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5 Freon 12 This chapter summarizes the relevant epidemiologic and toxicologic studies on Freon 12, or dichlorodifluoromethane. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation-exposure levels from the National Research Council (NRC) and other agencies are also presented. The committee considered all that information in its evaluation of the Navy’s current and proposed 1-h, 24-h, and 90-day exposure guidance levels for Freon 12. The committee’s recommendations for Freon 12 exposure levels are provided at the end of this chapter with a discussion of the adequacy of the data for defining those levels and research needed to fill the remaining data gaps. OCCURRENCE AND USE In industrial settings, Freon 12 has been used as an aerosol propellant, a foam-blowing agent, and a refrigerant (Garcia 2000; WHO 1990). The primary source of Freon 12 in the submarine environment is through the air-conditioning and refrigerant plants (Garcia 2000; Crawl 2003). Several measurements of Freon 12 on submarines have been reported.
Data collected on nine nuclear-powered ballistic missile submarines indicate an average Freon 12 concentration of 11 ppm (range, 0-61 ppm) and data collected on 10 nuclear-powered attack submarines indicate an average Freon 12 concentration of 13 ppm (range, 0-1,033 ppm) (Hagar 2003). Holdren et al. (1995) reported the results of air sam. TABLE 5-1 Physical and Chemical Properties of Freon 12 Synonyms and trade names FC 12, CFC-12, difluorodichloromethane, fluorocarbon-12, R 12 CAS registry number 75-71-8 Molecular formula CCl 2F 2 Molecular weight 120.92 Boiling point −29.8°C at 760 mm Hg Melting point −158°C Flash point NA Explosive limits NA Specific gravity 1.1834 g/mL (57°C) Vapor pressure 5.7 atm (20°C) Solubility Insoluble in water (0.028 g/100 g at 25°C); soluble in alcohol, ether Conversion factors 1 ppm = 4.95 mg/m 3; 1 mg/m 3 = 0.202 ppm Abbreviations: NA, not available or not applicable. Sources: Flash point and explosive limits from HSDB 2005; all other data from ACGIH 2001.
Pling at three locations conducted over 6 h during the missions of two submarines. Sampling indicated concentrations of 2.072-5.476 ppm and of 2.740-3.035 ppm, depending on the collection method, on one submarine, and concentrations of 0.452-3.015 ppm and of 2.092-2.938 ppm, depending on the collection method, on the other submarine. Raymer et al. (1994) reported the results of a similar sampling exercise (two submarines, three locations, and sampling duration of 6 h). Freon 12 concentrations were reported at 4.0 and 1.4 ppm in the fan rooms, 2.0 ppm in the galleys, and 1.8 and 4.0 ppm in the engine rooms. SUMMARY OF TOXICITY The toxicity of Freon 12 has been studied in a number of species exposed acutely and repeatedly.
Most of those studies, however, were conducted in the 1970s and earlier and lack complete documentation. Some studies, although frequently cited in review articles, are unpublished or were published in foreign journals and were available only in published reviews. The information evaluated indicates that Freon 12 has relatively low acute toxicity by inhalation (for example, LC 50s over 500,000 ppm in animals) with weak narcotic and moderate cardiac-sensitizing effects. The EC 50s (the concentrations at which a specified effect is observed in 50% of a test population) for cardiac sensitization, the most serious toxic effect, have been reported to be at least 50,000 ppm in dogs and other animals given intravenous epinephrine and over 100,000 ppm in animals.
With endogenous epinephrine. Respiratory and circulatory system effects, such as bronchoconstriction and changes in heart rate, have also been observed in animals acutely exposed at those concentrations.
In general, the few data in humans are consistent with data in animals in the types of effects and effect levels. Because administered doses of epinephrine that caused cardiac arrhythmia with Freon 12 exposure were considerably higher than would occur endogenously, under normal conditions, neurologic or other effects—such as pulmonary effects—are more likely than cardiac effects at lower Freon 12 concentrations.
Freon 12 concentrations associated with no or minimal effects in animals and a small number of healthy human subjects are about 1,000 ppm. Chlorofluorocarbon mixtures appear to have greater toxicity than individual compounds alone at the same concentration as the mixture, although reports are based on higher concentrations (for example, over 10,000 ppm), and no information is available on lower concentrations. Effects of repeated or longer-term exposures are generally similar to those of acute exposures. Thus, Haber’s law (concentration C × exposure time t = response k) for extrapolating toxicity between short-term and long-term exposures does not appear to apply for Freon 12. That observation is consistent with the pharmacokinetics of Freon 12, which is rapidly absorbed and eliminated almost entirely by inhalation with little metabolism. Equilibrium blood concentrations and appearance in cerebral spinal fluid occur within minutes of exposure, and elimination is complete within 20-50 min after exposure ceases. Freon 12 has not been reported to be genotoxic, and long-term studies in animals exposed orally or via inhalation and available epidemiologic data do not show evidence of carcinogenicity.
No evidence of male reproductive toxicity was found. No studies were available to evaluate immunotoxicity via inhalation. Accidental Exposures No published reports of deaths or other effects of humans resulting from accidental exposures to airborne Freon 12 were located. Freon 12 and other chlorofluorocarbons have been involved in cases of intentional inhalation that resulted in death that was most likely related to effects on the heart (for example, cardiac arrhythmia, possibly aggravated by increased catecholamine from stress or moderate hypercapnia) (NRC 1984; WHO 1990).
Chlorofluorocarbons, including Freon 12, have been evaluated in connection with deaths of people who had asthma and who used inhalers containing chlorofluorocarbons. Chlorofluorocarbon toxicity in those cases has been discounted because of the small amount of chlorofluorocarbon exposure compared with known toxic levels from experimental studies and cases of deliberate abuse (WHO 1990), although Aviado (1994) believes that chlorofluorocarbons may have contributed to the deaths of those who had asthma. (1972) reported a small reduction (7%) in performance on psychomotor tests (clerical tasks, sorting, manual dexterity, and mental arithmetic) in two healthy men after 150 min at 10,000 ppm but no effects at 1,000 ppm.
Subjects were tested in the chamber for 2.5 h/day, 5 days/week for 2 weeks separated by a week of no chamber exposures but 2 days of practice tests. During the weeks with testing in the chamber, control-air exposure was used on Mondays, Wednesdays, and Fridays. Exposure at 1,000 ppm and 10,000 ppm occurred on Tuesday and Thursday, respectively, in the first week, and the opposite order was used on these days in the second week of chamber testing. Scores at each concentration for each week were compared with the average of scores from the 3 days of control-air exposure. Other observations included clinical observations, blood tests, subjective impressions, and continuous EKG monitoring. The authors concluded that single exposures of 2.5 h or less at 10,000 ppm could be tolerated without permanently affecting health. In a more recent experimental study, Emmen et al.
(2000) exposed four healthy men and four healthy women (20-24 years old) to Freon 12 at 1,000 ppm and 4,000 ppm for 1 h. Subjects were exposed twice in different weeks. No clinically significant changes from reactions in clean air were measured in blood and urine (hematology and clinical chemistry) 24 h after exposure; in blood pressure, pulse, and EKG before, during, or after exposure; or in lung function (peak expiratory flow) 45 min before and 75 min after exposure. Stewart et al. (1978) exposed healthy volunteers for the longest period. Up to four healthy men and four healthy women were exposed to Freon 12 at 250, 500, and 1,000 ppm for 1 min to 8 h to assess absorption, excretion, and physiologic effects. When those exposures caused no health effects in any subjects, the subjects were exposed at 1,000 ppm 8 h/day, 5 days/week for 2-4 weeks.
Physical examinations, subjective symptom surveys, blood and urinary analysis for clinical measures, spirometry, EKG, EEG, adrenal gland function, motor or cognitive tests, or health monitoring over a year after exposure showed no treatment-related effects. In contrast, eight men exposed repeatedly to Freon 11 (considered to be more toxic than Freon 12) at 1,000 ppm showed minor decrements in some cognitive tests (Stewart et al. Occupational and Epidemiologic Studies Exposure to Freon 12 has been widespread because of its use as a refrigerant and as an aerosol propellant in consumer products and medicinal inhalers (Marier et al.
1973; Ritchie et al. Only a few occupational or epidemiologic studies that involved Freon 12 were located. Those studies also involve exposure to other chlorofluorocarbons. Edling and colleagues (Edling and Olson 1988 in Swedish, as cited in WHO 1990; Edling et al.
1990) examined 89 refrigeration workers exposed mainly to Freon 12 (56% of cases), although several other chlorofluorocarbons were involved. Chlorofluorocarbon concentrations measured by personal monitors exceeded 750 ppm at least once (as 1-min mean. Values) for 60 of the 89 workers. The highest concentration recorded was 14,000 ppm, and the highest time-weighted average concentration for 8 h was 280 ppm. No significant differences in EKG measurements between nonexposed and exposed periods were found, nor was a concentration-related trend found when subjects were grouped by exposure, although effects in subjects in the medium-exposure group were borderline significant (Wilcoxon’s test, p = 0.05, one-tailed).
No differences were found in simple reaction-time measurements before and after exposure. Mortality in 539 refrigeration construction and repair workers (employed more than 6 months) was not increased (18 deaths vs 26 expected) (Szmidt et al. 1981 in Swedish, as cited in WHO 1990 and Rusch 2000). Freon 12 was among several chlorofluorocarbons used by the workers.
No significant increases in total tumor deaths, lung cancer deaths, or cardiovascular deaths were reported. Restricting the analysis to those employed more than 3 or 10 years did not change the findings. Exposure of six refrigeration workers to Freon 12 and hydrochlorofluorocarbon (HCFC) 22 at concentrations that occasionally reached 1,300 to 10,000 ppm was not associated with cardiac problems compared with plumbers who had no such exposure (Antti-Poika et al. 1990, as cited in Rusch 2000). Effects in Animals Toxicity of Freon 12 has been examined in several animal species, including rats, mice, guinea pigs, dogs, cats, and monkeys.
Dogs in particular have been studied for the cardiac-sensitizing effects of Freon 12 and other chlorofluorocarbons. Studies in dogs have generally been conducted in conscious animals, whereas those in other species have used anesthetized animals. General anesthesia makes the heart less responsive to epinephrine, and this confounding factor needs to be taken into account in interpreting the animal data. Results of studies of Freon 12 in animals are generally consistent with those of experimental studies in humans (see ). In general, at equivalent air concentrations of Freon 12, effects noted after brief exposure (for example, 5 min) appear to be similar to those reported after longer exposure (for example, an hour) or repeated exposure. TABLE 5-3 Summary of Animal Toxicity of Freon 12 Species (no.) Exposure Period End Point NOAEL (ppm) Adverse-Effect Level (ppm) Reference Dog (12) 30 sec No cardiac arrhythmia with fright 80,000 — Reinhardt et al. 1971 Rat (5) 2 min Anesthetized; reduced pulmonary compliance and tidal volume — 50,000 Watanabe and Aviado 1975 Rat (5, 5, 4) 5 min Unanesthetized; no arrhythmias; acceleration of heart rate (10% at 400,000), although not statistically significant — 100,000, 200,000, 400,000 and 20% O 2 Watanabe and Aviado 1975 Mouse (3) 4 min Anesthetized; 8% increase in pulmonary resistance, 6% decrease in pulmonary compliance (tests of significance not reported) — 20,000 Brody et al.
1974 Mouse (4) 4 min Anesthetized before exposure; no cardiac arrhythmia with or without epinephrine; increase in height of QRS complex (13.9%) and decrease in heart rate (9.3%); slowing of heart rate reduced when epinephrine was also administered — 400,000 Brody et al. 1974 Dog (4) 5 min EC 50 for cardiac arrhythmia with epinephrine. 20,000, 40,000 80,000 Clark and Tinston 1972 Dog (12) 5 min Cardiac arrhythmia in 5 dogs with epinephrine — 50,000 Reinhardt et al.
1971 Monkey (3) 5 min Anesthetized before exposure; 9% decrease in aortic blood pressure; changes in other measures not significant — 50,000 Aviado and Smith 1975. Monkey (4) 15% increase in pulmonary resistance and 10% increase in aortic heart rate; changes in pulmonary compliance (−11%), respiration minute volume (−1%), and aortic blood pressure (−15%) not significant. — 100,000 Aviado and Smith 1975 Monkey (3) 5 min Anesthetized before exposure; no change in heart rate 50,000, 100,000 — Belej et al. Species (no.) Exposure Period End Point NOAEL (ppm) Adverse-Effect Level (ppm) Reference Dog (8) 16 min Cardiac arrhythmia with exercise; anesthetic effects in 6 animals — ≥100,000 Mullin et al. 1972 Rat (20). Cat (2), rat (5), guinea pig (3), dog (2) 3.5 h/day, 5 days/week for 4 weeks No adverse effects 100,000 — Scholtz 1962, as cited in WHO 1990 Rat (90 of each sex), mouse (60 of each sex) 4 h/day, 5 days/week; rat: 104 weeks; mouse: 78 weeks No evidence of carcinogenicity or effects on body weight 1,000, 5,000 — Maltoni et al. 1988 Dog (6) 6 h/day, 7 days/week for 90 days No adverse effects on behavior and appearance, food or water consumption, body weight, clinical measures, heart rate, EKG, blood pressure, sight, hearing, dentition, organ weights, or histologic examinations 5,000 — Leuschner et al.
1983 Rat (40) 6 h/day, 7 days/week for 90 days No adverse effects on behavior and appearance, food or water consumption, body weight, clinical measures, sight, hearing, dentition, organ weights, or histologic examinations 10,000 — Leuschner et al. 1983 Dog, monkey, guinea pig 7-8 h/day for 3.5-56 days Some deaths, CNS reactions. — 200,000 Summarized by Clayton 1967. Epinephrine doses used in these studies are reported to be higher than (for example, 10 times as high as) endogenous concentrations (Reinhardt et al. The epinephrine dose, 5 µg/kg, used by Clark and Tinston (1972) was the highest that could be administered without causing serious cardiac arrhythmia by itself. Sensitization of the heart to cardiac arrhythmia is reported to be temporary. Injection of epinephrine 10 min after 0.5-min exposure at a sensitizing concentration (80,000 ppm) of Freon 12 had no effect on cardiac rhythm (Clark and Tinston 1972).
Effects observed with acute exposure to Freon 12 at 100,000 ppm and above include bronchoconstriction in monkeys (Aviado and Smith 1975) and dogs (Belej and Aviado 1975) and increased heart rate and decreased myocardial force (Aviado and Smith 1975) in monkeys. Rats were reported to show pulmonary resistance and other lung-function effects at 50,000 ppm (Watanabe and Aviado 1975); except for a decrease in aortic blood pressure (which was not significant at 100,000 ppm), such changes at 50,000 ppm were not significant in monkeys (Aviado and Smith 1975). Mice exposed for 24 h at 10,000 ppm showed lung changes on histopathologic examination, including greater leukocyte infiltration of alveolar walls relative to controls and an exudate in the bronchioles (Quevauviller et al. Exposure to a mixture of Freon 12 and Freon 11 or Freon 114 was associated with no clinical signs but had microscopic effects, such as alveolar hemorrhage (Quevauviller et al.
However, the old report lacked sufficient details to evaluate whether the effects were entirely treatment-related. Control animals showed similar effects (focal congestion of the alveolar walls with leukocyte infiltration) to a lesser degree. The order in which mice from the various groups were euthanized and the method of euthanasia were not specified. Some of the lesions observed could be caused by the method of euthanasia. Background pulmonary inflammatory disease may also have contributed to the lesions observed.
Rats showed no significant differences in operant performance measures (such as number of food rewards and number of errors) during 15-min exposures at 40,000, 60,000, 80,000, or 100,000 ppm compared with effects of exposure to clean air; however, exposure at 140,000 ppm resulted in a significant reduction in the number of food rewards and an increase in the ratio of errors to rewards (Richie et al. Repeated Exposure and Subchronic Toxicity Animal studies provide useful information for assessing effects of repeated or longer-term inhalation exposure because of the few human studies, although the original papers on several of the studies could not be obtained for critical evaluation (see ). One of the useful studies for evaluating CEGLs for submariners is the 90-day exposure study of Prendergast et al. (1967), which used exposure for 24 h/day, 7 days/week (continuously) for 90 days and repeated exposure more similar to occupational settings (8 h/day, 5. Days/week for 6 weeks). They exposed 15 rats, 15 guinea pigs, three rabbits, two dogs, and three monkeys to Freon 12 at about 800 ppm under each of the two exposure regimens. Hematologic characteristics were measured before and after exposure, body weights were measured monthly, and visible signs of toxicity (behavior, physical appearance, respiration pattern, locomotor activity, and prostration) were monitored during the exposure period.
Animals were necropsied at the end of the study, and histopathologic evaluations of the heart, lungs, liver, spleen, and kidney were conducted. The same control group of animals was used for both repeated and continuous experiments. A few deaths were observed in rats (one after repeated and two after continuous exposure) and guinea pigs (one after continuous exposure).
No visible signs of toxicity were noted in the surviving exposed animals. Death rates observed in control animals were seven of 304 rats, two of 314 guinea pigs, none of 34 dogs, one of 57 monkeys, and two of 48 rabbits. After continuous exposure, body-weight gain in exposed rabbits and guinea pigs was decreased, although the starting weight of rabbits was greater than that of controls; and other species had similar (rats) or greater (dogs and monkeys) weight gain relative to controls.
A high incidence of lung congestion was reported in all species but dogs, and nonspecific inflammatory changes were observed in the lungs of all species, including control animals. Fatty infiltration of the liver was observed in all guinea pig liver sections examined; several sections displayed focal or submassive necrosis. Repeated exposure to Freon 12 for 6 weeks was also associated with no visible signs of toxicity (Prendergast et al. Other effects reported were similar to those observed after continuous exposure, although the liver changes (focal necrosis) in guinea pigs were considered less severe than those observed after continuous exposure. Weight loss occurred in dogs and monkeys. Lung congestion (except in dogs) and nonspecific interstitial inflammatory changes (in all species) were also noted in lung tissue; however, such changes were also noted in the lungs of control animals. Heavy pigment deposits in the liver, spleen, and kidney were reported in one monkey.
Although the authors attributed the focal liver necrosis to the treatment (repeated exposure), they expressed some uncertainty in concluding that the effect was caused by exposure to Freon 12. Regarding the submassive necrosis of the liver after continuous exposure, the authors stated that the effect may have been due to the continuous nature of the exposure or the greater susceptibility of guinea pigs. In a later study (Prendergast et al. 1967), they did not attribute lung congestion to the treatment. Four rats that received 20 acute exposures (15 min once a week) to Freon 12 at 40,000, 60,000, 80,000, 100,000, and 140,000 ppm showed a significant change in operant performance (measured by number of food rewards for and errors in completing learned tasks) only at 140,000 ppm (Richie et al. Operant performance was measured before, during, and after Freon 12 exposure. The rats were exposed to each concentration four times successively from the lowest to the highest concentration and received one exposure per week for a total of 20 weeks (four exposures at each of five concentrations).
Measured pre-exposure and postexposure showed no differences over the course of the study. Forty rats exposed at 10,000 ppm and six dogs exposed at 5,000 ppm 6 h/day, 7 days/week for 90 days showed no adverse effects in behavior, food or water consumption, feces, sight, dentition, hearing, or hematologic, urinary, or other clinical measures (Leuschner et al. No changes from controls were found in internal organ weights measured in 11 rats and 12 dogs or in histologic examinations of 27 organs of 20 exposed rats examined and all dogs. Chronic Toxicity Chronic studies of inhalation or oral exposure to Freon 12 have reported few effects. Smith and Case (1973) exposed 30 mice and three adult dogs of each sex to chlorofluorocarbon mixtures 49-50% Freon 12 and about 25% CFC-11, 25% CFC-114, and small amounts of CFC-113.
The authors reported daily doses rather than air concentrations: 970 mg/kg per day for mice and 2,240 mg/kg per day for dogs. Assuming an inhalation rate of 20 m 3/day and 70-kg body weight, those doses would be equivalent to 24-h air concentrations for a human of 686 ppm and 1,584 ppm. Mice exposed 5 min/day at the specified dose 5 days/week for 23 months showed no signs of toxicity or lung tumors. Dogs exposed once a day by face mask (exposure period not specified but probably much less than 24 h) 7 days/week for 1 year showed CNS-depressant effects immediately after dosing for a few minutes but no indication of toxicity or irritation when lung tissue sections were examined. The immediate CNS depression observed would probably not be expected if dogs were exposed at the same daily dose by inhalation of a lower Freon 12 concentration over 24 h. No changes were observed in hematology, EKG, heart histology, blood chemistry, or urinalysis. No effects on body weight were reported in an inhalation-carcinogenicity study in rats and mice by Maltoni et al.
(1988), described below under “.”. Reproductive Toxicity in Males Few reports mention male reproductive toxicity of Freon 12 (NRC 1984; WHO 1990; ACGIH 2001). A three-generation oral-gavage study administered Freon 12 in corn oil to rats at average doses of 15 and 150 mg/kg per day (Sherman 1974, as cited in WHO 1990). No adverse effects on fertility, percentage of live births, or viability of offspring were reported. Freon 113 was examined in a one-generation reproduction study in which male and female rats were exposed by inhalation at 5,000 ppm or 12,500 ppm 6 h/day, 5 days/week for 10 weeks (males) or 3 weeks (females). Males were then paired with two females and exposed 6 h/day for 14 days. Mated females were exposed 6 h/day until day 20 of gestation, when they were allowed to give birth, and the offspring were.
Carcinogenicity As noted above, Smith and Case (1973, as cited in WHO 1990) reported no evidence of lung tumors in mice and dogs after 23 months of inhalation exposure at 970 mg/kg per day and 12 months at 2,240 mg/kg per day, respectively, to a mixture of chlorofluorocarbons containing about 50% Freon 12 (25% Freon 11, 25% Freon 114, and 0.5-1% Freon 113). Maltoni et al. (1988) examined the carcinogenicity of Freon 12 and Freon 11 in 180 rats and 120 mice of both sexes exposed at 1,000 or 5,000 ppm 4 h/day, 5 days/week for 104 weeks. No evidence of carcinogenicity related to Freon 12 or Freon 11 was reported. Chronic oral-carcinogenicity studies of Freon 12 in rats and dogs have also been negative (Sherman, 1974; reviewed by WHO 1990 and EPA 1995 IRIS RECORD—1995 is the last revised date). Szmidt et al. (1981 in Swedish, as cited in WHO 1990) found no significant increases in total tumor deaths or lung-cancer deaths in refrigerator construction and repair workers.
Restricting the analysis to those employed more than 3 or 10 years did not change the findings. Freon 12 is not listed in the National Toxicology Program 11th Report on Carcinogens.
TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS The most serious and potentially life-threatening toxic effect of inhalation of chlorofluorocarbons, such as Freon 12, is cardiac toxicity, which has been demonstrated in multiple animal species. According to Aviado (1994), three situations increase the sensitivity of the heart to the effects of chlorofluorocarbons: the injection of epinephrine, coronary ischemia or cardiac necrosis, and experimental bronchitis or pulmonary thrombosis. A common feature of those situations is a direct or indirect increase in cardiac irritability caused by epineph. General anesthesia, however, reduces cardiac sensitivity to the effects of chlorofluorocarbons (Aviado 1994), so studies in which animals were anesthetized are not representative of exposures associated with cardiac effects in unanesthetized animals. Anesthesia in mice and rats has also been shown to block the accelerating effects of chlorofluorocarbons on heart rate and instead to result in bradycardia. According to Aviado (1994), the mechanism of chlorofluorocarbon toxicity originates in irritation of the respiratory tract, which by a simple reflex response influences the heart rate before absorption of the compound. That is followed by depression of cardiac function after chlorofluorocarbon absorption and by sensitization of the heart to sympathomimetic amines (Aviado 1994).
(2006) investigated potential mechanisms of cardiac-sensitization arrhythmia induced by simultaneous exposure to halocarbons and epinephrine. They used rat cardiomyocytes and found that the combination of the halocarbon CF 3Br and epinephrine had a unique effect on the electrophysiology of cardiomyocytes, specifically, reduction in conduction velocity associated with phosphorylation of gap-junction channel proteins. (2006) note that effects on other ion channels may contribute to the risk of arrhythmia during cardiac sensitization and that their cardiomyocyte recording system cannot directly demonstrate actual arrhythmic effects.
Among the species studied, the guinea pig is the most resistant to cardiovascular effects (Aviado 1994). The rat and mouse are intermediate in susceptibility, and the dog and monkey are more sensitive species. Experimental data indicate that the dog may be more sensitive than the monkey to cardiac effects. Aviado cautions against assuming that responses in the monkey would be more similar to those in humans, because of the lack of studies that would allow such a definitive comparison and because some studies had indicated that monkeys have no response or a response opposite that in dogs and other species. In addition to the reflex-induced bronchospasm, chlorofluorocarbons are postulated to reduce pulmonary compliance by reducing pulmonary surfactants (Aviado 1994). On the basis of the effect of atropine pretreatment in blocking pulmonary resistance caused by chlorofluorocarbons in the anesthetized mouse, bronchoconstriction in the mouse appears to result from vagal innervation of the lungs. Depression of respiratory movements at high exposure is related to the anesthetic properties of these compounds.
In general, the dog appears to be less sensitive to respiratory toxicity than the mouse or rat. The rapid onset and reversibility of symptoms (such as cardiac and CNS effects within seconds to minutes) and the little adherence to Haber’s Law are consistent with the rapid appearance of inhaled Freon 12 in the blood and its rapid elimination (Blake and Mergner 1974; Paulet et al. Inhaled Freon 12 (500,000 ppm for 10 min) in dogs and rabbits diffused rapidly into the bloodstream, cerebral spinal fluid (evaluated in dogs only), urine, and bile and reached equilibrium in blood within 2 min in rabbits and 5 min in dogs (Paulet et al. (2000) reported nearly maximal blood concentrations in eight human subjects (exposure at 1,000 ppm and 4,000 ppm) in 15 min. Ter 10-min exposure at 200,000 or 500,000 ppm, elimination of Freon 12 from the blood was complete within 85 sec in the rabbit and within 20-30 min in dogs (Paulet et al. Although inhalation of high concentrations of Freon 12 results in its rapid appearance in the blood because of its low blood:air partition coefficient, little is absorbed from the lungs.
Single breath studies in human volunteers indicated that much of what is inhaled is exhaled unabsorbed (Morgan et al. The amount that reached the bloodstream from such a brief exposure was rapidly cleared: only a small fraction remained 5 min after exposure (Morgan et al. (1975) reported that inhalation of an administered dose of 3,225-4,506 mg over 12-20 min to three dogs or a dose of 777 mg over 16.75 min to a human volunteer resulted in near maximal blood concentration within the first 5 min. Consistent with their finding of a blood:air partition coefficient for Freon 11 that is 5-6 times higher than that for Freon 12, Adir et al.
(1975) reported 77% of the administered dose of Freon 11 over the exposure period was absorbed in dogs compared with 55% of Freon 12. Freon 12 was also eliminated more rapidly from the blood within about 50 min for the dogs and the human subject compared with longer than 100 min for Freon 11. A review by WHO (1990) reported that studies in rats and monkeys indicated that Freon 12 is slightly more readily absorbed than Freon 114. (2000) reported biphasic elimination from blood in most of the eight human subjects that was independent of concentration (1-h exposure at 1,000 ppm or 4,000 ppm)—a mean half-life of 7 min for the first phase of elimination and a mean half-life of 36 min for the second phase. Elimination occurs largely by the lungs with little metabolism (less than 1%), as shown in dogs (6-20 min of ventilation at 8,000-12,000 ppm Blake and Mergner 1974 and humans (less than 0.2%; 7-17 min of inhalation at 1,000 ppm Mergner et al. In the study of anesthetized dogs (Blake and Mergner 1974), essentially all the radiolabeled Freon 12 was exhaled within an hour, and only traces of radioactivity appeared in the urine or with exhaled carbon dioxide. That longer exposures (50-90 min) or pretreatment with phenobarbital did not change the results indicates little biotransformation.
(1975) developed a pharmacokinetic model for predicting blood and tissue concentrations of Freon 12 in dogs and humans and concluded that continuous 8-h exposure at 1,000 ppm would result in a venous blood concentration that was well below concentrations reported to sensitize a dog’s heart to intravenously injected epinephrine (Azar et al.