Hazard identification and consumer safety characterization for trans-1-chloro-3,3,3-trifluoropropene (trans-1233zd).

Trans-1233zd was developed as a refrigerant and propellant in consumer products; its toxicity has been studied extensively. The scope of this assessment is to apply the confirmed NOAEC to conduct Benchmark Dose Modeling (BMD) and determine the Point of Departure (POD). In a previously published 13-week inhalation study, a NOAEC was identified at 4000 ppm. Due to uncertainty concerning the cardiac lesion, an external pathology peer review of heart tissues was undertaken using published best practices and consistent nomenclature and diagnostic criteria. The cardiac lesion observed at 4000 ppm was considered to be spontaneous based on lesion location and microscopic features. BMD was applied to derive the BMDL05 and BMDL10; the more conservative BMDL05 was used as the POD for risk assessment to calculate the Reference Exposure Levels (RELs). The 2-Box Air Dispersion Model was used to calculate the exposure to consumer products. Both the acute and chronic exposure concentrations calculated were compared to the acute and chronic RELs. The acute and chronic exposure to trans-1233zd in the assessed consumer products are below the RELs and deemed safe for their intended uses.

Unusual hand frostbite caused by refrigerant liquids and gases.

BACKGROUND: The refrigerant liquids and gases used widely in industry, farming and medicine for their cooling properties may cause severe frostbite. Despite their widespread use, only a few reports on frostbite of the hand involving these liquids and gases have been published. In this study, the circumstances accompanying these injuries, several adjunctive therapies and preventive measures are discussed. METHODS: A retrospective analysis of hand frostbite injuries was conducted between June 2005 to June 2009 in a burn care center in Istanbul, Turkey. Seventeen patients (13 men, 4 women) were treated for hand frostbite injuries due to contact with refrigerant liquids and gases. RESULTS: There was a preponderance of male patients (76.5%). Ages ranged from 22 to 52 years (mean age, 30.82 years). Eleven patients were treated conservatively. The hospital stay for treatment of their burns ranged from 16 to 52 days, with a mean stay of 30 days. CONCLUSION: Frostbite injuries of the hand are uncommon and their etiologies vary. Thus, the low incidence of these injuries and limited experience in handling rare cases of this nature may lead to misjudgments in treatment that can have grave consequences. Decreasing the exposure time is an important first step in the treatment approach. After exposure to gas, quick delivery of the patient to a burn center is essential.

Cardiotoxicity of Freon among refrigeration services workers: comparative cross-sectional study.

BACKGROUND: Freon includes a number of gaseous, colorless chlorofluorocarbons. Although freon is generally considered to be a fluorocarbon of relatively low toxicity; significantly detrimental effects may occur upon over exposure. The purpose of the present study is to investigate whether occupational exposure to fluorocarbons can induce arterial hypertension, myocardial ischemia, cardiac arrhythmias, elevated levels of plasma lipids and renal dysfunction. METHODS: This comparative cross-sectional study was conducted at the cardiology clinic of the Suez Canal Authority Hospital (Egypt). The study included 23 apparently healthy male workers at the refrigeration services workshop who were exposed to fluorocarbons (FC 12 and FC 22) and 23 likewise apparently healthy male workers (unexposed), the control group. All the participants were interviewed using a pre-composed questionnaire and were subjected to a clinical examination and relevant laboratory investigations. RESULTS: There were no significant statistical differences between the groups studied regarding symptoms suggesting arterial hypertension and renal affection, although a significantly higher percentage of the studied refrigeration services workers had symptoms of arrhythmias. None of the workers had symptoms suggesting coronary artery disease. Clinical examination revealed that the refrigeration services workers had a significantly higher mean pulse rate compared to the controls, though no significant statistical differences were found in arterial blood pressure measurements between the two study groups. Exercise stress testing of the workers studied revealed normal heart reaction to the increased need for oxygen, while sinus tachycardia was detected in all the participants. The results of Holter monitoring revealed significant differences within subject and group regarding the number of abnormal beats detected throughout the day of monitoring (p < 0.001). There were no significant differences detected in the average heart rate during the monitoring period within subject or group. Most laboratory investigations revealed absence of significant statistical differences for lipid profile markers, serum electrolyte levels and glomerular lesion markers between the groups except for cholesterol and urinary beta2-microglobulin (tubular lesion markers) levels which were significantly elevated in freon exposed workers. CONCLUSIONS: Unprotected occupational exposure to chlorofluorocarbons can induce cardiotoxicity in the form of cardiac arrhythmias. The role of chlorofluorocarbons in inducing arterial hypertension and coronary artery diseases is unclear, although significantly elevated serum cholesterol and urinary beta2-microglobulin levels raise a concern.

Evaluation of the butter flavoring chemical diacetyl and a fluorochemical paper additive for mutagenicity and toxicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells.

Diacetyl (2,3-butanedione) is a yellowish liquid that is usually mixed with other ingredients to produce butter flavor or other flavors in a variety of food products. Inhalation of butter flavoring vapors was first associated with clinical bronchiolitis obliterans among workers in microwave popcorn production. Recent findings have shown irreversible obstructive lung disease among workers not only in the microwave popcorn industry, but also in flavoring manufacture, and in chemical synthesis of diacetyl, a predominant chemical for butter flavoring. It has been reported that perfluorochemicals utilized in food packaging are migrating into foods and may be sources of oral exposure. Relatively small quantities of perfluorochemicals are used in the manufacturing of paper or paperboard that is in direct contact with food to repel oil or grease and water. Because of recent concerns about perfluorochemicals such as those found on microwave popcorn bags (e.g. Lodyne P208E) and diacetyl in foods, we evaluated both compounds for mutagenicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells. Lodyne P208E was less toxic than diacetyl and did not induce a mutagenic response. Diacetyl induced a highly mutagenic response in the L5178Y mouse lymphoma mutation assay in the presence of human liver S9 for activation. The increase in the frequency of small colonies in the assay with diacetyl indicates that diacetyl causes damage to multiple loci on chromosome 11 in addition to functional loss of the thymidine kinase locus.

An improved system for exposure of cultured mammalian cells to gaseous compounds in the chromosomal aberration assay.

A gas exposure system using rotating vessels was improved for exposure of cultured mammalian cells to gaseous compounds in the chromosomal aberration assay. This system was composed of 12 square culture vessels, a device for preparation of air containing test gas, and positive and negative control gases at target concentrations and for supplying these gases to the culture vessels, and a roller apparatus in an incubator. Chinese hamster lung cells (CHL/IU) were grown on one side of the inner surface of the square culture vessel in the MEM medium. Immediately prior to exposure, the medium was changed to the modified MEM. Air in the culture vessel was replaced with air containing test gas, positive or negative control gas. Then, the culture vessels were rotated at 1.0 rpm. The monolayered culture cells were exposed to test gas during about 3/4 rotation at upper positions and alternatively immersed into the culture medium during about 1/4 rotation at lower positions. This system allowed the chromosomal aberration assay simultaneously at least at three different concentrations of a test gas together with positive and negative control gases with and without metabolic activations, and duplicate culture at each exposure concentration. Seven gaseous compounds, 1,3-butadiene, chlorodifluoromethane, ethyl chloride, methyl bromide, methyl chloride, propyne, and vinyl chloride, none of which has been tested to date, were tested on CHL/IU for the chromosomal aberration assay using this gas exposure system. All the compounds except chlorodifluoromethane showed positive responses of the structural chromosomal aberrations, whereas polyploidy was not induced by any of these gases. This improved gas exposure system proved to be useful for detecting chromosomal aberrations of gaseous compounds.

Grand rounds: outbreak of hematologic abnormalities in a community of people exposed to leakage of fire extinguisher gas.

CONTEXT: Although there are ample data on the respiratory effects of exposure to fire extinguisher gas, the potential hematologic effects have not been fully documented. We conducted this study to determine the possible etiologic agent(s) for a decrease in red blood cells among community residents in Taipei, Taiwan, after they were exposed to leakage of mixed fire extinguishants containing bromotrifluoromethane (CF3Br, Halon 1301), bromochlorodifluoromethane (CF2BrCl, Halon 1211), and dichlorodifluoromethane (CCl2F2, CFC-12). CASE PRESENTATION: We studied 117 exposed residents who came into one hospital for physical examinations. We also selected age- and sex-matched referents for comparison from residents who came to the same hospital for health examinations. Nine months after the exposure to mixed fire extinguishants, 91 of the exposed residents came back for a second physical examination. In the first examination of the exposed residents, we found a significant reduction in red blood cell count and hemoglobin and a relationship between dose and response. DISCUSSION: After excluding iron-deficiency anemia, thalassemia, and other possible agents, we suspected that the hematologic effects might have resulted from pyrolytic products of CFC-12 and Halon 1211, which may contain phosgene, among other products. RELEVANCE TO CLINICAL PRACTICE: The acute transient hematologic effects observed in the exposed residents were associated with the incident of leakage of mixed fire-extinguisher gases and were most likely caused by a small amount of pyrolytic products, probably phosgene. Nine months after the exposure, we found a significant improvement in the abnormalities without any specific treatment.

Total toxicity equivalents emissions of SF6, CHF3, and CCl2F2 decomposed in a RF plasma environment.

Sulfur hexafluorine compound (SF6), trifluoromethane (CHF3) and diclorodifluoromethane (CCl2F2) are extensively used in the semiconductor industry. They are global warming gases. Most studies have addressed the effective decomposition of fluorine compounds, rather than the toxicity of decomposed by-products. Hence, the concepts of toxicity equivalents (TEQs) were applied in this work. The results indicated that HF and SiF4 were the two greatest contributors of TEQ to the SF6/H2/Ar plasma system, while F2 and SiF4 were the two greatest contributors to the SF6/O2/Ar system. Additionally, SiF4 and HF were the two greatest contributors of TEQ to both the CHF3/H2/Ar and CHF3/O2/Ar plasma systems. HF and HCl were the two greatest contributors of TEQ to the CCl2F2/H2/Ar plasma system, and Cl2 and COCl2 were the two greatest contributors to the CCl2F2/O2/Ar system. HCl and HF can be recovered using wet scrubbing, which reduces the toxicity of these emission gases. Consequently, the hydrogen-based plasma system was a better alternative for treating gases that contained SF6, CHF3 and CCl2F2 from the TEQs point of view.

Investigations on the liver toxicity of a blend of HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and HCFC-124 (2-chloro-1,1,1,2-tetrafluoroethane) in guinea-pigs.

2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) has been developed as a substitute for ozone-depleting chlorofluorocarbons (CFCs). It is a structural analogue of halothane and similarities in the metabolic pathways and liver toxicity of both compounds have been described. The present study was initiated after an accidental outbreak of hepatitis in an industrial setting to examine whether concomitant exposure to 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), which is not hepatotoxic, could enhance the liver toxicity of HCFC-123. Male Hartley guinea-pigs were exposed for 4 h to 5,000 ppm HCFC-123 alone or blended with 5,000 ppm HCFC-124, either once (single exposure) or on 5 consecutive days (repeated exposure). The animals were killed either 24 or 48 h after the last exposure. A transient cytolytic action of HCFC-123 was evident by increased mean serum levels of alanine aminotransferase at 24 h and isocitrate dehydrogenase at 24 and 48 h, both after a single or repeated exposure. The liver toxicity of HCFC-123 was confirmed by pathological examination of liver tissue, which showed mild (foci of necrotic hepatocytes) to moderate (multifocal random degeneration and necrosis) damage. Steatosis was also observed and was more pronounced after repeated exposure than after single. One animal out of 6 that were repeatedly exposed to the blend and sacrificed at 24 h showed liver lesions similar to halothane hepatitis. Although a few other animals responded markedly in the blend-treated group, on average, no significant difference in the biochemical or pathological lesions was found between the groups treated with HCFC-123 alone or with the blend. Urinary excretion of trifluoroacetic acid and chlorodifluoroacetic acid increased dose-dependently upon exposure to HCFC-123 and indicated accumulation after repeated exposure. No difference in metabolite excretion was found between animals treated with HCFC-123 alone or blended with HCFC-124. Treatment with HCFC-123 depleted hepatic glutathione levels by about 40 and 25% after single and repeated exposure, respectively; the amplitude of this reduction was not modified by co-exposure to HCFC-124. In conclusion, this study confirmed the hepatotoxicity of HCFC-123, based on biochemical, histopathological and metabolite studies, and found only very limited indication of a potentiation by HCFC-124 of this hepatotoxic effect.

Acute neurobehavioral effects in rats from exposure to HFC 134a or CFC 12.

1,1,1,2-Tetrafluoroethane (HFC 134a), a chlorine-free hydrofluoroalkane, is internationally replacing billions of pounds of dichlorodifluoromethane (CFC 12) for coolant, refrigerant and aerosol propellant applications. The ALC50 for HFC 134a in rats is 567,000 ppm for 4 h; its potential for cardiac epinephrine sensitization in beagle dogs is acceptable (75,000 ppm); and its capacity to induce carcinogenicity or developmental disorders in animals is minimal. HFC 134a, with a serum half life estimated at 4-11 min, has been accepted for use as a propellant in metered-dose inhalant products, implying a low human toxicity risk from periodic brief exposures. There has been little published human or animal research evaluating possible neurobehavioral toxicity from longer HFC 134a exposures, as may be expected to occur in operational scenarios. In this study, male Wistar rats were exposed to various concentrations of HFC 134a or CFC 12 for up to 30 min while performing in either a rotarod/motorized running wheel apparatus or in an operant chamber The relative neurobehavioral toxicity of CFC 12 and its ozone-depleting substance replacement HFC 134a was assessed by comparing both gross motor system incapacitation and more subtle changes in ability to perform an operant discrimination task. It was shown that exposure to HFC 134a or CFC 12 concentrations from 40,000 to 470,000 ppm, for up to 30 min, induced neurobehavioral deficits in every subject, ranging from reduced operant efficiency to apparent anesthesia. For neurobehavioral endpoints examined in these experiments, HFC 134a inhalation was shown to induce deficits more rapidly, and at lower concentrations when compared to CFC 12 exposure.

Setting safe acute exposure limits for halon replacement chemicals using physiologically based pharmacokinetic modeling.

Most proposed replacements for Halon 1301 as a fire suppressant are halogenated hydrocarbons. The acute toxic endpoint of concern for these agents is cardiac sensitization. An approach is described that links the cardiac endpoint as assessed in dogs to a target arterial concentration in humans. Linkage was made using a physiologically based pharmacokinetic (PBPK) model. Monte Carlo simulations, which account for population variability, were used to establish safe exposure times at different exposure concentrations for Halon 1301 (bromotrifluoromethane), CF(3)I (trifluoroiodomethane), HFC-125 (pentafluoroethane), HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane), and HFC-236fa (1,1,1,3,3,3-hexafluoropropane). Application of the modeling technique described here not only makes use of the conservative cardiac sensitization endpoint, but also uses an understanding of the pharmacokinetics of the chemical agents to better establish standards for safe exposure. The combined application of cardiac sensitization data and physiologically based modeling provides a quantitative approach, which can facilitate the selection and effective use of halon replacement candidates.

Induction of genetic damage in human lymphocytes and mutations in Salmonella by trihalomethanes: role of red blood cells and GSTT1-1 polymorphism.

The brominated trihalomethanes (THMs) are mutagenic and carcinogenic disinfection by-products frequently found in chlorinated drinking water. They can be activated to mutagens by the product of the glutathione S-transferase-Theta (GSTT1++-1) gene in Salmonella RSJ100, which has been transfected with this gene. To evaluate this phenomenon in humans, we have examined the genotoxicity of a brominated THM, bromoform (BF), using the Comet assay in human whole blood cultures exposed in vitro. No differences were found in the comet tail length between cultures from GSTT1-1(+) versus GSTT1-1(-) individuals (1.67 +/- 0.40 and 0.74 +/- 0.54 microm/mM, respectively, P = 0.28). The high variability was due to the relatively weak induction of comets by BF. Combining the data from both genotypic groups, the genotoxic potency of BF was 1.20 +/- 0.34 microm/mM (P = 0.003). GSTT1-1 is expressed in red blood cells but not in the target cells (lymphocytes), and expression within the target cell (as in Salmonella RSJ100) may be necessary for enhanced mutagenesis in GSTT1-1(+) relative to GSTT1-1(-) cultures. To examine this, we exposed Salmonella RSJ100 and a control strain not expressing the gene (TPT100) to the most mutagenic brominated THM detected in Salmonella, dibromochloromethane (DBCM), either in the presence or absence of S9 or red blood cells from GSTT1-1(+) or GSTT1-1(-) individuals. S9 did not activate DBCM in the non-expressing strain TPT100, and it did not affect the ability of the expressing strain RSJ100 to activate DBCM. As with S9, red cells from either genotypic group were unable to activate DBCM in TPT100. However, red cells (whole or lysed) from both genotypic groups completely repressed the ability of the expressing strain RSJ100 to activate DBCM to a mutagen. Such results suggest a model in which exposure to brominated THMs may pose an excess genotoxic risk in GSTT1-1(+) individuals to those organs and tissues that both express this gene and come into direct contact with the brominated THM, such as the colon. In contrast, those organs to which brominated THMs would be transported via the blood might be protected by erythrocytes. Such a proposal is reasonably consistent with the organ specificity of drinking water-associated cancer in humans, which shows slightly elevated risks for cancer of the colon and bladder but not of the liver.

Chronic toxicity, oncogenicity, and mutagenicity studies with chlorotetrafluoroethane (HCFC-124).

The chronic toxicity, oncogenicity, and mutagenicity of chlorotetrafluoroethane (HCFC-124) were evaluated. In the chronic toxicity/oncogenicity study, male and female rats were exposed to 0, 2000, 10,000, or 50,000 ppm HCFC-124 for 6 hr/day, 5 days/week, for 2 years. Body weights were obtained weekly during the first three months of the study and every other week for the remainder of the study. Food consumption was determined weekly. Clinical signs of toxicity were monitored throughout the study. An ophthalmological examination was performed on all animals prior to study start, and all surviving rats were examined at approximately 3, 12, and 24 months after study start. Clinical pathology was evaluated at 3, 6, 12, 18, and 24 months. An interim termination was conducted at 12 months. All surviving rats were necropsied at 24 months. A complete set of tissues was collected for microscopic examination, and selected tissues were weighed. There were no compound-related, adverse effects on body weight, food consumption, survival, clinical signs of toxicity, ophthalmoscopically observable ocular lesions, serum hormone concentrations, or clinical pathology parameters at any exposure concentration in either male or female rats. Compared to controls, urine fluoride was increased in males and females at all exposure concentrations, and plasma fluoride was increased in females at all exposure concentrations. Excretion of fluoride represents conversion of the parent molecule, and as such is not considered to be an adverse effect. There were no toxicologically significant, compound-related organ weight changes or gross or microscopic findings in male or female rats at any of the exposure concentrations tested. HCFC-124 was not toxic or carcinogenic in rats of either sex after inhalation exposure at concentrations of up to 50,000 ppm in this two-year chronic toxicity/oncogenicity study. After exposure to HCFC-124 for six hours per day, five days per week, for 24 months, the no-observed-adverse-effect level for male and female rats was 50,000 ppm. HCFC-124 was not mutagenic in Salmonella typhimurium strains TA1535, TA97, TA98, and TA100 with and without activation when evaluated at concentrations up to 60% HCFC-124 for 48 hours. No evidence of clastogenic activity was observed in cultured human lymphocytes at atmospheric concentrations up to 100% HCFC-124 for 3 hours, with and without metabolic activation. In vivo, no micronuclei were induced in mouse bone marrow cells following exposure of mice to concentrations of 99,000 ppm HCFC-124 6 hours/day for 2 days.

Effects of four trihalomethanes on DNA strand breaks, renal hyaline droplet formation and serum testosterone in male F-344 rats.

All four possible trihalomethanes (THMs) containing bromine and chlorine, as well as perchloroethylene (PCE), were evaluated for their ability to produce DNA strand breaks, alpha 2u-globulin rich renal deposits, and testosterone changes in male F-344 rats. Rats received daily equimolar doses (0.75 or 1.5 mmol/kg) of THMs or PCE (1000 mg/kg) in 4% Emulphor vehicle by oral gavage for 7 days. No significant DNA strand breaks were produced by any THM or PCE treatment. PCE treatment produced increased hyaline droplet formation in renal tubules. However, all THM treatments reduced or eliminated the appearance of renal hyaline droplets. All four THM treatments also produced a decrease in serum testosterone concentrations on day 7, which might account for decreased hyaline droplet formation. No significant increase in cell proliferation, measured by [3H]thymidine incorporation in vivo, appeared in this 1-week study.

Subchronic toxicity and teratogenicity of 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124).

Inhalation studies were conducted to determine the potential toxicity of HCFC-124. Groups of rats and mice were exposed to HCFC-124 6 hr/day, 5 days/week for 13 weeks at 0, 5000, 15,000, and 50,000 ppm. Subgroups of rats and mice were held for a 1-month recovery period. A functional observational battery (FOB) was conducted on rats at 0, 4, 13, and 16 weeks. Clinical pathology evaluations were conducted at 7, 13, and 17 weeks. Thirteen or 17 weeks after study initiation, rats and mice underwent gross and microscopic evaluation, and livers were evaluated for hepatic beta-oxidation activity. In addition, groups of female rats and rabbits were exposed to HCFC-124 by inhalation during gestation to 0, 5000, 15,000, or 50,000 ppm. Exposure of rats and mice to HCFC-124 caused minimal compound-related effects. Compound-related changes occurred in several clinical pathology parameters in rats and mice. Hepatic beta-oxidation activity was significantly higher in 5000, 15,000, and 50,000 ppm male mice; however, there were no compound-related effects on beta-oxidation activity in rats. During the daily exposures, rats, mice, and rabbits exposed to 50,000 ppm were less responsive to auditory stimuli or less active compared to controls. At the 13-week FOB, male rats exposed to 15,000 or 50,000 ppm had decreased arousal. There were no compound-related effects on mortality, clinical signs, ocular tissues, hematology parameters, organ weights, and tissue morphology at any concentration in rats or mice. Maternal toxicity in rats was evident by a significant decrease in weight gain and food consumption at 50,000 ppm. Similarly, 50,000 ppm pregnant rabbits had lower food consumption. However, for both rats and rabbits, there was no evidence of fetal toxicity at any concentration.

Water chlorination: essential process or cancer hazard?

Chlorine has been successfully used for the control of waterborne infectious disease for nearly a century. In the 1970s it was found that chlorine reacted with natural organic matter present in surface waters to produce disinfection by-products (DBP). Concern focused initially on the trihalomethanes (THM), but a wide variety of DBPs are now known to result from chlorination. Chlorination of drinking water has been one of the most effective public health measures ever undertaken. There are a number of alternatives to chlorination that are in active use in many parts of the world, but the risks associated with their by-products are even less well established than for chlorination. Moreover, the use of these alternatives vary in their effectiveness and some require greater sophistication in their application. This can mean less protection to public health as a result of inappropriate application and control. Therefore, hazards associated with the use of such a clearly beneficial process as chlorination must be carefully considered not only in an absolute sense, but also in the context of alternative approaches for producing a safe drinking water. The key question is whether the hazards associated with by-products have been sufficiently well established to warrant regulations that will undoubtedly have both positive and negative impacts on the public health. This symposium examined the toxicological and epidemiological data on chemical hazards associated with chlorination and attempted to measure this hazard against competing microbial risks. The first presentation discussed the available analytical epidemiological studies. A second presentation dealt with the importance of chlorination to the prevention of waterborne infectious disease. Pharmacokinetic, mechanistic, and modeling information on the prototypical DBP, chloroform, were discussed and contrasted with data on brominated THMs to determine if it was scientifically appropriate to regulate THMs as a single toxicological class. The fifth presentation dealt with the carcinogenic properties of a potent mutagen that is produced by chlorination. The final presentation discussed the haloacetates, carcinogenic DBPs whose concentrations approach and occasionally exceed those of the THMs. Clearly, there is a need to carefully weigh these different types and sometimes competing risks when considering the delivery of drinking water to ever-increasing populations for which there are finite sources of fresh water.

Evaluation of the acute cardiac and central nervous system effects of the fluorocarbon trifluoromethane in baboons.

The gaseous fluorocarbon trifluoromethane has recently been investigated for its potential as an in vivo gaseous indicator for nuclear magnetic resonance studies of brain perfusion. Trifluoromethane may also have significant value as a replacement for chlorofluorocarbon fire retardants. Because of possible species-specific cardiotoxic and anesthetic properties, the toxicological evaluation of trifluoromethane in primates (Papio anubis) is necessary prior to its evaluation in humans. We report the acute cardiac and central nervous system effects of trifluoromethane in eight anesthetized baboons. A dose-response effect was established for respiratory rate, electroencephalogram, and cardiac sinus rate, which exhibited a stepwise decrease from 10% trifluoromethane. No spontaneous arrhythmias were noted, and arterial blood pressure remained unchanged at any inspired level. Intravenous epinephrine infusions (1 microgram/kg) induced transient cardiac arrhythmia in 1 animal only at 70% FC-23 (v/v) trifluoromethane. Trifluoromethane appears to induce mild dose-related physiological changes at inspired levels of 30% or more, indicative of an anesthetic effect. These data suggest that trifluoromethane may be safe to use in humans, without significant adverse acute effects, at an inspired level of 30%.

Characterization of trihalomethane (THM)-induced renal dysfunction in the rat. I: Effects of THM on glomerular filtration and renal concentrating ability.

Single non-lethal doses (3 mmol/kg) of chloroform (CHCl3), dichlorobromomethane (CHCl2Br), dibromochloromethane (CHClBr2), and bromoform (CHBr3) were administered by intraperitoneal injection to male Sprague-Dawley rats and glomerular filtration and renal concentrating ability were assessed at varied times (5-8 h, 21-24 h, and 45-58 h) following treatment. At this dose, each of the four trihalomethanes (THMs) elevated blood urea nitrogen (BUN) and reduced renal concentrating ability (as measured by H2O intake/output ratios, urinary total osmolality, and electrolyte levels). Three of the four THMs also significantly reduced glomerular filtration rate (GFR), with only CHCl3 failing to demonstrate an effect at 3 mmol/kg. In general, CHCl2Br demonstrated the greatest interference with these renal function parameters. The times of maximal THM-induced effect on BUN and glomerular filtration rate were observed to be 24 h and 21-24 h post-treatment, respectively. These data suggest that a single acute THM treatment can inhibit mammalian renal concentrating ability and glomerular filtration.

Characterization of trihalomethane (THM)-induced renal dysfunction in the rat. II: Relative potency of THMs in promoting renal dysfunction.

Single non-lethal doses (3 mmol/kg) of chloroform (CHCl3), dichlorobromomethane (CHCl2Br), dibromochloromethane (CHClBr2), and bromoform (CHBr3) were administered by intraperitoneal injection to male Sprague-Dawley rats and proximal tubular secretion and reabsorption was assessed at varied times following treatment. Each of the trihalomethanes (THMs) at this dose inhibited proximal tubular secretion, as indicated by decreased in vitro renal cortical slice accumulation of organic anion p-aminohippuric acid (14C PAH). The time of maximal THM interference with 14C PAH uptake occurred at 8 h, with recovery being demonstrated by 48 h. Each of the THMs also demonstrated interference with tubular reabsorption, as assessed by urinary glucose excretion, with maximal interference occurring during the first day post-treatment and recovery being observed during the second day post-treatment. In each case, CHCl2Br was the most potent inhibitor of proximal tubular function. Combining these data with those of the preceding paper, the relative potency in disrupting renal function was, in general, CHCl2Br > CHCl3 > CHClBr2 > CHBR3. Since the time course of this investigation indicates that proximal tubular dysfunction precedes other THM-induced renal function interferences, it also appears that proximal tubular damage is the primary event leading to further manifestations of renal dysfunction.