Modeling cardiac sensitization potential of humans exposed to Halon 1301 or Halon 1211 aboard aircraft.

BACKGROUND: Halon 1301 and Halon 1211 are being replaced because they contribute to the depletion of ozone. Many of the potential candidate chemicals for replacing them are, like them, halogenated hydrocarbons. These chemicals have the potential to cause cardiac sensitization at high enough exposure concentrations. METHODS: A physiologically based pharmacokinetic model, which mathematically describes the uptake, distribution, metabolism, and elimination of chemicals, was used to relate exposure to these chemicals with arterial blood concentrations resulting from the exposure. This information was then used to evaluate the potential for the occurrence of a cardiac-sensitizing event. The model was used to analyze the exposures to Halon 1301 and Halon 1211 in three aircraft (Navy E-2B, Cessna-421B, and Cessna-210C). RESULTS: Halon 1301 exposures were shown to be safe, but Halon 1211 resulted in arterial concentrations in exposed individuals that reached levels that could potentially cause cardiac sensitization. CONCLUSIONS: Use of the model for evaluating the risk from exposure to Halon 1301 and Halon 1211 is a moot point since both chemicals are being replaced. However, demonstration of the validity of the approach provides a tool for the evaluation of the health safety of replacement candidates. The National Fire Protection Association has approved use of this model for assessing times for safe egress from situations where agents are used to flood an area to extinguish a fire.

PBPK modeling of canine inhalation exposures to halogenated hydrocarbons.

Human exposure guidelines for halogenated hydrocarbons (halons) and halon replacement chemicals have been established using dose-response data obtained from canine cardiac sensitization studies. In order to provide a tool for decision makers and regulators tasked with setting guidelines for egress from exposure to halon replacement chemicals, a quantitative approach, using a physiologically based pharmacokinetic model, was established that allowed exposures to be assessed in terms of the chemical concentrations in blood during the exposure. This model, which includes a respiratory tract compartment containing a dead-space region, a pulmonary exchange area, and a breath-by-breath description of respiratory tract uptake, allows successful simulation of exhaled breath concentrations of humans during the first minute of exposure to the anesthetics halothane, isoflurane, and desflurane. In the current study, the human model was modified with canine parameters and validated with data obtained from dog studies with halothane, isoflurane, desflurane, and CFC-11. With consideration of appropriate values for ventilation and cardiac output, the model successfully simulated data collected under a variety of exposure scenarios. The canine model can be used for simulating blood concentrations associated with the potential for cardiac sensitization. These target blood concentrations can then be used with the human model for establishing safe human exposure duration. Development of the canine model stresses the need for appropriate data collection for model validation.

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.

Reproductive toxicity screen of trifluoroiodomethane (CF(3)I) in Sprague-Dawley rats.

CF(3)I is being considered by the U.S. Air Force as a replacement for Halon 1301 for fire-extinguishing requirements in unoccupied spaces. The purpose of this study was to determine and evaluate the potential for CF(3)I to produce reproductive toxicity and to provide additional information on the effect of CF(3)I exposure on the thyroid. Groups of 16 male and 16 female rats were exposed (6 h/day) to CF(3)I vapor at concentrations of 0 (control), 0.2, 0.7, and 2.0% using whole-body inhalation chambers. Prior to mating, rats were exposed to CF(3)I for 4 wk (5 days/wk). Exposures were 7 days/wk during the periods of mating (2 wk), gestation (3 wk), and lactation (3 wk). First-generation pups were not exposed to CF(3)I vapor. In parental animals, there were no clinical signs of toxicity except for a minimal decrease in mean body weight in female rats at 2.0% CF(3)I. At necropsy, gross findings, mean serum chemistry levels, mean hematology values, mean bone marrow micronuclei scores, and mean organ weights were similar for all exposure groups, including the air control group. Statistically significant differences did not show a pattern and/or were considered incidental. There were no treatment-related microscopic tissue findings, including the thyroid organ. Analysis of reproductive indices and parameters indicates CF(3)I is not a reproductive toxicant. Results of serum thyroid hormone levels (e.g., T(3), T(4), rT(3), and TSH), showed concentration-related increases in TSH, T(4), and rT(3). T(3) levels were decreased. First-generation pup survival and mean body weights were similar in all exposure groups, including the control. Exposure of 2.0% CF(3)I vapor for approximately 14 wk produced minimal general toxicity and no reproductive toxicity in Sprague-Dawley rats. On the basis of reproductive indices and parameters, the NOAEL for this study is 2.0% CF(3)I.

Simulated blood levels of CF3I in personnel exposed during its release from an F-15 jet engine nacelle and during intentional inhalation.

Of the agents under consideration for protecting unoccupied areas from fire, CF3I (trifluoroiodomethane) has physicochemical properties that give it potential as a "drop-in" replacement for halon 1301. One of the issues concerning the use of CF3I is the potential hazard to ground crews should an inadvertent discharge occur while workers are in or near an engine nacelle. A discharge test of CF3I was conducted on an F-15A jet to record CF3I concentration time histories at locations near the aircraft. The conditions of the discharges simulated an inadvertent ground discharge with the engine nacelle doors open and also with the doors closed. The use of three types of gas analysis instrumentation allowed gas sampling from several locations during the discharge tests. Concentrations measured at selected sensor locations were used as the input to a physiologically based pharmacokinetic model to simulate blood levels that would be attained by individuals inhaling CF3I at sensor locations. Blood levels reached during these exposures were compared with the blood level associated with the lowest observable adverse effect level (LOAEL) for cardiac sensitization to evaluate the possibility of safe egress. The highest blood concentrations simulated were twice the target blood concentration associated with cardiac sensitization. However, simulated blood concentrations of subjects who actually inhaled CF3I reached levels that were 100 times the target level without reported adverse effect. Thus, actual human data may supersede the use of the cardiac sensitization LOAEL obtained from animal studies.

Cardiac sensitization testing of the halon replacement candidates trifluoroiodomethane (CF3I) and 1,1,2,2,3,3,3-heptafluoro-1-iodopropane (C3F7I).

Trifluoroiodomethane (CF3I) and 1,1,2,2,3,3,3-heptafluoro-1-iodopropane (C3F7I) have been considered as replacement candidates for halon fire suppressants due to their excellent fire extinguishant capabilities and low ozone depletion potential compared to halon fire extinguishants in use currently. As part of the process to develop environmental and health effects criteria for halon substitutes, a cardiac sensitization test was conducted in beagle dogs. Cardiac sensitization to adrenaline is a phenomenon associated with the inhalation of a number of unsubstituted and halogenated hydrocarbons. Adrenaline was administered by intravenous injection before and during inhalation of the test substance. CF3I was administered to dogs at concentrations in air of 0.1, 0.2, 0.4 or 1% v/v. At each of 0.4 and 1.0% CF3I, the first dog exposed developed fatal ventricular fibrillation, and no further dogs were exposed at these concentrations. There was no cardiac sensitization at 0.1 or 0.2% CF3I. For the C3F7I experiment, dogs were exposed to concentrations in air of 0.1, 0.2 or 0.4% v/v. At each of 0.1 and 0.4% C3F7I, one dog responded with multifocal ventricular ectopic beats. Thus, CF3I and C3F7I are potent cardiac sensitizers in the adrenaline-challenged dog model.

Acute and subchronic inhalation studies on trifluoroiodomethane vapor in Fischer 344 rats.

Trifluoroiodomethane (CF3I) is being considered as a replacement compound for halon fire suppressants. Its structure is similar to that of Halon 1301 (CF3Br), but it has very low ozone depletion potential compared to CF3Br. As part of the process of developing environmental and health effects criteria, acute, 2-week, and 13-week nose-only inhalation toxicity studies were conducted in Fischer 344 rats. In the acute study, three groups of 30 male rats each were exposed to 0 (control), 0.5, or 1.0% (v/v) CF3I for 4 hr and euthanized immediately following exposure, 3 days postexposure, or 14 days postexposure. There were no deaths and no clinical signs of toxicity throughout the study. Histopathologic examination of select tissues showed no lesions of pathologic significance. In the 2-week study, four groups of 5 male rats each were exposed for 2 hr/day, 5 days/week to 0, 3, 6, or 12% CF3I. No deaths were observed, though lethargy and slight incoordination were noted in rats of the 6 and 12% groups at the conclusion of each daily exposure. Mean body weight gains were depressed in rats of the 6 and 12% groups. Serum thyroglobulin and reverse T3 (rT3) values were increased at all exposure levels. At necropsy, no gross lesions or differences in absolute or relative organ weights were noted. Histopathologic examination of the thyroid and parathyroid glands indicated no morphological abnormalities in the CF3I-exposed rats. In the 13-week study, four groups of 15 male and 15 female rats were exposed to 0, 2, 4, or 8% CF3I 2 hr/day, 5 days/week for 13 weeks. Rats exposed to 4 or 8% CF3I had lower mean body weights than the controls. Deaths observed in the 2 and 8% groups were attributed to accidents resulting from the restraint system employed. Hematologic alterations were minimal and considered insignificant. Increases in the frequency of micronucleated bone marrow polychromatic erythrocytes were observed in rats of all three CF3I groups. Serum chemistry alterations observed in rats of all CF3I exposure groups included decreases in T3 and increases in thyroglobulin, rT3, T4, and TSH. Relative organ weight increases (8% CF3I group) occurred in the brain, liver, and thyroid glands; decreases were observed in the thymus and testes. A decrease in relative thymus weights and an increase in relative thyroid weights were observed also in rats of the 2 and 4% groups. Histopathological findings included a mild inflammation in the nasal turbinates of rats exposed to 4 or 8% CF3I, mild atrophy and degeneration of the testes (4 and 8% CF3I groups), and a mild increase in thyroid follicular colloid content in rats of all CF3I exposure groups. Though NOAELs were observed for select target organs (e.g., nasal turbinates, testes), NOAELs were not apparent in all target organs examined (e.g., thyroid glands, bone marrow).

Cardiac sensitization thresholds of halon replacement chemicals predicted in humans by physiologically-based pharmacokinetic modeling.

Human exposure to halons and halon replacement chemicals is often regulated on the basis of cardiac sensitization potential. The dose-response data obtained from animal testing are used to determine the no observable adverse effect level (NOAEL) and lowest observable adverse effect level (LOAEL) values. This approach alone does not provide the information necessary to evaluate the cardiac sensitization potential for the chemical of interest under a variety of exposure concentrations and durations. In order to provide a tool for decision-makers and regulators tasked with setting exposure guidelines for halon replacement chemicals, a quantitative approach was established which allowed exposures to be assessed in terms of the chemical concentrations in blood during the exposure. A physiologically-based pharmacokinetic (PBPK) model was used to simulate blood concentrations of Halon 1301 (bromotrifluoromethane, CF3Br), HFC-125 (pentafluoroethane, CHF2CF3), HFC-227ea (heptafluoropropane, CF4CHFCF3), HCFC-123 (dichlorotrifluoroethane, CHCl2CF3), and CF3I (trifluoroiodomethane) during inhalation exposures. This work demonstrates a quantitative approach for use in linking chemical inhalation exposures to the levels of chemical in blood achieved during the exposure.

Rat to human extrapolation of HCFC-123 kinetics deduced from halothane kinetics: a corollary approach to physiologically based pharmacokinetic modeling.

The goal of this study was to develop a human physiologically based pharmacokinetic (PBPK) model for the chemical HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and its major metabolite, trifluoroacetic acid (TFA). No human kinetic data for HCFC-123 are available, thus a corollary approach was developed. HCFC-123 is a structural analog of the common anesthetic agent halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) and follows a common pathway of oxidative biotransformation, resulting in the formation of the same metabolite, TFA. In this study, halothane models for rats and humans were developed and validated. Then the corollary approach was used to develop a human HCFC-123 model from a rat HCFC-123 model. This strategy was implemented by using a previously validated PBPK model for HCFC-123/TFA in the Fisher 344 rat as a template model for halothane in rats. Model predictions were then compared to, and were in good agreement with, measured values for the concentration of halothane in rat blood and fat tissue. A human PBPK model for halothane was developed. The identical mode structure (with the exception of the description for the fat compartment) that was used to describe halothane and TFA in the rat was used for describing halothane and TFA in the human. Human physiological parameters for tissue volumes and flows were taken from the literature, and human tissue partition coefficients for halothane were measured in the laboratory. Based on reported similarity in metabolism of halothane by humans and rats, metabolic constants for halothane in the rat were used in the human model, and specific parameters describing the kinetics of TFA were estimated by optimization. The model was validated against human exposure data for halothane from six published studies (expired breath concentrations of halothane and serum/urine data for TFA). A similar approach was then used to derive a human HCFC-123 model for humans from the HCFC-123 rat model. The corollary approach described here illustrates the innovative use of template model structures to aid in the development and validation of models for structural analogs with similar metabolism and activity in biologic systems. Furthermore, given that the PBPK model adequately describes the kinetics of halothane in rats and humans and of HCFC-123 in rats, use of the human PBPK model is proposed for deriving dose-response estimates of human health risks in the absence of human kinetic data.

Dose-dependent metabolism of 2,2-dichloro-1,1,1-trifluoroethane: a physiologically based pharmacokinetic model in the male Fischer 344 rat.

2,2-Dichloro-1,1,1-trifluorethane (HCFC-123) is used industrially as a refrigerant, as a foam blowing agent, and as a solvent. It is also being considered as a replacement for halons and chlorinated fluorocarbons which have been banned by the Montreal Protocol because they deplete atmospheric ozone. Male Fischer 344 rats were exposed to 1.0, 0.1, and 0.01% HCFC-123 by inhalation. Parent compound was measured in blood, fat, and exhaled breath and trifluoroacetic acid (TFA) was measured in blood and urine. A physiologically based pharmacokinetic (PBPK) model was developed which included a gut compartment and a variable size fat compartment in addition to the standard flow-limited compartments. Compartment volumes and flows were chosen from the literature, partition coefficients were measured in the laboratory, and metabolic parameters were optimized from experimental data using model simulations. Laboratory experiments showed that the TFA blood concentration during the 1.0% exposure was more than 50% less than the TFA blood concentration during the 0.1% exposure. After cessation of the 4-hr exposure, TFA blood concentrations from the 1.0% exposure rebounded and peaked between 12 and 26 hr after the exposure at about the same concentration as the 0.1% peak. This rebound phenomenon suggested that it was not killing of the metabolic enzymes but substrate inhibition that made the TFA blood concentrations lower than expected. Substrate inhibition by halothane, a structural analog of HCFC-123, has been described in the literature. Only by including a term for substrate inhibition in the PBPK model could pharmacokinetic data for TFA in blood be simulated adequately. This combination of laboratory experimentation and PBPK modeling can be applied to relate the levels of parent and metabolite to toxic effects with some hope of elucidating the toxic species. This work is the first step toward developing models that can be used to predict the toxicokinetics of HCFC-123 in humans throughout various potential use scenarios.

Hepatotoxicity in guinea pigs following acute inhalation exposure to 1,1-dichloro-2,2,2-trifluoroethane.

Groups of 10 male Hartley guinea pigs were exposed to 3.0, 2.0, 1.0, or 0.1% (v/v) 1,1-Dichloro-2,2,2-trifluoroethane (HCFC-123) or 1.0% (v/v) halothane by inhalation for 4 hr. A sixth group of 10 guinea pigs received only air. All animals were sacrificed 48 hr postexposure. Gross and histopathologic examination of the liver, heart, and kidney and routine hematology and clinical chemistry analyses [including isocitrate dehydrogenase (ICDH)] were done on all guinea pigs. Lesions related to HCFC-123 and halothane exposure were limited to the liver and included centrolobular vacuolar (fatty) change, multifocal random degeneration and necrosis, and centrolobular degeneration and necrosis. These lesions were observed in 90-100% of the exposed animals and were absent in the air-only controls. There was significant individual animal variation in susceptibility to both HCFC-123 and halothane, resulting in a spectrum of histologic lesions and clinical chemistry values within each exposure group. Alanine aminotransferase, aspartate aminotransferase, and ICDH were the most significant predictors of hepatocellular damage. Similarities in the response between halothane and HCFC-123 in this guinea pig model suggests that humans susceptible to halothane-induced hepatitis may be susceptible to HCFC-123 by a common mechanism of toxicity.

Mechanistic insights aid the search for CFC substitutes: risk assessment of HCFC-123 as an example.

An international consensus on the need to reduce the use of chlorofluorocarbons (CFCs) and other ozone-depleting gases such as the halons led to the adoptions of the 1987 Montreal Protocol and Title VI of the 1990 Clean Air Act Amendments, "Protecting Stratospheric Ozone." These agreements included major provisions for reducing and eventually phasing out production and use of CFCs and halons as well as advancing the development of replacement chemicals. Because of the ubiquitous use and benefits of CFCs and halons, an expeditious search for safe replacements to meet the legislative deadlines is of critical importance. Toxicity testing and health risk assessment programs were established to evaluate the health and environmental impact of these replacement chemicals. Development and implementation of these programs as well as the structural-activity relationships significant for the development of the replacement chemicals are described below. A dose-response evaluation for the health risk assessment of the replacement chemical HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) is also presented to show an innovative use of physiologically based pharmacokinetic (PBPK) modeling. This is based on a parallelogram approach using data on the anesthetic gas halothane, a structural analog to HCFC-123. Halothane and HCFC-123 both form the same metabolite, trifluoroacetic acid (TFA), indicative of the same metabolic oxidative pathway attributed to hepatotoxicity. The parallelogram approach demonstrates the application of template model structures and shows how PBPK modeling, together with judicious experimental design, can be used to improve the accuracy of health risk assessment and to decrease the need for extensive laboratory animal testing.

Metabolism and pharmacokinetics of selected halon replacement candidates.

Metabolism studies were conducted using Fischer 344 and Sprague-Dawley rats following inhalation exposure to 1.0% (v/v) air atmospheres of 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123), 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), 1-chloro-1,1-difluoroethane (HCFC-142b), bromochlorodifluoromethane (Halon 1211), and perfluorohexane (PFH) for 2 h. There were no remarkable differences in results between the two strains of rats. Animals exposed to HCFC-123 or HCFC-124 excreted trifluoroacetic acid in their urine. Urinary fluoride concentrations were increased in rats exposed to HCFC-124, and urinary bromide levels were increased in rats exposed to Halon 1211. Small quantities of volatile metabolites 2-chloro-1,1,1-trifluoroethane (HCFC-133a) and 2-chloro-1,1-difluoroethylene were observed in the livers of rats exposed to HCFC-123. Rats exposed to HCFC-142b excreted chlorodifluoroacetic acid in their urine; no volatile metabolites were detected in tissue samples. For PFH studies, no metabolites were detected in the urine or tissues of exposed animals. These results are consistent with proposed oxidative and reductive pathways of metabolism for these chemicals. Pharmacokinetic studies were carried out in rats exposed by inhalation to 1.0%, 0.1%, or 0.01% of HCFC-123. Following exposure, blood concentrations of HCFC-123 fell sharply, whereas trifluoroacetic acid levels rose for approx. 5 h and then declined gradually. Using a physiologically based pharmacokinetic model, saturation of HCFC-123 metabolism was estimated to occur at approx. 0.2% (2000 ppm) HCFC-123.

In vivo metabolism of chloroform in B6C3F1 mice determined by the method of gas uptake: the effects of body temperature on tissue partition coefficients and metabolism.

Mice exposed to various chemicals have been shown to respond by decreasing their core body temperature. To examine what effect such a response might have on the determination of in vivo metabolism, core body temperatures of B6C3F1 mice were recorded with temperature telemetry devices during exposure to chloroform (CHCl3) in a closed, recirculating chamber (100 to 5500 ppm). Significant decreases in body temperature occurred in all mice exposed to greater than 100 ppm CHCl3, with the greatest decrease of 14 degrees C occurring at 5500 ppm. A starting CHCl3 concentration of 4000 ppm had no effect on the 7-ethoxycoumarin O-deethylase (ECOD) activity or P450 levels determined at the end of a 5-hr gas uptake exposure. A physiologically based pharmacokinetic (PB-PK) model was developed to describe the effects of decreased body temperature on the analysis of metabolic data. In vitro ECOD activity as a measure of in vivo P450 metabolism was determined for temperatures ranging from 24 to 40 degrees C. In vitro enzyme activity decreased linearly from a maximum at 37 degrees C to one-third of this activity at 24 degrees C. A linear equation describing this enzymatic activity-temperature correlation was incorporated into the PB-PK model structure to describe decreases in metabolic activity resulting from decreases in core body temperature. In vitro blood/air and tissue/air partition coefficients were determined for CHCl3 at temperatures ranging from 24 to 40 degrees C. All blood/air and tissue/air partitions increased with decreasing temperature, while the tissue/blood partition coefficients calculated from the tissue/air and blood/air partitions decreased with decreasing temperature. Adding these temperature corrections to the model greatly improved the overall fit of the gas uptake curves at all concentrations. Incorporation of a first-order metabolic rate constant was also required to provide an adequate representation of the data at high concentrations. The analysis of gas uptake data by the use of a PB-PK computer model is a very powerful technique for determining in vivo metabolism of many volatile compounds, but the incorporation of significant deviations from a generally used model structure (i.e., Ramsey-Andersen model) to account for shortcomings of the model's ability to adequately analyze a gas uptake data set should be based on data collection when possible.

Polychlorotrifluoroethylene (PCTFE) oligomer pharmacokinetics in Fischer 344 rats: development of a physiologically based model.

The hydraulic fluid oil polychlorotrifluoroethylene (PCTFE) is hepato- and nephrotoxic in the rat. Male Fischer 344 rats were exposed to PCTFE either for a single 6-hr exposure (0.5 or 0.25 mg/liter) or daily 5 days/week, 6 hr/day, for 13 weeks (0.5, 0.25, or 0.01 mg/liter). Blood, tissue, and urinary PCTFE concentrations measured postexposure were used to develop a physiologically based pharmacokinetic (PB-PK) model. The PCTFE hydraulic fluid used was a mixture of trimeric and tetrameric oligomers with minor amounts of other chain lengths. The PB-PK model was designed to describe the behavior, not of individual oligomers, but of total mass for the trimer and tetramer in each tissue. Partition coefficients were estimated using the model to optimize tissue/blood concentration ratios measured at the end of the 13-week exposure. First-order metabolic rate constants for both trimeric (2.0 hr-1) and tetrameric (1.0 hr-1) portions were estimated by optimization against urinary fluoride data assuming release of 0.77 mole fluoride per mole trimer and 0.844 mole fluoride per mole tetramer metabolized. To obtain accurate simulation of pharmacokinetic data it was necessary to hypothesize two fat compartments with diffusion-limited exchange of PCTFE oligomer with the blood. Relative concentrations of trimer and tetramer in venous blood, liver, and fat after a single 6-hr exposure were proportional to inhaled concentrations. Tetramer accumulated preferentially with multiple exposure. Components of PCTFE were metabolized to carboxylic acids with release of fluoride. Due to their persistence tetrameric oligomers appear to be more important than trimeric oligomers as causative agents of PCTFE hepato- and nephrotoxicity in the rat.

A physiologically based pharmacokinetic model for chloropentafluorobenzene in primates to be used in the evaluation of protective equipment against toxic gases.

Chloropentafluorobenzene (CPFB) has been proposed as an innocuous simulant for the uptake of toxic gases. Exposure to CPFB in a training exercise could be inferred afterwards from a measurement of CPFB in expired breath. To understand the relationship between exposure and measurement, we have developed a physiologically-based pharmacokinetic (PB-PK) model for CPFB in primates. To test the model, inhalation exposures were conducted on anesthetized rhesus monkeys. CPFB concentration in expired breath was measured during and after exposure. Simulations of CPFB uptake and clearance agreed with experimental measurements in seven of eight monkeys. A human version of the model was used to simulate exposures consisting of a single breath or a few breaths. By showing a measurable CPFB concentration in expired breath after several hours of clearance, simulations with the human model indicated the suitability of CPFB as a simulant for toxic gases.

Effects of short-term oral dosing of polychlorotrifluoroethylene (polyCTFE) on the rhesus monkey.

Polychlorotrifluoroethylene (polyCTFE--primarily oligomers with 3-4 monomer units), a non-flammable hydraulic fluid for aircraft, was given daily for 15 days by oral gavage to four Rhesus monkeys at a concentration of 0.725 g kg-1. The administered dose was at a level that had caused toxicity in rats. Steady-state blood and liver concentrations reached were the same in both species. In monkeys, polyCTFE did not cause the electrolyte, serum protein, liver enzyme and anemic disturbances previously seen in rats. Liver sections taken at 15 days, analyzed for palmitoyl Co-A beta-oxidation rates or by electron microscopy, showed no significant indication of peroxisomal proliferation. An increased blood urea nitrogen (BUN) at 15 days was the only clinical pathological abnormality seen in both monkeys and rats. Previously unobserved effects were increased triglycerides and glycogen depletion.

Chloropentafluorobenzene: short-term inhalation toxicity, genotoxicity and physiologically-based pharmacokinetic model development.

Ten Fischer 344 rats and six B6C3F1 mice of each sex were exposed to air, 0.25, 0.80, or 2.50 mg chloropentafluorobenzene (CPFB)/liter of air for three weeks, excluding weekends. Exposure to 2.50 mg/liter caused a reduction in the growth rate of rats but did not affect the growth rate of mice. Following the exposure there was reduced SGOT activity in the blood serum of exposed rats and a dose related increase in liver weights. Increased liver weights were observed in mice as well; the response in the female groups was clearly dose dependent. Histologically the livers of both rats and mice presented single cell necrosis. In exposed mice hepatocytes exhibited mild hepatocytomegaly with increased granular eosinophilic cytoplasm. In evaluations for its potential to induce chromosomal damage following this exposure regimen, CPFB did not alter the rate of bone marrow cellular proliferation. Assessment of the micronucleated polychromatic erythrocytes and normochromatic erythrocyte populations during the inhalation exposures indicated a general absence of genotoxic activity.

Action by the lungs on circulating xenobiotic agents, with a case study of physiologically based pharmacokinetic modeling of benzo(a)pyrene disposition.

The lungs contain enzyme systems that metabolize xenobiotic agents, and the structure and position in the circulation render this organ potentially important in the metabolic removal of substances from the blood. Pulmonary enzyme systems that oxidize xenobiotic agents include cytochrome P450- or flavin-containing monooxygenases. In addition, the lungs accumulate certain agents, notably basic amines, without substantially metabolizing them. Benzo(a)pyrene (B(a)P) is one example of a xenobiotic agents that is eliminated from the circulation largely by oxidative metabolism. We have described the metabolic elimination of B(a)P using a physiologically based pharmacokinetic model applied retrospectively to existing data sets of B(a)P metabolism and disposition in rats. The result suggests that the lungs may, under certain conditions, contribute significantly to xenobiotic disposition and that this contribution is greater than that predicted by the activity of dispositional enzyme in this organ. Thus, the lungs may play a significant role in the metabolic elimination of some xenobiotic agents under certain circumstances.