Toxicity of Alternatives to Chlorofluorocarbons HFC-134a and HCFC-123 (1996) / Chapter Skim
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2 EVALUATION OF THE DOG CARDIAC SENSITIZATION TEST
2 EVALUATION OF THE DOG CARDIAC SENSITIZATION TEST
Pages 13-22
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From page 13... ...
. Since the early 19OOs, it was known that inhalation of volatile anesthetics, such as cyclopropane and chloroform, can make the mammalian heart abnormally sensi live to epinephrine, resulting in cardiac arrhythmia and possibly death.
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From page 14... ...
MECHANISM OF ACTION FOR CHEMICAELY INDUCED ARRHYTHMIAS CFCs, their substitutes, and some other hydrocarbons decrease the threshoic3 for epinephrine incluced arrhythmias by reducing the ability of the cardiovascular system to respond to stress. The major cardiac effects of epinephrine, which is produced by the ad renal gland, involve increasing the rate and force of cardiac con traction (Aviado and Belej, 19741.
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From page 15... ...
by some CFCs, but only at concentrations 2 to 4 times those neecled to induce sensitization in the preceding screening studies using injected epinephrine (Mullin et al., 19721. Therefore, administration of exogenous epinephrine following exposure to a test compound tends to overprectict the potential for a chemical to induce cardiac arrhythmia uncler nor mat or physiological levels of enclogenous epinephrine.
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From page 16... ...
The dog continues breathing air for 5 min more and, if no arrhythmias occur, exposure to the test chemical is initiated at 7 min through the flow through face mask. The car diac response is continuously monitored by electrocardiography
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From page 17... ...
Exposure to the test chemical remains un interrupted for an adclitional 5 min. The criterion for a cardiac sensitization response is the appearance of a burst of multifocal ventricular ectopic activity (MVEA)
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From page 18... ...
CARDIAC SENSITIZATION EXPERIMENTS INVOLVING SELECTED HALOCARBONS The protocol described above has evolved from many expert mental studies using a variety of techniques. CFC 113, a common solvent and clegreasing agent, was evaluated in many of these stucI ies.
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From page 19... ...
However, with other CFCs, tests involving endogenous epinephrine production dill induce cardiac sensitization in C3OgS but only at exposure concentrations 2 4 times those neecled to induce sensitization in the experimental screening studies using exogenous epinephrine. In the absence of any stim uti, spontaneous arrhythmias couicI not be induced in dogs even with CFC concentrations up to 100,000 ppm, clearly clemonstrat ing that CFCs alone do not induce the arrhythmias.
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From page 20... ...
Although these human studies in volvec3 a small number of subjects, the absence of cardiac effects supports the premise that the clog cardiac sensitization model is a very sensitive test that can be used to evaluate the risk of cardiac arrhythmias in humans exposed to CFCs. The reason for the use fulness of the test in humans is because it is very sensitive ant!
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From page 21... ...
The subcommittee recommends that the mechanism of cardiac sensitization be cleterminec3 ant! that a more sensitive test be developed that permits adequate safety evaluation of halocar bons that will replace the currently used CFCs.
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From page 22... ...
1972. Halogenated hydrocarbon induced cardiac arrhythmias associ ated with release of endogenous epinephrine.
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