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Iodotrifluoromethane and Iodoheptafluoropropane Assessment of Cardiac Sensitisation Potential in Dogs
Abstract
This study was designed to assess the cardiac sensitisation potential of CF3I and C3F7I in beagle dogs. Adrenaline was administered by intravenous injection before and during inhalation of test substances. The effect of the adrenaline of the ECG pattern was examined. Positive evidence of cardiac sensitisation would be observed as the presence of multifocal ventricular ectopic activity or ventricular fibrillation following adrenaline administration during inhalation of the test substance. CF3I was administered to dogs at concentration in air of 0.1, 0.2, 0.4, and l%v/v. At 0.1 and 0.2% there was no positive result. At each of 0.4 and 1.0% the first dog exposed responded positively with fatal ventricular fibrillation and consequently no other dogs were exposed at these levels. C3F%I was administered to 3 dogs at concentrations in air of 0.1, 0.2, and 0.4%v/v. At each of 0.1 and 0.4% one dog responded positively with multifocal ventricular ectopic bets. The dog responding positively at 1.0% was not subsequently exposed to any higher concentrations. At 0.2% there was no positive result. It is concluded that CF3I has cardiac sensitisation potential at concentrations of 0.4%v/v in air and that C3F71 has cardiac sensitisation potential at concentrations of 0. 1%v/v in air.
Trifluoroiodomethane (CF3I) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea) are fluorocarbon replacement candidates for ozone depletion substances and were tested for genotoxicity using an exposure chamber modification of the Salmonella typhimurium histidine +/reversion mutagenesis assay, a modification of the L5178Y/tk mouse lymphoma cell mutagenesis assay, and a mouse micronucleus test in which exposures were by nose-only inhalation. When tested without and with metabolic activation over a concentration range of 0.1-8.6% (v/v), CF3I was mutagenic in S. typhimurium. In the mouse micronucleus test, CF3I induced dose-related toxicity and was genotoxic as evidenced by dose-related increases in micronuclei in mice exposed to 5 or 7.5% CF3I. But in the mouse lymphoma assay without and with activation, CF3I was negative for mutant induction up to a conReceived centration of approximately 50%. When tested without and with metabolic activation over a concentration range of 43.9-93.5%, HFC-227ea was toxic at the highest concentrations tested but not mutagenic in S. typhimurium. Neither toxicity nor mutagenicity was observed in the mouse lymphoma assay when HFC-227ea was tested to a concentration of 56.8%. Neither toxicity nor an increase in micronuclei was observed in mice exposed to 10.5% HFC-227ea. Thus, toxicity was observed only in the Salmonella assay, and there was no evidence that HFC-227ea was capable of inducing gene or chromosomal mutations in vitro or chromosomal effects in vivo. Though CF3I was negative also for gene and chromosomal mutations in the mouse lymphoma assay, it was positive for gene mutations in the Salmonella assay and positive for chromosomal effects in the mouse micronucleus test. More information is needed to clarify these findings and to extrapolate the potential for CF3I to produce genotoxicity in additional mammalian systems.
Human exposure to halons and halon replacement chemicals is often regulated on the basis of cardiac sensitization potential. The dose-response data obtained from animal testing are used to determine the no observable adverse effect level (NOAEL) and lowest observable adverse effect level (LOAEL) values. This approach alone does not provide the information necessary to evaluate the cardiac sensitization potential for the chemical of interest under a variety of exposure concentrations and durations. In order to provide a tool for decision-makers and regulators tasked with setting exposure guidelines for halon replacement chemicals, a quantitative approach was established which allowed exposures to be assessed in terms of the chemical concentrations in blood during the exposure. A physiologically-based pharmacokinetic (PBPK) model was used to simulate blood concentrations of Halon 1301 (bromotrifluoromethane, CF3Br), HFC-125 (pentafluoroethane, CHF2CF3), HFC-227ea (heptafluoropropane, CF3CHFCF3), HCFC-123 (dichlorotrifluoroethane, CHCl2CF3), and CF3I (trifluoroiodomethane) during inhalation exposures. This work demonstrates a quantitative approach for use in linking chemical inhalation exposures to the levels of chemical in blood achieved during the exposure.
1 The relative potency of effect of a wide range of halogenated and unsubstituted hydrocarbons on the central nervous system (CNS) and the heart of experimental animals have been determined.
2 The chemicals used caused either stimulation or depression of the rat CNS after 10 minutes' inhalation of concentrations ranging from 0.24% to > 80% (v/v), and cardiac sensitization in dogs after 5 minutes' inhalation of 0.12% to approximately 80% (v/v).
3 The toxicity could not be correlated with chemical structure, molecular weight, the presence or absence of various halogen atoms or the degree of saturation, but it was inversely related to the saturated vapour pressure. When the results were expressed on a thermodynamic scale the chemicals had similar potencies at relative saturations of 0.004 to 0.04
4 It is suggested that the effects of these chemicals on the CNS and the heart are probably structurally non-specific, and the chemicals may be regarded as physical toxicants whose effects are predictable from their physico-chemical properties.
Exposure of conscious rats, mice, guinea pigs, dogs and a monkey to atmospheres of bromochlorodifluoromethane (BCF or Halon 1211) resulted in sings of central nervous system stimulation after a few minutes' exposure to concentrations ranging from 5 to 30%. A fall in systolic blood pressure, a decrease in cardiac contractile force and pulsus alternans occurred during the exposure of urethane anesthetized rats. Rats exposed to 3300 ppm BCF 6 hr/day, 5 days/wk for 3 wk did not show any adverse signs. Cardiac arrhythmias ranging from ventricular ectopic beats to ventricular fibrillation resulted when dogs and rabbits were given an iv injection of 5 μg/kg of epinephrine during exposure to 1% and 4% BCF, respectively, for 5 min. In the dog, this cardiac sensitization was associated with venous blood concentrations of 21–24 μg/ml BCF, irrespective of the length of exposure. The susceptibility of the heart to epinephrine-induced arrhythmias was only temporary and was lost within a few minutes of cessation of exposure. Dogs repeatedly exposed to BCF over 4 wk did not become more susceptible to cardiac sensitization.
The compounds selected for this study are commonly used in industrial operations and in many households, e.g. paint products, spot removers, repellant sprays for fabrics, etc. They include dichloromethane (methylene chloride), 1,1,1 trichloroethane (methyl chloroform), tetrachloroethylene (perchloroethylene), trichloroethylene, and trichlorotrifluoroethane. The experimental procedures were performed on unanesthetized, healthy male beagle dogs which were trained to breathe through a one way face mask and to accept venipuncture. The results confirm earlier reports that 1,1,1 trichloroethane and trichloroethylene are capable of sensitizing the mammalian (dog) heart to epinephrine. Trichlorotrifluoroethane was also found to produce this effect. Furthermore, the present results indicate that these 3 agents possess essentially the same cardiac sensitization potential. Dichloromethane and tetrachloroethylene did not produce sensitization in this study. It is concluded on the basis of this and other studies, that some of the common industrial solvents, which are also used as household products, are capable of sensitizing the heart to epinephrine induced arrhythmias at moderately elevated concentrations, and that this property should be taken into account when assessing potential toxic hazards associated with their use.
The cardiac sensitizing potencies of a range of 14 halogenated hydrocarbons were assessed in conscious dogs by comparing the partial pressures (Pcs) needed to sensitize the heart to adrenaline. These were found to be directly related to their saturated vapour pressures (Ps) and the ratio Pcs/Ps was approximately constant although the values of partial pressures differed nearly 700-fold. It is suggested that cardiac sensitization is probably a structurally non-specific action and may be regarded as another example of physical toxicity.
Poster Presentation at Society of Toxicology
- C J Hardy
- P C Kieran
- I J Sharman
HARDY, C.J., KIERAN, P.C. and SHARMAN, I.J. (1994). Poster Presentation at Society of
Toxicology 1994 Annual Meeting, Dallas, Texas.