Leslie P. McCarty

Kinetics and Metabolism of Inhaled Methyl Chloroform (1,1,1-Trichloroethane) in Male Volunteers

The kinetics of inhaled methyl chloroform (MC) and its principal metabolites, trichloroethanol (TCE) and trichloroacetic acid (TCA), were defined in six healthy male volunteers following single 6-hr exposures of 350 and 35 ppm. Blood and expired air MC concentrations were proportional to the exposure concentration and indicated that about 25% of the MC inhaled during the 6-hr exposure was absorbed. Elimination of MC was triexponential with half-lives estimated as 44 min, 5.7 hr, and 53 hr for the initial, intermediate, and terminal phases. Over 91% of the absorbed MC was excreted unchanged via the lungs, 5-6% was metabolized and excreted as TCE and TCA, and less than 1% remained in the body after 9 days. Urinary TCE and TCA excretion was extremely variable and indicated that urinary TCE and TCA measurements provide at best only a rough estimate of the exposure. These data suggest that the kinetics of MC in man are essentially first order at or below the current TLV of 350 ppm. Based on a comparison of the blood MC levels and amounts of MC metabolized, the rat is a better model than the mouse to predict the toxicity of MC in man.

The Effects of Deuteration on the Metabolism of Halogenated Anesthetics in the Rat

The authors studied the effects of substituting deuterium for hydrogen in several volatile anesthetics on their metabolism in the Fischer rat. Substitution of deuterium in the ethyl portion of methoxyflurane increased the metabolic production of fluoride ion by 19 per cent when administered at a concentration of 0.05 per cent. Total replacement of hydrogen by deuterium resulted in a 29 per cent decrease in the amount of fluoride produced, while deuteration of only the methoxyl group produced a 33 per cent decrease in fluoride produced. Deuteration of halothane resulted in a 15 or 26 per cent decrease in serum bromide at 0.75 per cent or 1.0 per cent, respectively. Deuteration in the ethyl portions of enflurane and two experimental agents, CF2HOCF2CFBrH and CF2HOCF2CCl2H resulted in 65, 76, and 29 per cent decreases in urinary fluoride, respectively. Anesthesia with deuterated chloroform at a concentration of 0.36 per cent produced a 35 per cent decrease in serum glutamic pyruvic transaminase (SGPT). It is concluded that deuteration of volatile anesthetics changes their metabolism, in most cases producing decreases in metabolism. This effect may lessen the organ toxicity believed to occur with some of these anesthetics.

Pharmacokinetics of Inhaled Methyl Chloride (CH3Cl) in Male Volunteers

Six volunteers, 25-41 years of age, were exposed for 6 hr on separate days to 50 and 10 ppm of CH3Cl. Blood and expired air CH3Cl concentrations reached an apparent plateau during the first hour of the exposure and were proportional to the exposure concentration. Consistent with previous reports, the volunteers could be separated into two discrete groups based on the differences observed in their blood and expired air CH3Cl concentrations. Both groups eliminated CH3Cl rapidly once the exposure was terminated, but CH3Cl was eliminated more rapidly by those volunteers with the lower blood and expired air CH3Cl concentrations. The existence of these two groups can be explained by a twofold difference in the rate at which they metabolized CH3Cl; however, this difference is of questionable toxicological significance. Urinary excretion of the putative metabolite S-methyl cysteine was not related to the exposure; thus, it is not a valid means of monitoring occupational exposure to CH3Cl.

INCORPORATION OF [14CICHOLINE INTO PHOSPHOLIPIDS IN THE ISOLATED PHRENIC NERVE-DIAPHRAGM PREPARATION OF THE RAT1

Abstract— The metabolism of [14C]choline has been studied in the isolated perfused phrenic nerve‐diaphragm of the rat. We obtained no evidence that acetylcholine was synthesized from labelled choline in this system. There was extensive incorporation of the choline into phosphatidylcholine and its precursors, cytidinediphosphocholine (CDP‐choline) and phosphocholine. Autoradiographic studies indicated that the lipids of myelin sheaths and nerve endings were the primary sites labelled.

Acute Toxicity in Rats of Chlorinated Hydrocarbons Given via the Intratracheal Route

1 The approximate lethal dose (ALD) of six chlorinated hydrocarbons via the intratracheal route has been determined in rats and compared with published oral LD50 values. 2 The compounds tested in this study were dichloromethane, perchloroethylene, trichloroethylene, carbon tetrachloride, chloroform and ethylene dichloride. 3 A method of administering the materials intratracheally to unanaesthetized animals was developed. 4 The intratracheal ALD of the chlorinated hydrocarbons ranged from 3.1 to 17.5% of the oral LD 50 and death was peracute. 5 Aspiration of chlorinated hydrocarbons may present more of a hazard than oral toxicity and should be considered when rendering first aid or emergency medical treatment.