Inverse Modeling Revealed Reversed Trends in HCFC-141b Emissions for China during 2018-2020.

Having the highest ozone-depleting potential among hydrochlorofluorocarbons (HCFCs), the production and consumption of HCFC-141b (1,1-dichloro-1-fluoroethane, CH3CCl2F) are controlled by the Montreal Protocol. A renewed rise in global HCFC-141b emissions was found during 2017-2020; however, the latest changes in emissions across China are unclear for this period. This study used the FLEXible PARTicle dispersion model and the Bayesian framework to quantify HCFC-141b emissions based on atmospheric measurements from more sites across China than those used in previous studies. Results show that the estimated HCFC-141b emissions during 2018-2020 were on average 19.4 (17.3-21.6) Gg year-1, which was 3.9 (0.9-7.0) Gg year-1 higher than those in 2017 (15.5 [13.4-17.6] Gg year-1), showing a renewed rise. The proportion of global emissions that could not be exactly traced in 2020 was reduced from about 70% reported in previous studies to 46% herein. This study reconciled the global emission rise of 3.0 ± 1.2 Gg year-1 (emissions in 2020 - emissions in 2017): China's HCFC-141b emissions changed by 4.3 ± 4.5 Gg year-1, and the combined emissions from North Korea, South Korea, western Japan, Australia, northwestern Europe, and the United States changed by -2.2 ± 2.6 Gg year-1, while those from other countries/regions changed by 0.9 ± 5.3 Gg year-1.

Biotic and Abiotic Dehalogenation of 1,1,2-Trichloro-1,2,2-trifluoroethane (CFC-113): Implications for Bacterial Detoxification of Chlorinated Ethenes.

Chlorofluorocarbons including 1,1,2-trichloro-1,2,2-trifluoroethane (CFC-113) often occur in groundwater plumes comingled with chlorinated solvents such as trichloroethene (TCE). We show that CFC-113 inhibits reductive dechlorination by Dehalococcoides mccartyi (Dhc) in a concentration-dependent manner, causing cis-1,2-dichloroethene (cis-DCE) stalls. Following a 17-day exposure of Dhc-containing consortium SDC-9 to 76 µM CFC-113, cis-DCE dechlorination activity did not recover after CFC-113 removal. River sediment microcosms demonstrated that CFC-113 was subject to microbial degradation under anoxic conditions, and chlorotrifluoroethene (CTFE) was observed as a transformation product. No degradation of CFC-113 was observed in killed controls and in incubations with reactive minerals including mackinawite, green rust, magnetite, and manganese dioxide. In vitro experiments with reduced corrinoid (i.e., vitamin B12) mediated reductive dechlorination of CFC-113 to CTFE and trifluoroethene (TFE) followed by reductive defluorination of TFE to cis-1,2-difluoroethene (cis-DFE) as an end product. This biomimetic degradation of CFC-113 to cis-DFE was also demonstrated in vivo using the corrinoid-producing homoacetogen Sporomusa ovata, suggesting the cometabolic microbial reductive dechlorination and reductive defluorination of CFC-113 to cis-DFE is feasible under anoxic in situ conditions. The CFC-113 degradation intermediates CTFE, TFE, and cis-DFE did not inhibit TCE dechlorination by Dhc, indicating that the initial reductive transformation step can overcome cis-DCE stalls.

[Liver injury caused by exposure to silica and 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123):a case report].

This case report presents two males with drug-induced liver injury acquired from working at a glass factory dealing with silica and 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123). Within one month of work, both patients presented with fever, icterus with liver dysfunction, and eosinophilia. Case 1 had experienced recurrence of symptoms twice while working and showed positive results for the drug-induced lymphocyte stimulation test (DLST). Meanwhile, case 2 was diagnosed by liver biopsy and clinical course but was negative for DLST. Hazard of exposure to non-crystalline silica is low, but drug-induced liver injury after exposure to HCFC-123 has been reported. Allergic liver injury is also caused by chemical substances;however, the insight into whether this injury is caused by exposure to silica or HCFC-123 remains unclear. Further studies are required to examine the influence of silica and HCFC-123 on drug-induced liver injury among glass-factory employees.

The development of environmentally acceptable fluorocarbons.

Chlorofluorocarbons (CFCs) were introduced in the 1930s as the safe replacements for the toxic and flammable refrigerants being used at that time. Subsequently, hydrochlorofluorocarbons (HCFCs) were also developed. In addition to refrigerant applications, they were used as foam blowing agents, as solvents and as propellants for many aerosols. In the 1970s and 1980s, concern developed about their environmental impact, specifically on stratospheric ozone depletion. Industry began to consider acceptable replacements. In 1987, many of the governments of the world came together and drafted the Montreal Protocol, calling upon Industry to initially phase out production of the CFCs and later HCFCs. Within 4 months of the signing of the Montreal Protocol, the 15 global major producers joined together to form the Alternative Fluorocarbons Environmental Acceptability Study (AFEAS), which sponsored research into environmental effects and the Program for Alternative Fluorocarbons toxicity Testing, PAFT), which examined the toxicology of potential replacements for the CFCs and HCFCs. Nine replacements were identified by companies and, through this international cooperation; toxicology programs were designed, conducted, and evaluated without duplication of effort and testing; consequently these new products were introduced within less than 10 years. Indeed the Montreal Protocol has been recognized as the most appropriate international treaty to phase-down HFCs. In 2016 the Kigali Amendment to the Montreal Protocol set out a phase-down schedule for the consumption and production of HFCs. In order to reduce the consumption and emissions of high GWP HFCs. Recently lower GWP HFCs and very low GWP HFOs (hydrofluoroolefins and HCFOs (hydrochlorofluoroolefins) have been introduced into a range of applications. Summaries of the toxicology profiles of some of the original CFCs and HCFCs, the replacements and the new post-PAFT replacements are described. The chemicals in this review include CFC-11, CFC-12, CFC-113, CFC-114, HCFC 22, HCFC-123, HCFC-124, HCFC-141b, HCFC-142b, HCF-32, HFC-125, HFC-134a, HFC-143a, HFC-152a, HFC-245ea, HFC-245fa, HFO-1234yf, HFO-1234ze, and HCFO-1233zd.

Atmospheric Degradation Initiated by OH Radicals of the Potential Foam Expansion Agent, CF3(CF2)2CH═CH2 (HFC-1447fz): Kinetics and Formation of Gaseous Products and Secondary Organic Aerosols.

The assessment of the atmospheric impact of the potential foam expansion agent, CF3(CF2)2CH═CH2 (HFC-1447fz), requires the knowledge of its degradation routes, oxidation products, and radiative properties. In this paper, the gas-phase reactivity of HFC-1447fz with OH radicals is presented as a function of temperature, obtaining kOH (T = 263-358 K) = (7.4 ± 0.4) × 10(-13)exp{(161 ± 16)/T} (cm(3)·molecule(-1)·s(-1)) (uncertainties: ±2σ). The formation of gaseous oxidation products and secondary organic aerosols (SOAs) from the OH + HFC-1447fz reaction was investigated in the presence of NOx at 298 K. CF3(CF2)2CHO was observed at low- and high-NOx conditions. Evidence of SOA formation (ultrafine particles in the range 10-100 nm) is reported with yields ranging from 0.12 to 1.79%. In addition, the absolute UV (190-368 nm) and IR (500-4000 cm(-1)) absorption cross-sections of HFC-1447fz were determined at room temperature. No appreciable absorption in the solar actinic region (λ > 290 nm) was observed, leaving the removal by OH radicals as the main atmospheric loss process for HFC-1447fz. The major contribution of the atmospheric loss of HFC-1447fz is due to OH reaction (84%), followed by ozone (10%) and chlorine atoms (6%). Correction of the instantaneous radiative efficiency (0.36 W m(-2)·ppbv(-1)) with the relatively short lifetime of HFC-1447fz (ca. 8 days) implies that its global warming potential at a time horizon of 100 year is negligible (0.19) compared to that of HCFC-141b (782) and to that of modern foam-expansion blowing agents (148, 882, and 804 for HFC-152a, HFC-245fa and HFC-365mfc, respectively).

An outbreak of refrigerant-induced acute hepatitis in Hong Kong.

We report a cluster of acute hepatitis in five air-conditioning maintenance workers following accidental exposure to 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123). They presented to us with complaints of feverishness, generalised malaise, and epigastric discomfort. Their blood biochemistry tests were compatible with acute hepatitis. Viral hepatitis serology, tests for autoimmune hepatitis, and analyses for drugs and alcohol consumption were all negative. No focal hepatic lesion was detected by ultrasound imaging. Percutaneous liver biopsy samples were taken from two of them. The patients were managed with supportive treatment. All had spontaneous, but slow, recovery. Their liver function tests returned to normal after 4 months and their outcomes were favourable. Physicians should be aware of this occupational disease entity.

Immunosuppressant medication behaviours in solid organ transplant recipients: a cross-sectional study from south-central China during COVID-19 reopening period.

OBJECTIVE: Medication non-adherence to immunosuppressants threatens allograft survival and function maintenance among solid organ transplant (SOT) recipients. This study aimed to investigate the prevalence of immunosuppressant medication non-adherence and associated factors during the COVID-19 reopening period among Chinese SOT recipients. DESIGN: Cross-sectional study. SETTING: South-central China. POPULATION: Adult patients who received SOT with functioning graft. METHODS: Sociodemographic questionnaire and scales to measure physical activity, depression and medication non-adherence were used to collect data. Logistic regression analysis was conducted to identify factors associated with medication non-adherence. Mediation and moderated mediation analyses were performed to examine the potential mechanisms influencing medication behaviour during the pandemic reopening period using SPSS PROCESS macro 4.3 software. RESULTS: A total of 1121 participants were recruited and the prevalence of medication non-adherence was 36.3% in this study. Recipients who were men, had a higher monthly income, lived alone, had received transplantation for a minimum of 3 years, had received COVID-19 vaccination and experienced depressive symptoms exhibited an increased risk of non-adherence. Contrarily, those who engaged in high-intensity physical activity exhibited a decreased risk. Physical activity was negatively associated with medication non-adherence (r=-0.124, p<0.001) with depression fully mediating this relationship (B=-0.014, 95% CI: -0.032 to -0.003). COVID-19 vaccination significantly moderated the relationship between physical activity and depression (B=-0.303, 95% CI: -0.515 to -0.090). CONCLUSION: This study investigated the prevalence of medication non-adherence among SOT recipients during the COVID-19 reopening period in China, its associated factors and a potential mechanism. Depression fully mediated the association between physical activity and medication non-adherence, and COVID-19 vaccination moderated the relationship between physical activity and depression. These findings provide some insights for managing medication behaviour when confronting public health emergencies. However, relationships displayed in the moderated mediation model should be tracked after returning to normal life and other potential relationships should be explored to deeply understand medication non-adherent behaviour.

Reformulation of Stmerin(®) D CFC formulation using HFA propellants.

Stmerin(®) D was reformulated using hydrofluoroalkanes (HFA-134a and HFA-227) as alternative propellants instead of chlorofluorocarbons (CFCs), where the active ingredients were suspended in mixed CFCs (CFC-11/CFC-12/CFC-114). Here, we report the suspension stability and spray performance of the original CFC formulation and a reformulation using HFAs. We prepared metered dose inhalers (MDI) using HFAs with different surfactants and co-solvents, and investigated the effect on suspension stability by visual testing. We found that the drug suspension stability was poor in both HFAs, but was improved, particularly for HFA-227, by adding a middle chain fatty acid triglycerides (MCT) to the formulation. However, the vapor pressure of HFA-227 is higher than a CFC mixture and this increased the fine particle dose (FPD). Spray performance was adjusted by altering the actuator configuration, and the performance of different actuators was tested by cascade impaction. We found the spray performance could be controlled by the configuration of the actuator. A spray performance comparable to the original formulation was obtained with a 0.8 mm orifice diameter and a 90° cone angle. These results demonstrate that the reformulation of Stmerin(®) D using HFA-227 is feasible, by using MCT as a suspending agent and modifying the actuator configuration.

How to improve reliability in groundwater analysis: over a decade of experience with external quality control in field campaigns on volatile halogenated compounds.

The reliability in measurement results obtained during environmental monitoring is crucial for the assessment and further planning of remediation efforts on the respective contaminated sites by the responsible authorities. A case study concerned with groundwater contaminated with perchloroethylene, trichloroethylene and 1,1,2-trichlorotrifluoroethane including their degradation products which involves private contract laboratories and an independent provider of quality assurance (QA) is presented. The experience gained with biannual monitoring campaigns over 14 years indicates that the selection of contractors on basis of accreditation status and successful performance in interlaboratory comparisons are not sufficient. Rather the auditing of the contractors by the QA provider prior to each campaign and the crosschecking of selected monitoring samples by the QA provider led to a lasting improvement of reliability in the contractors' measurement results. A mean deviation of 20% from the reference value determined by the QA provider for the crosschecked samples was reached.

Acute liver failure caused by occupational exposure to HCFC-123: Two case reports.

RATIONALE: Hydrochlorofluorocarbon 123 (HCFC-123, Freon123; 2,2-dichloro-1,1,1-trifluoroethane) has been widely used in refrigeration and heat-transfer applications as a substitute for chlorofluorocarbons due to its lower ozone-depleting potentials. Occupational exposure to HCFC-123 may cause mild reversible hepatoxicity, but no fatal cases have been reported yet. PATIENT CONCERNS: In this report, we present cases of severe hepatitis with fatal outcome by HCFC-123. Two industrial workers from a manufacturing factory of fire extinguishers which use HCFC-123 were presented with diarrhea, fever, myalgia, and jaundice. Patients had been repeatedly exposed to the liquid form of HCFC-123 for the past three weeks before flare of symptoms. DIAGNOSIS: The blood biochemistry tests showed acute cholestatic hepatitis and liver biopsy findings indicated inflammatory hepatocellular injury. The diagnosis of HCFC-123 induced hepatitis was made. INTERVENTIONS: The treatment for both patients were generally supportive. The second patient went through hemodialysis, ventilatory care, and artificial liver support therapy (molecular adsorbent recirculating system) at intensive care unit. OUTCOMES: One patient recovered uneventfully, whereas the other patient showed rapid deterioration leading to acute liver failure complicated with cerebral edema, subdural hemorrhage, and death on hospital day 10. LESSONS: The HCFC-123-induced hepatitis showed similarities with halothane hepatitis, both of which may share pathophysiologic mechanisms. Exposure to HCFC-123 needs to be listed as a potential cause of acute liver failure, and to be considered in patients with acute hepatitis of uncertain etiology and negative viral serology.

pH-sensitive pullulan-doxorubicin nanoparticles loaded with 1,1,2-trichlorotrifluoroethane as a novel synergist for high intensity focused ultrasound mediated tumor ablation.

Nanoemulsions as synergists of high intensity focused ultrasound (HIFU) have been widely investigated, since they possess huge potential for improving the efficiency to ablate tumor. However, their clinical applications are limited due to the unsatisfactory phase-transition effect of nanoemulsions during the process of generating nanobubbles. Herein, a novel synergist for HIFU therapy was designed by encapsulating 1,1,2-trichlorotrifluoroethane (CFC) into pH-sensitive pullulan-doxorubicin (Pu-DOX/CFC) nanoparticles. These Pu-DOX/CFC nanoemulsions, with moderate vaporization temperature threshold of 47 °C, could provide favorable phase-transition effect, thus facilitating HIFU energy deposition. Meanwhile, Pu-DOX/CFC nanoemulsions could effectively deliver DOX/CFC to the tumor site and carry out combined therapy. The in vitro and in vivo results confirmed that Pu-DOX/CFC nanoemulsions notably enhanced both ablation and therapeutic efficiency comparing with other synergists. In conclusion, Pu-DOX/CFC nanoemulsions might serve as a novel synergist for HIFU therapy, and possess great potential in clinical implication.

Transport of hydrocarbons from an emplaced fuel source experiment in the vadose zone at Airbase Vaerløse, Denmark.

An emplaced hydrocarbon source field experiment was conducted in the relatively homogeneous sandy geology of the vadose zone at Airbase Vaerløse, Denmark. The source (10.2 l of NAPL) consisted of 13 hydrocarbons (n-, iso- and cyclo-alkanes and aromates) and CFC-113 as a tracer. Monitoring in the 107 soil gas probes placed out to 20 m from the centre of the source showed spreading of all the compounds in the pore air and all compounds were measured in the pore air within a few hours after source emplacement. Seven of the fourteen compounds were depleted from the source within the 1 year of monitoring. The organic vapours in the pore air migrated radially from the source. The CFC-113 concentrations seemed to be higher in the deeper soil gas probes compared with the hydrocarbons, indicating a high loss of CFC-113 to the atmosphere and the lack of degradation of CFC-113. For the first days after source emplacement, the transport of CFC-113, hexane and toluene was successfully simulated using a radial gas-phase diffusion model for the unsaturated zone. Groundwater pollution caused by the vadose zone hydrocarbon vapours was only detected in the upper 30 cm of the underlying groundwater and only during the first 3 months of the experiment. Only the most water-soluble compounds were detected in the groundwater and concentrations decreased sharply with depth (approximately one order of magnitude within 10 cm depth) to non-detect at 30 cm depth. The groundwater table varied more than 1 m within the measurement period. However that did not influence the direction of the groundwater flow. Approximately 7 months after source emplacement the groundwater table rose more than 1 m within 1 month. That did not cause additional pollution of the groundwater.

Interaction of fluoroethane chlorofluorocarbon (CFC) substitutes with microsomal cytochrome P450. Stimulation of P450 activity and chlorodifluoroethene metabolism.

The abilities of halothane and the fluoroethane chlorofluorocarbon (CFC) substitutes, FC-123, FC-133a, FC-124, FC-134a and FC-125, to stimulate cytochrome P450 activities and 2-chloro-1,1-difluoroethene (CDE) defluorination in hepatic microsomes from phenobarbital-treated rabbits were compared. At 1% (v/v) each, halothane and FC-123 similarly increased the consumption of NADPH and O2 by 300 and 100%, respectively, over that in microsomes without substrate. FC-133a and FC-124 were less effective, increasing NADPH and O2 consumption by 150-200 and 70%. FC-134a and FC-125 were the least effective, increasing NADPH and O2 consumption by only 70 and 50%, respectively. No metabolism of any fluoroethane could be detected under the incubation conditions used. Halothane and FC-123 were most effective in stimulating CDE metabolism with increases of CDE defluorination ranging from 1.5- to 2-fold. FC-133a and FC-124 enhanced CDE oxidation 89 and 74%, respectively, and FC-134a and FC-125 had no effect. While CDE metabolism was enhanced in the presence of the fluoroethanes, no additional NADPH or O2 was consumed when halothane or FC-124 was incubated with CDE compared with incubations containing only halothane or FC-124. Log-log plots of NADPH consumption and CDE metabolism with the olive oil/gas partition coefficients of each fluoroethane showed linear relationships. These data demonstrate that the activity of the fluoroethanes in stimulating P450 activity and CDE metabolism is a function of their lipid solubility, and fluoroethane-enhanced CDE metabolism is related to the ability of these compounds to increase uncoupled P450 activity.

Toxicology of chlorofluorocarbon replacements.

Chlorofluorocarbons (CFCs) are stable in the atmosphere and may reach the stratosphere. They are cleaved by UV-radiation in the stratosphere to yield chlorine radicals, which are thought to interfere with the catalytic cycle of ozone formation and destruction and deplete stratospheric ozone concentrations. Due to potential adverse health effects of ozone depletion, chlorofluorocarbon replacements with much lower or absent ozone depleting potential are developed. The toxicology of these compounds that represent chlorofluorohydrocarbons (HCFCs) or fluorohydrocarbons (HFCs) has been intensively studied. All compounds investigated (1, 1-dichloro-1-fluoroethane [HCFC-141b], 1,1,1,2-tetrafluoroethane [HFC-134a], pentafluoroethane [HFC-125], 1-chloro- 1,2,2,2-tetrafluoroethane [HCFC-124], and 1,1-dichloro-2,2,2-trifluoroethane [HCFC-123]) show only a low potential for skin and eye irritation. Chronic adverse effects on the liver (HCFC-123) and the testes (HCFC-141b and HCFC-134a), including tumor formation, were observed in long-term inhalation studies in rodents using very high concentrations of these CFC replacements. All CFC replacements are, to varying extents, biotransformed in the organism, mainly by cytochrome P450-catalyzed oxidation of C-H bonds. The formed acyl halides are hydrolyzed to give excretable carboxylic acids; halogenated aldehydes that are formed may be further oxidized to halogenated carboxylic acids or reduced to halogenated alcohols, which are excretory metabolites in urine from rodents exposed experimentally to CFC replacements. The chronic toxicity of the CFC replacements studied is unlikely to be of relevance for humans exposed during production and application of CFC replacements.

Fluorinated oils as experimental vitreous substitutes.

Two kinds of fluorinated oils (a fluorosilicone oil and a perfluoroether [Freon E15]) that have a higher density than water were evaluated as long-term vitreous substitutes. Vitreous compression using perfluoropropane gas was performed to create a space for the vitreous substitute in rabbit eyes. Two fluorosilicone oils (1000 and 10 000 centistokes) induced edema of the inner retinal layers and occasionally of the outer retinal layers regardless of viscosity or period of observation up to six months, but they were well tolerated clinically. Control eyes injected with silicone oils of comparable viscosities showed similar histopathologic findings. Freon E15 induced formation of bubbles and precipitates by one month after injection, and retinal disorganization, formation of preretinal membranes, and tractional retinal detachment by six months. Thus, Freon E15 proved to be unsuitable, but fluorosilicone oil is a possible high-density vitreous substitute.

Basic characteristics and evaluation of a partially automated Behring laser nephelometer for the measurement of IgG, IgA, IgM and C3c in serum.

We have evaluated a partially automated Behring laser nephelometer for the measurement of IgG, IgA, IgM and C3c in serum. The system consisted of a manual Behring laser nephelometer, an automatic cuvette carrier and a Hewlett-Packard 9815 A calculator/printer. The system could process 240 preincubated samples per h when the interval between each voltage reading was set at 15 s. Day-to-day precision was near 6%. We obtained the worst precision for the determination of IgG which requires the smallest volume of diluted sample (10 microliters). The Frigen treatment used to clarify turbid sera seems to decrease IgG and increase C3c concentrations. The addition of polyethylene glycol 6000 at a concentrations of 40 micro/L in the reaction mixture did not improve the assay ranges. Comparison studies with radial immunodiffusion for the four proteins and with the IgM - BMC Immunological Turbidity Test using either least-squares or Deming's regressions gave very good correlation figures, except for C3c and for some IgM paraproteins. We could decrease the cost per test by re-using the plastic cuvettes. The utilization of the calculator-printer greatly simplified data handling but the automatic carrier was not considered a real asset without complete automation.

Surface free energy of a solid from contact angle hysteresis.

Nature of contact angle hysteresis is discussed basing on the literature data (Colloids Surf. A 189 (2001) 265) of dynamic advancing and receding contact angles of n-alkanes and n-alcohols on a very smooth surface of 1,1,2,-trichloro-1,2,2,-trifluoroethane (FC-732) film deposited on a silicon plate. The authors considered the liquid absorption and/or retention (swelling) processes responsible for the observed hysteresis. In this paper hysteresis is considered to be due to the liquid film left behind the drop during retreating of its contact line. Using the contact angle hysteresis an approach is suggested for evaluation of the solid surface free energy. Molecular spacing and the film structure are discussed to explain the difference in n-alkanes and n-alcohols behaviour as well as to explain the difference between dispersion free energy gamma(s)(d) and total surface free energy gamma(s)(tot) of FC-732, as determined from the advancing contact angles and the hysteresis, respectively.

Dose-related hepatotoxicity of 1,1,2-trichloro-1,2,2-trifluoroethane in short-term intermittent inhalation exposure in rats.

Male Wistar rats were exposed to 200, 1000 or 2000 ppm of 1,1,2-trichloro-1,2,2-trifluoroethane vapor 5 days a week 6 h daily for 1 or 2 weeks. Proliferation and vacuolisation of the smooth endoplasmic reticulum (SER) of the liver was seen electron microscopically after 1 and 2 weeks in the rats exposed to 1000 and 2000 ppm. Among the hepatic drug metabolizing enzymes, NADPH cytochrome c reductase activity showed a dose-related decrease whereas the tightly membrane-bound UDPglucuronosyltransferase exhibited a dose-dependent enhancement in its measurable activity. The overall drug oxidation reaction, 7-ethoxycoumarin O-deethylase was not affected by the 1,1,2-trichloro-1,2,2,-trifluoroethane inhalation at all, either in the liver or in the kidneys. 1,1,2-Trichloro-1,2,2-trifluoroethane binds to cytochrome P-450 with the production of a type I difference spectrum, suggesting that it may act as a substrate for this enzyme. The binding affinity is increased by phenobarbital-treatment of the rats.

Neoantigen formation and clastogenic action of HCFC-123 and perchloroethylene in human MCL-5 cells.

In this study, the metabolic activation of 2,2-dichloro-1,1,1-trifluoroethane (hydrochlorofluorocarbons-123, HCFC-123), halothane or 1,1-dichloro-1-fluoroethane (HCFC-141b) was compared to that of perchloroethylene, using lymphoblastoma derived cell lines expressing human CYP1A1, CYP1A2, CYP2E1, CYP2A6 and CYP3A4 (MCL-5 cells). A dose dependent increase in micronucleus formation was detected over a nominal concentration range of 0.05-2 mM for HCFC-123 and halothane, but this was not seen with HCFC-141b. No dose response for HCFC-123 was seen in a control cHo1 cell line not expressing this cytochrome P450's. Cell lines expressing individual human cytochrome P-450 (CYP) forms were also used to define the enzymes responsible for the clastogenic events and to investigate the formation of immunoreactive protein by microsomal fractions. It was shown that CYP2E1 or CYP2B6 catalysed the clastogenic response, but CYP2D6, CYP3A4, CYP1A2 or CYP1A1 all appeared to be inactive. The formation of neoantigenic trifluoroacetylated protein adducts by microsomal mixtures incubated with HCFC-123 and NADPH was catalysed primarily by CYP2E1 and to a lesser extent by CYP2C19, whereas, only trace levels of immunoreactive protein were seen with microsomes expressing CYP2B6 or CYP2C8. With perchloroethylene as a substrate, the extent of activation was low in comparison with HCFC-123, as judged by the absence of micronuclei formation in the MCL-5 cell line and the weak immunoreactivity of proteins following Western blotting. CYP1A2, CYP2B6 and CYP2C8 appeared to be responsible for perchloroethylene immunoreactivity and in contrast to the findings with the HCFC's, no activation of perchloroethylene by CYP2E1 could be detected. These results show that even though both saturated and unsaturated halocarbons can result in neoantigen formation, there is a marked difference in the specificity of the CYP enzymes involved in their metabolic activation.

The role of CYP forms in the metabolism and metabolic activation of HCFCs and other halocarbons.

The use of hydrochlorofluorocarbons (HCFCs) such as HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and HCFC-141b (1,1-dichloro-1-fluoroethane) is becoming widespread as replacements for the ozone depleting chlorofluorocarbons. Hepatic activation of HCFC-123 or the unsaturated perchloroethylene through oxidative pathways leads to the formation of the electrophiles trifluoroacetyl chloride or trichloroacetyl chloride, respectively. These can react with epsilon-NH(2) functions of lysine in proteins and give rise to neoantigens. In the case of HCFC-123, this reaction is catalysed primarily by CYP2E1 and to a much lesser extent by the constitutive CYP2C19, CYP2B6 and CYP2C8. For perchloroethylene, the extent of activation is less and the reaction is catalysed primarily by the CYP2B family. While acute hepatotoxicity has been seen in humans exposed to HCFC-123 or halothane, little short- or long-term toxicity in rodents is observed. No immunological related toxicity of perchloroethylene has been reported in exposed humans. Long-term exposure of rats can lead to renal tubule carcinomas and in mice, hepatocellular carcinomas. These toxic reactions do not appear to be directly related to the formation of the putative trichloroacetyl chloride intermediate.