A Post Hoc Exploratory Analysis: Induced Abortion Complications Mistaken for Miscarriage in the Emergency Room are a Risk Factor for Hospitalization.

Introduction: Previous research indicates that an increasing number of women who go to an emergency room for complications following an induced abortion are treated for a miscarriage, meaning their abortion is miscoded or concealed. Objective: To determine if the failure to identify a prior induced abortion during an ER visit is a risk factor for higher rates of subsequent hospitalization. Methods: Post hoc analysis of hospital admissions following an induced abortion and ER visit within 30 days: 4273 following surgical abortion and 408 following chemical abortion; abortion not miscoded versus miscoded or concealed at prior ER visit. Results: Chemical abortion patients whose abortions are misclassified as miscarriages during an ER visit subsequently experience on average 3.2 hospital admissions within 30 days. 86% of the patients ultimately have surgical removal of retained products of conception (RPOC). Chemical abortions are more likely than surgical abortions (OR 1.80, CL 1.38-2.35) to result in an RPOC admission, and chemical abortions concealed are more likely to result (OR 2.18, CL 1.65-2.88) in a subsequent RPOC admission than abortions without miscoding. Surgical abortions miscoded/concealed are similarly twice as likely to result in hospital admission than those without miscoding. Conclusion: Patient concealment and/or physician failure to identify a prior abortion during an ER visit is a significant risk factor for a subsequent hospital admission. Patients and ER personnel should be made aware of this risk.

Subchronic JP-8 jet fuel exposure enhances vulnerability to noise-induced hearing loss in rats.

Both laboratory and epidemiological studies published over the past two decades have identified the risk of excess hearing loss when specific chemical contaminants are present along with noise. The objective of this study was to evaluate the potency of JP-8 jet fuel to enhance noise-induced hearing loss (NIHL) using inhalation exposure to fuel and simultaneous exposure to either continuous or intermittent noise exposure over a 4-wk exposure period using both male and female Fischer 344 rats. In the initial study, male (n = 5) and female (n = 5) rats received inhalation exposure to JP-8 fuel for 6 h/d, 5 d/wk for 4 wk at concentrations of 200, 750, or 1500 mg/m³. Parallel groups of rats also received nondamaging noise (constant octave band noise at 85 dB(lin)) in combination with the fuel, noise alone (75, 85, or 95 dB), or no exposure to fuel or noise. Significant concentration-related impairment of auditory function measured by distortion product otoacoustic emissions (DPOAE) and compound action potential (CAP) threshold was seen in rats exposed to combined JP-8 plus noise exposure when JP-8 levels of 1500 mg/m³ were presented with trends toward impairment seen with 750 mg/m³ JP-8 + noise. JP-8 alone exerted no significant effect on auditory function. In addition, noise was able to disrupt the DPOAE and increase auditory thresholds only when noise exposure was at 95 dB. In a subsequent study, male (n = 5 per group) and female (n = 5 per group) rats received 1000 mg/m³ JP-8 for 6 h/d, 5 d/wk for 4 wk with and without exposure to 102 dB octave band noise that was present for 15 min out of each hour (total noise duration 90 min). Comparisons were made to rats receiving only noise, and thosereceiving no experimental treatment. Significant impairment of auditory thresholds especially for high-frequency tones was identified in the male rats receiving combined treatment. This study provides a basis for estimating excessive hearing loss under conditions of subchronic JP-8 jet fuel exposure.

Marginal iodide deficiency and thyroid function: dose-response analysis for quantitative pharmacokinetic modeling.

Severe iodine deficiency (ID) results in adverse health outcomes and remains a benchmark for understanding the effects of developmental hypothyroidism. The implications of marginal ID, however, remain less well known. The current study examined the relationship between graded levels of ID in rats and serum thyroid hormones, thyroid iodine content, and urinary iodide excretion. The goals of this study were to provide parametric and dose-response information for development of a quantitative model of the thyroid axis. Female Long Evans rats were fed casein-based diets containing varying iodine (I) concentrations for 8 weeks. Diets were created by adding 975, 200, 125, 25, or 0 µg/kg I to the base diet (~25 µg I/kg chow) to produce 5 nominal I levels, ranging from excess (basal+added I, Treatment 1: 1000 µg I/kg chow) to deficient (Treatment 5: 25 µg I/kg chow). Food intake and body weight were monitored throughout and on 2 consecutive days each week over the 8-week exposure period, animals were placed in metabolism cages to capture urine. Food, water intake, and body weight gain did not differ among treatment groups. Serum T4 was dose-dependently reduced relative to Treatment 1 with significant declines (19 and 48%) at the two lowest I groups, and no significant changes in serum T3 or TSH were detected. Increases in thyroid weight and decreases in thyroidal and urinary iodide content were observed as a function of decreasing I in the diet. Data were compared with predictions from a recently published biologically based dose-response (BBDR) model for ID. Relative to model predictions, female Long Evans rats under the conditions of this study appeared more resilient to low I intake. These results challenge existing models and provide essential information for development of quantitative BBDR models for ID during pregnancy and lactation.

Partition coefficients for nonane and its isomers in the rat.

Jet Fuel 8 (JP-8) is a major fuel source used by US and NATO military. JP-8 is a complex mixture of aliphatic and aromatic isomers of hydrocarbons. Tissue/blood partition coefficient (PC) values are chemical-specific parameters used in modeling the kinetic behavior of chemicals. The partition coefficient values for n-alkanes tend to increase with the increasing carbon number, but less is known about the trend for isomers of n-alkanes. PC values were obtained for the n-alkane nonane (C9) and five of its isomers, namely 3-methyloctane, 4-ethylheptane, 2,3-dimethylheptane, 2,2,4-trimethylhexane, 2,2,4,4-tetramethylpentane. The blood:air and tissue:air PC values correlated with the published log octanol/water (O:W) PC values for n-nonane and its isomers. Experimentally determined blood:air and tissue:air PC values for n-nonane with the largest O:W value were greatest and smallest for the isomer 2,2,4,4-tetramethylpentane with the lowest O:W value. As expected the fat tissue had the highest PC values and muscle the lowest for n-nonane and its isomers. For each tissue, a linear relationship was observed between the tissue/blood PC values for the isomers of n-nonane and n-nonane. This suggests that tissue/blood PC values for all isomers of an alkane could be estimated using data collected from only a sub-set of alkanes of equal carbon number. These reported tissue/blood PC values will support the development of a jet fuel physiologically-based pharmacokinetic (PBPK) model.

Evaluation of potassium iodide (KI) and ammonium perchlorate (NH4ClO4) to ameliorate 131I- exposure in the rat.

Nuclear reactor accidents and the threat of nuclear terrorism have heightened the concern for adverse health risks associated with radiation poisoning. Potassium iodide (KI) is the only pharmaceutical intervention that is currently approved by the Food and Drug Administration for treating (131)I(-) exposure, a common radioactive fission product. Though effective, KI administration needs to occur prior to or as soon as possible (within a few hours) after radioactive exposure to maximize the radioprotective benefits of KI. During the Chernobyl nuclear reactor accident, KI was not administered soon enough after radiation poisoning occurred to thousands of people. The delay in administration of KI resulted in an increased incidence of childhood thyroid cancer. Perchlorate (ClO(4)(-)) was suggested as another pharmaceutical radioprotectant for 131I- poisoning because of its ability to block thyroidal uptake of iodide and discharge free iodide from the thyroid gland. The objective of this study was to compare the ability of KI and ammonium perchlorate to reduce thyroid gland exposure to radioactive iodide (131I-). Rats were dosed with 131I- tracer and 0.5 and 3 h later dosed orally with 30 mg/kg of either ammonium perchlorate or KI. Compared to controls, both anion treatments reduced thyroid gland exposure to 131I- equally, with a reduction ranging from 65 to 77%. Ammonium perchlorate was more effective than stable iodide for whole-body radioprotectant effectiveness. KI-treated animals excreted only 30% of the (131)I(-) in urine after 15 h, compared to 47% in ammonium perchlorate-treated rats. Taken together, data suggest that KI and ammonium perchlorate are both able to reduce thyroid gland exposure to 131I- up to 3 h after exposure to 131I-. Ammonium perchlorate may offer an advantage over KI because of its ability to clear 131I- from the body.

Methods for the characterization of Jet Propellent-8: vapor and aerosol.

Jet Propellant-8 (JP-8) has been responsible for the majority of reported chemical exposures by the US Department of Defense. Concerns related to human exposure to JP-8 are relatively new; therefore, there is a lack of literature data. Additionally, health effects related to the composition of the exposure have only recently been considered. Two major questions exist: (1) what is the compositional difference between the aerosol and vapor portions of JP-8 under controlled conditions and (2) what is the most representative method to sample JP-8 aerosol and vapor? Thirty-seven standards, representing more than 40% of the mass of JP-8, were used for characterization of the neat fuel, vapor and aerosol portions. JP-8 vapor samples at a concentration of 1600 mg/m(3) were prepared in Tedlar bags. A portion of the vapor samples was adsorbed on charcoal, Tenax and custom mixed phase sorbents. These samples were then extracted using organic solvent and analyzed using gas chromatography/mass spectrometry. The vapor samples extracted from the sorbent tubes were directly compared with a vapor bag. The samples collected using Tenax sorbent tubes were found to be most representative of the composition of the vapor bags. In another set of experiments, aerosolized JP-8 was generated using a collision nebulizer. Aerosol samples were collected and the chemical composition was characterized. The entire aerosol distribution was collected on a glass filter, extracted into solvent, and analyzed by GC-MS. Finally, the composition of the vapor and aerosol was compared. The vapor was found to represent the lower molecular weight components of JP-8, while the aerosol was composed of higher molecular weight components. Therefore, the vapor and aerosol should be treated as two discrete forms of exposure to JP-8.

Trichloroethylene, trichloroacetic acid, and dichloroacetic acid: do they affect eye development in the Sprague-Dawley rat?

Maternal exposure to high doses of trichloroethylene (TCE) and its oxidative metabolites, trichloroacetic acid (TCA) and dichloroacetic acid (DCA), has been implicated in eye malformations in fetal rats, primarily micro-/anophthalmia. Subsequent to a cardiac teratology study of these compounds (Fisher et al. 2001, Int. J. Toxicol. 20:257-267), their potential to induce ocular malformations was examined in a subset of the same experimental animals. Pregnant, Sprague-Dawley Crl:CDR BR rats were orally treated on gestation days (GDs) 6 to 15 with bolus doses of either TCE (500 mg/kg/day), TCA (300 mg/kg/day), DCA (300 mg/kg/day), or all-trans retinoic acid (RA; 15 mg/kg/day). The heads of GD 21 fetuses were not only examined grossly for external malformations, but were sectioned using a modified Wilson's technique and subjected to computerized morphometry that allowed for the quantification of lens area, globe area, medial canthus distance, and interocular distance. Gross ocular malformations were essentially absent in all treatment groups except for the RA group in which 26% of fetuses exhibited micro-/anophthalmia. Using the litter as the experimental unit of analysis, lens area, globe area, and interocular distance were statistically significantly reduced in the DCA treatment group. Statistically significant reductions in lens and globe areas also occurred in the RA treatment group, all four ocular measures were reduced in the TCA treatment group but none significantly so, and TCE was without effect. Because DCA, TCA, and RA treatments were associated with significant reductions in fetal body weight (bw), data were also statistically analyzed after bw adjustment. Doing so dramatically altered the results of treatment group comparisons, but the severity of bw reduction and the degree of change in ocular measures did not always correlate. This suggests that bw reduction may not be an adequate explanation for all the changes observed in ocular measures. Thus, it is unclear whether DCA specifically disrupted ocular development even under these provocative exposure conditions. Clearly, however, if TCE is capable of disrupting ocular development in the Sprague-Dawley rat, a higher dose than that employed in the present study is required.

Rat tissue and blood partition coefficients for n-alkanes (C8 to C12).

Rat tissue:air and blood:air partition coefficients (PCs) for octane, nonane, decane, undecane, and dodecane (n-C8 to n-C12 n-alkanes) were determined by vial equilibration. The blood:air PC values for n-C8 to n-C12 were 3.1, 5.8, 8.1, 20.4, and 24.6, respectively. The lipid solubility of n-alkanes increases with carbon length, suggesting that lipid solubility is an important determinant in describing n-alkane blood:air PC values. The muscle:blood, liver: blood, brain:blood, and fat:blood PC values were octane (1.0, 1.9, 1.4, and 247), nonane (0.8, 1.9, 3.8, and 274), decane (0.9, 2.0, 4.8, and 328), undecane (0.7, 1.5, 1.7, and 529), and dodecane (1.2, 1.9, 19.8, and 671), respectively. The tissue:blood PC values were greatest in fat and the least in muscle. The brain:air PC value for undecane was inconsistent with other n-alkane values. Using the measured partition coefficient values of these n-alkanes, linear regression was used to predict tissue (except brain) and blood:air partition coefficient values for larger n-alkanes, tridecane, tetradecane, pentadecane, hexadecane, and heptadecane (n-C13 to n-C17). Good agreement between measured and predicted tissue:air and blood:air partition coefficient values for n-C8 to n-Cl2 offer confidence in the partition coefficient predictions for longer chain n-alkanes.

Development of a physiologically based pharmacokinetic model for decane, a constituent of jet propellent-8.

Decane, a 10-carbon n-alkane and one of the highest vapor phase constituents of jet propellent-8 (JP-8), was selected to represent the semivolatile fraction for the initial development of a physiologically based pharmacokinetic (PBPK) model for JP-8. Rats were exposed to decane vapors at time-weighted average concentrations of 1200, 781, or 273 ppm in a 32-L Leach chamber for 4 h. Time-course samples for 1200 ppm and end-of-exposure samples for 781 and 273 ppm decane exposures were collected from blood, brain, liver, fat, bone marrow, lung, skin, and spleen. The pharmacokinetics of decane could not be described by flow-limited assumptions and measured in vitro tissue/air partition coefficients. A refined PBPK model for decane was then developed using flow-limited (liver and lung) and diffusion-limited (brain, bone marrow, fat, skin, and spleen) equations to describe the uptake and clearance of decane in the blood and tissues. Partition coefficient values for blood/air and tissue/blood were estimated by fitting end-of-exposure pharmacokinetic data and assumed to reflect the available decane for rapid exchange with blood. A portion of decane is speculated to be sequestered in "deep" pools in the body, unavailable for rapid exchange with blood. PBPK model predictions were adequate in describing the tissues and blood kinetics. For model validation, the refined PBPK model for decane had mixed successes at predicting tissue and blood concentrations for lower concentrations of decane vapor, suggesting that further improvements in the model may be necessary to extrapolate to lower concentrations.

The use of rice hulls for sustainable control of NOx emissions in deep space missions.

The use of the activated carbon produced from rice hulls to control NOx emissions for future deep space missions has been demonstrated. The optimal carbonization temperature range was found to be between 600 and 750 degrees C. A burnoff of 61.8% was found at 700 degrees C in pyrolysis and 750 degrees C in activation. The BET surface area of the activated carbon from rice hulls was determined to be 172 m2/g when prepared at 700 degrees C. The presence of oxygen in flue gas is essential for effective adsorption of NO by activated carbon. On the contrary, water vapor inhibits the adsorption efficiency of NO. Consequently, water vapor in flue gas should be removed by drying agents before adsorption to ensure high NO adsorption efficiency. All of the NO in the flue gas was removed for more than 1.5 h when 10% oxygen was present and the ratio of the carbon weight to the flue gas flow rate (W/F) was 15.4 g min/L. Reduction of the adsorbed NO to form N2 could be effectively accomplished under anaerobic conditions at 550 degrees C. The adsorption capacity of NO on the activated carbon was found to be 5.02 mg of NO/g of carbon. The loss of carbon mass was determined to be about 0.16% of the activated carbon per cycle of regeneration if the regeneration occurred when the NO in the flue gas after the carbon bed reached 4.8 ppm, the space maximum allowable concentration. The reduction of the adsorbed NO also regenerated the activated carbon, and the regenerated activated carbon exhibited an improved NO adsorption efficiency.

Method for the control of NOx emissions in long-range space travel.

The wheat straw, an inedible biomass that can be continuously produced in a space vehicle has been used to produce activated carbon for effective control of NOx emissions from the incineration of wastes. The optimal carbonization temperature of wheat straw was found to be around 600 degrees C when a burnoff of 67% was observed. The BET surface area of the activated carbon produced from the wheat straw reached as high as 300 m2/g. The presence of oxygen in flue gas is essential for effective adsorption of NO by activated carbon. On the contrary, water vapor inhibits the adsorption efficiency of NO. Consequently, water vapor in flue gas should be removed by drying agents before adsorption to ensure high NO adsorption efficiency. All of the NO in the flue gas was removed for more than 2 h by the activated carbons when 10% oxygen was present and the ratio of carbon weight to the flue gas flow rate (W/F) was 30 g min/L, with a contact time of 10.2 s. All of NO was reduced to N2 by the activated carbon at 450 degrees C with a W/F ratio of 15 g min/L and a contact time of 5.1 s. Reduction of the adsorbed NO also regenerated the activated carbon, and the regenerated activated carbon exhibited an improved NO adsorption efficiency. However, the reduction of the adsorbed NO resulted in a loss of carbon which was determined to be about 0.99% of the activated carbon per cycle of regeneration. The sufficiency of the amount of wheat straw in providing the activated carbon based on a six-person crew, such as the mission planned for Mars, has been determined. This novel approach for the control of NOx emissions is sustainable in a closed system such as the case in space travel. It is simple to operate and is functional under microgravity environment.

Sensitive high-performance liquid chromatography method for the determination of low levels of perchlorate in biological samples.

A rapid and sensitive high-performance liquid chromatography (HPLC) method was developed to detect perchlorate in tissues of male and female rats, both pregnant and lactating (including milk) after administration of perchlorate. Supernatants of ethanol precipitated rat fluids and tissues were evaporated to dryness under nitrogen and reconstituted in deionized water. Reconstituted samples were injected into HPLC system coupled with conductivity detection. Isocratic separation of perchlorate was achieved using an anion-exchange column with sodium hydroxide as mobile phase and a conductivity detector. In this method, perchlorate showed a linear response range from 5 to 100 ng/ml. The lower detection limits for perchlorate in fluids and tissues of rats were 3-6 ng/ml and 0.007-0.7 mg/kg, respectively. The described method has the unique advantage over the existing methods of determining low traces of perchlorate in different biological matrices without complex sample preparation.

Adenosine A(2A) and A(2B) receptor activation of erythropoietin production.

We have examined the effects of adenosine receptors and protein kinases A and C in the regulation of erythropoietin (Epo) production using hepatocellular carcinoma (Hep3B) cells in culture and in vivo in normal mice under normoxic and hypoxic conditions. CGS-21680, a selective adenosine A(2A) agonist, significantly increased levels of Epo in normoxic Hep3B cell cultures and in serum of normal mice under both normoxic and hypoxic conditions. CGS-21680 also produced a significant increase in Epo mRNA levels in Hep3B cell cultures. SCH-58261, a selective adenosine A(2A) receptor antagonist, significantly inhibited the increase in medium levels of Epo in Hep3B cell cultures exposed to hypoxia (1% O(2)). Enprofylline, a selective adenosine A(2B) receptor antagonist, significantly inhibited the increase in plasma levels of Epo in normal mice exposed to hypoxia. Chelerythrine chloride, an antagonist of protein kinase C activation, significantly inhibited hypoxia-induced increases in serum levels of Epo in normal mice. A model is presented for adenosine in hypoxic regulation of Epo production that involves kinases A and C and phospholipase A(2) pathways.

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous system of the offspring. In addition, unique physical features such as the presence or absence of a placental barrier and the gradual development of the blood--brain barrier influence chemical disposition and thus modulate developmental neurotoxicity. Neonatal exposure may depend on maternal pharmacokinetic processes and transfer of the xenobiotic through the milk, although direct exposure may occur through other routes (e.g., inhalation). Measurement of the xenobiotic in milk and evaluation of biomarkers of exposure or effect following exposure can confirm or characterize neonatal exposure. Physiologically based pharmacokinetic and pharmacodynamic models that incorporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can characterize dose--response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experimenter to determine whether exposure to the test chemical is adequate, whether exposure occurs during critical periods of nervous system development, whether route and duration of exposure are appropriate, and whether developmental neurotoxicity can be differentiated from direct actions of the xenobiotic.

Trichloroethylene, trichloroacetic acid, and dichloroacetic acid: do they affect fetal rat heart development?

Trichloroethylene (TCE), trichloroacetic acid (TCA), and dichloroacetic acid (DCA) are commonly found as groundwater contaminants in many regions of the United States. Cardiac birth defects in children have been associated with TCE, and laboratory studies with rodents report an increased incidence of fetal cardiac malformations resulting from maternal exposures to TCE, TCA, and DCA. The objective of this study was to orally treat pregnant CDR(CD) Sprague-Dawley rats with large bolus doses of either TCE (500 mg/kg), TCA (300 mg/kg), or DCA (300 mg/kg) once per day on days 6 through 15 of gestation to determine the effectiveness of these materials to induce cardiac defects in the fetus. All-trans retinoic acid (RA) dissolved in soybean oil was used as a positive control. Soybean oil is commonly used as a dosing vehicle for RA teratology studies and was also used in this study as a dosing vehicle for TCE. Water was used as the dosing vehicle for TCA and DCA. Fetal hearts were examined on gestation day (GD) 21 by an initial in situ, cardiovascular stereomicroscope examination, and then followed by a microscopic dissection and examination of the formalin-fixed heart. The doses selected for TCA and DCA resulted in a modest decrease in maternal weight gain during gestation (3% to 8%). The fetal weights on GD 21 in the TCA and DCA treatment groups were decreased 8% and 9%, respectively, compared to the water control group and 21% in the RA treatment group compared to soybean oil control group. The heart malformation incidence for fetuses from the TCE-, TCA-, and DCA-treated dams did not differ from control values on a per fetus or per litter basis. The rate of heart malformations, on a per fetus basis, ranged from 3% to 5% for TCE, TCA, and DCA treatment groups compared to 6.5% and 2.9% for soybean oil and water control groups. The RA treatment group was significantly higher with 33% of the fetuses displaying heart defects. For TCE, TCA, and DCA treatment groups 42% to 60% of the litters contained at least one fetus with a heart malformation, compared to 52% and 37% of the litters in the soybean oil and water control groups. For the RA treatment group, 11 of 12 litters contained at least one fetus with a heart malformation. Further research is needed to quantify the spontaneous rates of heart defects for vehicle control rats and to explain the disparity between findings in the present study and other reported findings on the fetal cardiac teratogenicity of TCE, TCA, and DCA.

Metabolism of trichloroethylene.

A major focus in the study of metabolism and disposition of trichloroethylene (TCE) is to identify metabolites that can be used reliably to assess flux through the various pathways of TCE metabolism and to identify those metabolites that are causally associated with toxic responses. Another important issue involves delineation of sex- and species-dependent differences in biotransformation pathways. Defining these differences can play an important role in the utility of laboratory animal data for understanding the pharmacokinetics and pharmacodynamics of TCE in humans. Sex-, species-, and strain-dependent differences in absorption and distribution of TCE may play some role in explaining differences in metabolism and susceptibility to toxicity from TCE exposure. The majority of differences in susceptibility, however, are likely due to sex-, species-, and strain-dependent differences in activities of the various enzymes that can metabolize TCE and its subsequent metabolites. An additional factor that plays a role in human health risk assessment for TCE is the high degree of variability in the activity of certain enzymes. TCE undergoes metabolism by two major pathways, cytochrome P450 (P450)-dependent oxidation and conjugation with glutathione (GSH). Key P450-derived metabolites of TCE that have been associated with specific target organs, such as the liver and lungs, include chloral hydrate, trichloroacetate, and dichloroacetate. Metabolites derived from the GSH conjugate of TCE, in contrast, have been associated with the kidney as a target organ. Specifically, metabolism of the cysteine conjugate of TCE by the cysteine conjugate ss-lyase generates a reactive metabolite that is nephrotoxic and may be nephrocarcinogenic. Although the P450 pathway is a higher activity and higher affinity pathway than the GSH conjugation pathway, one should not automatically conclude that the latter pathway is only important at very high doses. A synthesis of this information is then presented to assess how experimental data, from either animals or from (italic)in vitro (/italic)studies, can be extrapolated to humans for risk assessment. (italic)Key words(/italic): conjugate beta-lyase, cysteine glutathione, cytochrome P450, glutathione (italic)S(/italic)-transferases, metabolism, sex dependence, species dependence, tissue dependence, trichloroethylene.

Physiologically based pharmacokinetic models for trichloroethylene and its oxidative metabolites.

Trichloroethylene (TCE) pharmacokinetics have been studied in experimental animals and humans for over 30 years. Compartmental and physiologically based pharmacokinetic (PBPK) models have been developed for the uptake, distribution, and metabolism of TCE and the production, distribution, metabolism, and elimination of P450-mediated metabolites of TCE. TCE is readily taken up into systemic circulation by oral and inhalation routes of exposure and is rapidly metabolized by the hepatic P450 system and to a much lesser degree, by direct conjugation with glutathione. Recent PBPK models for TCE and its metabolites have focused on the major metabolic pathway for metabolism of TCE (P450-mediated metabolic pathway). This article briefly reviews selected published compartmental and PBPK models for TCE. Trichloroacetic acid (TCA) is considered a principle metabolite responsible for TCE-induced liver cancer in mice. Liver cancer in mice was considered a critical effect by the U.S. Environmental Protection Agency for deriving the current maximum contaminant level for TCE in water. In the literature both whole blood and plasma measurements of TCA are reported in mice and humans. To reduce confusion about disparately measured and model-predicted levels of TCA in plasma and whole blood, model-predicted outcomes are compared for first-generation (plasma) and second-generation (whole blood) PBPK models published by Fisher and colleagues. Qualitatively, animals and humans metabolize TCE in a similar fashion, producing the same metabolites. Quantitatively, PBPK models for TCE and its metabolites are important tools for providing dosimetry comparisons between experimental animals and humans. TCE PBPK models can be used today to aid in crafting scientifically sound public health decisions for TCE.

Analysis of respiratory exchange of methanol in the lung of the monkey using a physiological model.

A physiologically based pharmacokinetic (PBPK) model was developed for the monkey, to account for fractional systemic uptake of inhaled methanol vapors in the lung. Fractional uptake of inhaled [14C]-methanol was estimated using unreported exhaled breath time course measurements of [14C]-methanol from the D.C. Dorman et al. (1994, Toxicol Appl Pharmacol. 128, 229-238) lung-only exposure study. The cumulative amount of [14C]-methanol exhaled was linear with respect to exposure duration (0.5 to 2 h) and concentration (10 to 900 ppm). The model estimated that forty to eighty-one percent of the of inhaled [14C]-methanol delivered to the lung was taken into systemic circulation in female Cynomolgus monkeys exposed for two h to 10-900 ppm of [14C]-methanol. There was no apparent trend between the percent of inhaled [14C]-methanol absorbed systemically and the [14C]-methanol exposure concentration. Model simulations were conducted using a single saturable Michaelis-Menten equation with Vmaxc, the metabolic capacity set to 15.54 mg/kg/h and Km, the affinity constant, to 0.66 mg/l. The [14C]-methanol blood concentrations were variable across [14C]-methanol exposure groups and the PBPK model tended to over-predict systemic clearance of [14C]-methanol. Accounting for fractional uptake of inhaled polar solvents is an important consideration for risk assessment of inhaled polar solvents.

Avoiding transfusion in head and neck surgery: feasibility study of erythropoietin.

OBJECTIVE: To determine the feasibility of perioperative erythropoietin to avoid blood transfusion in head and neck cancer surgery. STUDY DESIGN: Retrospective chart review. METHODS: Ninety-nine patients undergoing surgical resection of head and neck tumors at our institution were assessed for demographic data, nutritional parameters, tumor/surgical information, hematological/transfusion data, and contraindications to erythropoietin. Each transfusion was classified as to its appropriateness, and the potential benefit of erythropoietin was assessed in each patient. A cost analysis was also performed. RESULTS: Most transfused patients (63%) received too many units. A subgroup at high risk of transfusion was identified who would benefit most from perioperative erythropoietin. Assuming that perioperative erythropoietin therapy is equivalent to the transfusion of 4 units, we estimate that the majority (741%) of transfused patients would not have required a transfusion if more stringent transfusion criteria were followed and those at high risk were given perioperative erythropoietin. Although the cost for transfusing 4 units is equivalent to that of a perioperative course of erythropoietin, the overall direct cost of erythropoietin treatment would actually have been more expensive. CONCLUSIONS: Perioperative erythropoietin therapy may be appropriate for a subgroup of head and neck cancer patients, but a prospective randomized controlled study in such a subgroup is needed to better define those most likely to benefit from it and to assess actual cost/benefit ratios.

Can incineration technology convert CELSS wastes to resources for crop production? A working hypothesis and some preliminary findings.

Considerable evidence exists to support the hypothesis that human-generated wastes can be utilized as resources in crop production. In the waste mix from a Closed Ecological Life Support System (CELSS), the elemental resources are found mainly in the solid fraction. In order to make these resources available for crop growth, it is necessary to convert the solid wastes to either an aqueous or a gaseous phase. Incineration is one method for processing solid wastes to produce a gaseous fraction and a small solid fraction of ash. Evidence from literature provides a compelling case for a working hypothesis that plants can utilize the gases of incineration. Although uptake and utilization of inorganic elements in the aqueous phase is well established, the uptake and utilization of inorganic elements in the gaseous phase, with the exception of CO2 and O2, is not fully understood. This paper attempts to (a) summarize existing literature on uptake/metabolism of inorganic elements in the gaseous fraction, with the exception of CO2 and O2 and (b) develop a working hypothesis to predict the use of incineration flue gases by plants. Preliminary experimental findings on effects of carbon monoxide, a component of the flue gas, are also presented.