Iodotrifluoromethane Toxicity Review (2004) / Chapter Skim
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4 Cardiac Sensitization
4 Cardiac Sensitization
Pages 28-48
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From page 28... ...
pattern, that is, shortpauses in heartbeat followed by tachycardia. Continued administration of chloroform ultimately resulted m ventricular fibrillation.
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From page 29... ...
The deaths were thought to be due to ventricular fibrillation resulting from cardiac sensitization caused by the combination of inhalation of high concentrations of aerosol propellants and high blood concentrations of endogenous epinephrine produced by excitement. At autopsy, there were no unusual pathologic findings, and no anatomic changes were seen m the heart, brain, or other organs.
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. A conscious male beagle is fitted with a flow-through mask and exposed to various concentrations of the test chemical m air.
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High doses of epinephrine produce ventricular fibrillation, so cardiac-sensidza60n tests must use smaller doses. Reinhardt et al.
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. The studies that they reviewed strongly indicate that arrhythmias that occur after epinephrine challenge result from exposure to the test chemical and are potentially life-threatening.
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Using the Reinhardt protocol with a titrated epinephrine dose, the potential for iodotrifluoromethane (CF31) to induce cardiac sensitization in the dog was evaluated (Kenny et al.
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No blood concentrations of CF31 were measured in any dog. On the basis of these responses in dogs, the NOAEL for the 5-mm exposure (before epinephrine challenge)
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for 30 sec while being frightened with loud noise. bLOAEL determined in screening studies with intravenous exogenous epinephrine.
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Source: Adapted from Mullinet al. 1972 The inhaled concentrations of CFCs required to induce cardiac sensitization m exercising dogs were 2-4 times as high as those needed for animals receiving intravenous exogenous epinephrine.
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1974) attempted to correlate the concentration of the test chemical m air that would induce cardiac sensitization with the arterial and venous blood concentrations of the chemical at the time of sensitization.
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The observed Increase m blood concentrations for these and other halocarbons clearly mdicates a multiplicative relationship between concentration and length of exposure: steady-state blood concentrations occur withm about 5 min of exposure.
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Determining peak blood concentrations requires knowledge of the arterial and venous concentrations of the test chemical. As shown in Figure 4-1, arterial blood concentrations of halocarbons are greater than venous concentrations during exposure, but this reverses when exposure ceases.
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, albeit at halocarbon concentrations greater than those which produce cardiac arrhythmias in the presence of exogenous epinephrine (Reinhardt et al. 1971, Mullin et al.
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It is dangerous to presume that all sudden deaths result from ventricular fibrillation even if fibrillation can be produced in combination with halocarbons in dogs. If the mechanism of death is not fibrillation, studies conducted on dogs exposed to both epinephrine and halocarbons, although perhaps interesting, are not relevant to human deaths.
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From page 43... ...
The lack of mformation makes it important to understand the mechanism of sensitization. For example, if patch-clamp studies show that halocarbons or halocarbons with catecholamines alter conductance over the delayed rectifier currents, animal surrogates that might possess polymorphisms similar to those of humans should be used.
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From page 44... ...
Thus, one explanation of cardiac sensitization may be synergism between halocarbons and sympathetic activity on calcium kinetics; and an avenue to prevent cardiac sensitization for example, with beta adrenergic blockade may be to minimize the synergism at the ryanodine receptors, possibly by preventing hyperphosphorylation or depletion of FKBP12.6. cardiac sensitizers, and it will still be unknown whether halocarbons or particular halocarbon concentrations that are arrhythmogenic in the dog are also arrhythmogenic in humans As discussed previously in this chapter, it is known that CFC- 11 and CFC-113 produce cardiac arrhytb~mas in dogs at5,000ppm and inhurnans at estimated concentrations of over 20,000 ppm without the use of exogenous epinephrine.
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From page 45... ...
Box 4-2 identifies some considerations that should be included m refirlmg cardiac-sensitization testing. No uncertainty factors are necessary for extrapolation from dogs to humans, because the doses of exogenous epinephrine achieve plasma concentrations that are 10 times greater than those achieved durmg physiologic stress, such as exercise or loud noise.
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From page 46... ...
of increasing doses of epinephrine, norepinephrine, and permutations of epinephrine and norepinephrineS to determine the arrhythmogenic threshold of each. There may be a number of thresholds (such as, first premature ventricular depolarization, f rst monomorphic paroxysmal ventricular tachycardia, sustained monomorphic ventricular tachycardia, sustained pleomorphic ventricular tachycardia, and ventricular fibrillation)
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From page 47... ...
and others reported on deaths resulting from deep breathing of aerosol propellants. Other catecholamines may be responsible, either m part or completely, for the development of cardiac arrhythmias in humans after overexposure to halocarbons, but in the dog model, administration of exogenous epinepbrine gives rise to a cardiac response (ventricular premature depolarizations)
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From page 48... ...
The subcommittee found that although it is difficult to ascertain absolutely that cardiacsensitization studies m the dog are appropriate for developing safe exposures for humans, a substantial body of evidence nevertheless indicates that many halocarbons that produce cardiac arrhythmias m the dog also cause them m humans. No uncertainty factors are necessary for extrapolation from dogs to humans, because the doses of exogenous epinephrine achieve plasma concentrations that are 10 times greater than those achieved durmg physiologic stress.
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