, may be

more

relevant than COHb levels.

Institute of Occupational Medicine, University of Padua Medical School, 35127 Padua, Italy

M. MANNO

Department of Clinical Chemistry and Forensic Medicine, Treviso Hospital

R. CHIRILLO G. DANIOTTI

"Clinica del Lavoro" Foundation,

V. COCHEO F. ALBRIZIO

Padua

Department of Obstetrics and Gynaecology, University Hospital of Wales, Cardiff CF4 4XN

A. PRYS-DAVIES J. G. THORNTON

1. Slater RM, Wilcox FL, Smith WM, et al. Phenytoin infusion in severe pre-eclampsia. 2.

Lancet 1987; i: 1417-21. on Confidential Enquiries into Maternal Deaths 1982-84. London: HM Stationery Office, 1989: 16.

Report

m

England

and Wales

CARBOXYHAEMOGLOBIN AND FATAL METHYLENE CHLORIDE POISONING

StR,—Since a 1972 report that exposure to methylene chloride results in significant production of carboxyhaemoglobin (COHb), concern has increased as to the importance of endogenous CO formation during acute and chronic methylene chloride exposure or poisoning, especially in patients with ischaemic heart disease. In one fatal case2 three myocardial infarctions were attributed to presumably increased COHb levels following exposure to the solvent. In other published cases of acute methylene chloride poisoning exposure was not well documented and/or COHb levels were not measured.2-8 We now describe two fatal cases of poisoning after inhalation of very high concentrations of methylene chloride in which both solvent exposure and COHb were measured. Two men aged 49 and 55 were found dead, close to each other, in a well at about 2 m below ground level in a building where they had been burying barrels containing mixed waste from a small chemical factory, including solvents, resins, and polymers. Air samples collected a few hours later and analysed by gas chromatography/ mass spectrometry (GC/MS) contained up to 583 mg/1 methylene chloride and much lower or trace amounts of other solvents. Blood collected at necropsy contained 571 and 601 mg/1 methylene chloride and trace to a few mg/1 of other solvents. The two bodies had no signs of trauma or lesions. Both men had marked congestion and oedema of the brain and lungs. Bronchial mucosa and trachea were hyperaemic and covered by a foamy reddish fluid. The heart was flaccid, and one man had early sclerotic changes in the coronary arteries. Other organs showed minor congestive changes. COHb levels were 30% of total haemoglobin (15 and 16 g/dl) accompanied by severe acidosis (CO2 levels of 250 and 300 mm Hg and pH values of62 and 6-18). The high concentrations found in blood and air leave little doubt that the two men died from inhalation of massive concentrations of methylene chloride that had built up in the well, as reported for another fatal case.6 Less clear is the toxic mechanism. Methylene chloride undergoes two alternative metabolic reactions—oxidative dehalogenation to form carbon monoxide and inorganic halide9 and glutathione conjugation and hydrolysis to give formaldehyde, formic acid, and CO2.lO The first pathway is responsible for the high COHb levels. These values were not as high as those reported by others.4 The first pathway is readily saturable (Vm in rats 47 umot/kg per h)" and may have been overwhelmed by the high concentrations (about 7 mmol/1 blood) of methylene chloride resulting in the predominance of the alternative, non-saturable pathway. Significant inhibition of the first pathway by tissue hypoxia and CO itself, both potent inhibitors of cytochrome P450

RD, Fisher TN, Hosko MJ, Peterson JE, Baretta ED, Dodd HC Carboxyhemoglobm elevation after exposure to dichloromethane. Science 1972;

1. Stewart

176: 295-96. 2. Stewart RD, Hake CL. Paint-remover hazard. JAMA 1976; 235: 398-401. 3. Benzon HT, Claybon L, Brunner EA. Elevated carbon monoxide levels from exposure to methylene chloride JAMA 1978; 239: 2341. 4 Fagin J, Bradley J, Williams D. Carbon monoxide poisoning secondary to inhaling methylene chloride Br Med J 1980; 281: 1461. 5 Winek CL, Collom WD, Esposito F. Accidental methylene chloride fatality. Forens Sci Int 1981; 18: 165-68. 6. Moskowitz S, Shapiro H. Fatal exposure to methylene chloride vapor Arch Ind Hyg Occup Med 1952; 6: 116-23. 7. Buie SE, Pratt DS, May JJ. Diffuse pulmonary injury following paint remover exposure Am J Med 1986; 81: 702-04. 8. Miller L, Pateras V, Friederici H, Engel G. Acute tubular necrosis after inhalation exposure to methylene chloride Arch Int Med 1985; 145: 145-46. 9 Kubic VL, Anders MW. Metabolism of dilhalomethanes to carbon monoxide III. studies on the mechanism of the reaction Biochem Pharmacol 1978; 27: 2349-55. 10. Ahmed AE, Anders MW. Metabolism of dihalomethanes to formaldehyde and inorganic halide II: studies on the mechanism of the reaction. Biochem Pharmacol 11.

1978; 27: 2021-25. Gargas ML, Clewell HJ, Andersen

ME. Metabolism of inhaled dihalomethanes in vivo. differentiation of kinetic constants for two independent pathways. Toxicol Appl Pharmacol 1986; 82: 211-23.

POLYCYSTIC KIDNEY DISEASE IN THE FETUS

SIR,-We have reported prenatal diagnosis of autosomal polycystic kidney disease (ADPKD) in a 28-year-old woman by chorionic villus biopsy and genetic linkage analysis with dominant

the 3’HVR marker.! The pregnancy was terminated in the 12th week of gestation. At necropsy, both fetal kidneys showed numerous glomerular and tubular microcysts with diameters up to 300 wm. We have since examined two further fetuses from ADPKD families after genetic linkage analysis from a chorionic villus sample. The pregnancies were terminated during the 14th and 16th week of gestation, respectively. Morphological examination of both fetal kidneys disclosed microcystic dilatations of tubules and, especially, of glomeruli (glomerular cysts) in both cases. Tubular microcysts were lined by an increased number of tubular epithelial cells. Polypoid hyperplasia suggestive of tubular obstruction was not seen, thus excluding the hypothesis that tubular obstruction and increased intratubular pressure are the primary cause for cyst formation. The liver was normal in all three fetuses. Severe early manifestation of ADPKD with massive cystic enlargement of both kidneys has been detected by prenatal ultrasound examination or at birth in a few patients. Linkage analyses showed no evidence for genetic heterogeneity of ADPKD in families with early and adult onset disease.4 The morphology of our three fetuses differs from these early cases since the kidneys appeared normal macroscopically. Microscopic glomerular and tubular cysts were the most striking finding. Microcysts are not seen to such an extent in normal fetal kidneys of comparable gestational age. Whether microscopic cysts can be detected consistently at this developmental stage in ADPKD, or whether they are part of the spectrum of prenatal manifestation observed in only exceptional cases cannot be fully established. However, the fact that all three fetuses presented with similar morphological changes suggests that