Kenneth C. Back

Short-term inhalation exposure to bromotrifluoromethane

Abstract Exposure of dogs and monkeys to 10–80% bromotrifluoromethane (CBrF 3 ) caused cardiovascular and central nervous system effects which increased in severity with increasing CBrF 3 concentration. An initial fall in mean arterial blood pressure of 10–20 mm Hg at the lower CBrF 3 concentrations and 40–60 mm Hg at the higher CBrF 3 concentrations was observed. Most animals developed spontaneous cardiac arrhythmias within 1–3 min of exposure to 40% or more CBrF 3 . Arrhythmias could be produced in those animals not developing arrhythmias spontaneously by the intravenous injection of a pressor dose of epinephrine. Larger doses of epinephrine (5–10 μg/kg) caused ventricular fibrillation with cardiac arrest in dogs and, commonly, spontaneous defibrillation in monkeys. Epileptiform convulsions were seen in about 50% of the dogs exposed to 50–80% CBrF 3 while conscious. Conscious monkeys, on the other hand, became lethargic, and no convulsions were seen.

Absorption, distribution, and excretion of 1,1-dimethylhydrazine (UDMH)

Abstract The absorption, distribution, and excretion of 1,1-dimethylhydrazine (UDMH) have been studied in rats, rabbits, cats, dogs, and monkeys by use of C 14 -tracer and colorimetric methods. UDMH was rapidly absorbed into the blood regardless of route of administration and was also quite rapidly excreted by the kidneys as evidenced by early high concentrations in both blood and urine. Simultaneous tracer and colorimetric studies indicated that 30–50% of the compound was excreted in its unchanged form in the urine of hydrated cats and dogs in 5 hours. Tracer experiments have shown that UDMH is not preferentially concentrated in the vital organs of the body. Peak concentrations of UDMH in blood are found in 15–60 minutes after injection. The compound was not detectable in the blood of any species after doses of less than 10 mg/kg. Wide variations in individual levels of UDMH in blood with respect to dose and time made it extremely difficult to predict accurately the extent of exposure by examination of blood concentration. The most sensitive indication of exposure to UDMH was the presence of the compound in the urine. Urinary concentrations were found at dose levels which did not produce detectable blood concentrations. The relationships of UDMH blood and urine levels and their correlations with symptomatology have been discussed.

Effects of continuous inhalation of dichloromethane in the mouse: Morphologic and functional observations

Abstract Continuous inhalation of 5000 ppm CH 2 Cl 2 caused balloon degeneration, transient severe fatty change and partial inhibition of leucine incorporation into liver proteins of 20–32 g female mice of the ICR stain. The earliest lesion was identified at 12 hr of exposure and consisted of dissociation of polyribosomes and swelling of hepatocyte rough endoplasmic reticulum (so-called “balloon” degeneration). Balloon degeneration peaked in severity at 2 days of exposure and then partially reversed. Liver fatty change was also partially reversible. There was a 12-fold increase in liver triglycerides with 3 days of exposure, but at 1 wk of continuous exposure liver triglycerides were two to three times control values. Necrosis was observed in a few isolated hepatocytes. The reversibility of the liver changes suggests that partial tolerance develops in hepatocytes with continuous exposure to 5000 ppm dichloromethane. Liver lesions produced in the mouse liver by dichloromethane bear some resemblance to the lesions of carbon tetrachloride hepatotoxicity but appear to be less severe.

Comparative mutagenicity of 4 dna-intercalating agents in l5178y mouse lymphoma cells.

The mutagenicity of 4 known intercalating agents acridine orange (AO), quinacrine mustard (QM), proflavin (PF) and ethidium bromide (EB) has been investigated in L5178Y mouse lymphoma cells. Methyl methanesulfonate (MMS) was used as a positive control in these studies. AO, QM and PF induced mutation in the excess thymidine- and thioguanine-selective systems. These 3 compounds were negative in the ouabain- and cytosine-arabinoside-selective systems while EB was positive only in the cytosine arabinoside system. It would appear that the EB-induced mutagenesis is different from that of AO, QM and PF though all are intercalating agents. Since the molecular origin of cytosine arabinoside mutants is unknown, further interpretation of the EB results is not possible.

Comparative mutagenicity of hydrazine and 3 methylated derivatives in L5178Y mouse lymphoma cells

The mutagenicity of hydrazine, monomethylhydrazine (MMH), 1,1-dimethylhydrazine (UDMH) and 1,2-dimethylhydrazine (SDMH) in L5178Y mouse-lymphoma cells has been investigated. Hydrazine, UDMH and SDMH induced thymidine mutation, in the absence of extraneous metabolic activation. Dose-response curves were produced for these compounds. MMH did not induce thymidine mutation. All 4 compounds were negative in the ouabain, thioguanine and cytosine arabinoside selective systems. Induction of mutation by hydrazine and UDMH is correlated with toxicity. This is not the case for SDMH-induced mutation. Hydrazine, UDMH and SDMH produce different ratios of large and small thymidine-resistant clones. The compounds appear to have different modes of action in the cell.

The mechanism of the peripheral vascular resistance change during exposure of dogs to bromotrifluoromethane.

Abstract Thirtytwo male beagle dogs were used in 16 cross-circulation experiments wherein arterial blood from one dog (donor) was perfused at constant flow rate through a hind limb (HL) of another dog (recipient). The HL innervation remained intact. Exposure of the donor to 67–70% CBrF 3 was accompanied by a reversible decrease in the donors mean arterial blood pressure. The HL perfusion pressure (and therefore vascular resistance in HL) was unaltered. Exposure of the recipient to 67–70% CBrF 3 was accompanied by a reversible decrease in the recipient mean arterial blood pressure and HL perfusion pressure. The HL perfusion pressure change was greatly attenuated by pretreatment of the HL with phenoxybenzamine and abolished by pretreatment of the recipient with hexamethonium. Nictitating membrane tension and vagal inhibition of the heart in response to electrical stimulation of the corresponding cut ends of the vagosympathetic trunks were measured in 5 dogs before, during and after exposure to 80% CBrF 3 . The CBrF 3 exposure was accompanied by a reversible decrease in both nictitating membrane tension and vagal inhibition of the heart. The mechanism of the decrease in mean arterial blood pressure during CBrF 3 exposure was concluded to be a decrease in vasomotor tone resulting from ganglionic blockade. No direct vascular smooth muscle effect of CBrF 3 was observed.

The effect of bromotrifluoromethane on operant behavior in monkeys

Abstract Seven monkeys trained on continuous and discrete avoidance performance tasks were exposed to concentrations of bromotrifluoromethane 2 (CBrF 3 ) ranging from 10.5% to 42.0%. Significant performance decrements were observed in all subjects during exposures of 20–25% CBrF 3 . Higher concentrations resulted in impaired performance to the point of complete disruption of operant behavior in some subjects. No visible signs of central nervous system depression or analgesia accompanied this loss of ability to perform on conditioned performance tasks. These results suggest that the mechanism by which CBrF 3 causes impaired performance differs from the central nervous system depression and analgesia produced by halogenated anesthetics.

Therapeutics of monomethylhydrazine intoxication

Abstract Exposure to monomethylhydrazine (MMH), a missile propellant, can produce convulsions and death probably because of the inhibitory effect of MMH on γ-aminobutyric acid (GABA) synthesis. The current recommented therapeutic agent is pyridoxine but because of the large amounts required and the low solubility of pyridoxine the injection volumes required for effective treatment can result in severe tissue irritation and trauma. This study compares the therapeutic effects of muscimol, diazepam, and pyridoxine, and certain combinations of these compounds, against MMH-induced convulsions and lethality. Mice were injected with convulsive and lethal doses of MMH and with varying doses of the three or combinations of them. The incidence of convulsions and death and the times to effect were recorded. All drugs had a protective effect but combinations containing diazepam and either pyridoxine or muscimol were the most effective antagonists to MMH convulsions and death. The dose-response curves were shifted to the right, and the times to convulsion and to death were significantly prolonged.

The effects of three halogenated alkanes on excitation and contraction in the isolated, perfused rabbit heart.

Abstract Two series of experiments were conducted to determine the effects of CBrF 3 , CBrClF 2 and CCl 2 F 2 on the isolated, perfused rabbit heart. Hearts were perfused through the aorta according to the modified method of Langendorff. Left ventricular mechanical activity was monitored concurrently with action potentials recorded from left ventricular myocardial fibers. In the first series, mechanical performance curves were determined for each of seven hearts using intraventricular balloons to control end diastolic pressure. The relative effectiveness of these compounds as negative inotropic agents was CBrClF 2 > CCl 2 F 2 > CBrF 3 . In the second series of experiments, hearts were exposed to increasing concentrations of each fluorocarbon. Controls were exposed to equivalent concentrations of N 2 . Exposure to increasing concentrations of CBrF 3 decreased peak left ventricular pressure ( P max ), the integral of the pressure curve ( P × T ), and the time to 20% repolarization of the action potential (AP-D 20 ). Exposure to increasing concentrations of CBrClF 2 reduced P max , the maximal rate of rise of the pressure curve ( dP dt max ), and P × T in a dose-related manner, and the AP-D 90 was prolonged. Exposure to increasing levels of CCl 2 F 2 decreased P max and dP dt max .

The determination of the inotropic effect of exposure of dogs to bromotrifluoromethane and bromochlorodifluoromethane

Seventeen beagle dogs representing both sexes and weighing an average of 10 kg each were used in open-chest experiments. The dogs were anesthetized by the continuous iv infusion of a mixture of 10% ethanol and 60 mg/liter morphine sulfate in 5% glucose in water. Left ventricular pressure was monitored through a metal cannula inserted through the left ventricular free wall following a left-side thoractomy. Left ventricular pressure was used to control the horizontal deflection and dPdt was used to control the vertical deflection of a vector oscilloscope. Peak dPdt÷P was calculated from the Lissajous figures generated, and provided an index of the inotropic state of the left ventricular myocardium. The method was validated using isoproterenol and propranolol, known inotropic agents. Since CBrF3 and CBrClF2 cause changes in mean arterial pressure, the effects of variable afterload on peak dPdt÷P were determined by aortic constriction. Both fluoroalkanes were demonstrated to produce concentration-dependent decreases in peak dPdt÷P that reflected decreased mycocardial contractility.