Genetic diversity and population structure of castor (Ricinus communis L.) germplasm within the US collection assessed with EST-SSR markers.

Castor is an important oilseed crop and although its oil is inedible, it has multiple industrial and pharmaceutical applications. The entire US castor germplasm collection was previously screened for oil content and fatty acid composition, but its genetic diversity and population structure has not been determined. Based on the screening results of oil content, fatty acid composition, and country origins, 574 accessions were selected and genotyped with 22 polymorphic EST-SSR markers. The results from cluster analysis, population structure, and principal component analysis were consistent, and partitioned accessions into four subpopulations. Although there were certain levels of admixtures among groups, these clusters and subpopulations aligned with geographic origins. Both divergent and redundant accessions were identified in this study. The US castor germplasm collection encompasses a moderately high level of genetic diversity (pairwise dissimilarity coefficient = 0.53). The results obtained here will be useful for choosing accessions as parents to make crosses in breeding programs and prioritizing accessions for regeneration to improve germplasm management. A subset of 230 accessions was selected and will be planted in the field for establishing a core collection of the US castor germplasm. Further evaluation of the US castor germplasm collection is also discussed.

Genetic diversity of Crotalaria germplasm assessed through phylogenetic analysis of EST-SSR markers.

The genetic diversity of the genus Crotalaria is unknown even though many species in this genus are economically valuable. We report the first study in which polymorphic expressed sequence tag-simple sequence repeat (EST-SSR) markers derived from Medicago and soybean were used to assess the genetic diversity of the Crotalaria germplasm collection. This collection consisted of 26 accessions representing 4 morphologically characterized species. Phylogenetic analysis partitioned accessions into 4 main groups generally along species lines and revealed that 2 accessions were incorrectly identified as Crotalaria juncea and Crotalaria spectabilis instead of Crotalaria retusa. Morphological re-examination confirmed that these 2 accessions were misclassified during curation or conservation and were indeed C. retusa. Some amplicons from Crotalaria were sequenced and their sequences showed a high similarity (89% sequence identity) to Medicago truncatula from which the EST-SSR primers were designed; however, the SSRs were completely deleted in Crotalaria. Highly distinguishing markers or more sequences are required to further classify accessions within C. juncea.

Acute respiratory responses of the mouse to chlorine.

In human subjects 15-min exposure to 0.5-1.0 ppm chlorine gas causes a nasal obstructive response in the absence of a marked sensation of irritation. The current investigation was designed to assess the response of the mouse for comparative purposes. Respiratory physiological responses were measured in female C57Bl/6J mice exposed to 0.8 to 4.0 ppm chlorine gas. Chlorine was a potent sensory irritant with an RD50 of 2.3 ppm. The gas produced airway obstruction as indicated by a concentration-dependent increase in specific airways resistance (sRaw) during the 15-min exposure. At 0.8 ppm, chlorine produced only mild sensory irritation (<20% change in breathing frequency) and a 65% increase in sRaw. Pretreatment with atropine was without effect on the obstructive response, suggesting a lack of involvement of muscarinic cholinergic pathways. Pretreatment with the sensory nerve toxin, capsaicin, dramatically reduced both the sensory irritation and obstructive responses to chlorine, suggesting the involvement of sensory nerves. Studies were also performed using the surgically isolated upper respiratory tract of the anesthetized mouse. Chlorine was efficiently scrubbed from the airstream (>97%) in that site and produced an obstructive response that was of sufficient magnitude to account for the entire response observed in the intact animal. In summary, chlorine gas produces an immediate nasal obstructive response in the mouse that appears to be similar to that in the human.

Non-traditional legumes as potential soil amendments for nematode control.

Dried ground plant tissues from 20 leguminous species were mixed with Meloidogyne incognita-infested soil at 1, 2 or 2.5, and 5% (w/w) and incubated for 1 week at room temperature (21 to 27 degrees C). Tomato ('Rutgers') seedlings were transplanted into infested soil to determine nematode viability. Most tissues reduced gall numbers below the non-amended controls. The tissue amendments that were most effective include: Canavalia ensiformis, Crotalaria retusa, Indigofera hirsuta, I. nummularifolia, I. spicata, I. suffruticosa, I. tinctoria, and Tephrosia adunca. Although certain tissues reduced the tomato dry weights, particularly at the higher amendment rates (5%), some tissues resulted in greater dry weights. These non-traditional legumes, known to contain bioactive phytochemicals, may offer considerable promise as soil amendments for control of plant-parasitic nematodes. Not only do these legumes reduce root-knot nematodes but some of them also enhance plant height and dry weight.

Long term survival after pancreatic resection for pancreatic adenocarcinoma.

OBJECTIVE: The aim of this study was to determine the long term survival of patients with pancreatic adenocarcinoma who underwent surgical resection and to assess the association of clinical, pathological, and treatment features with survival. METHODS: Between January, 1990, and December, 1998, 125 patients underwent a pancreaticoduodenal or partial pancreatic resection for pancreatic ductal adenocarcinoma at our institution. The records of these patients were reviewed for demographics, tumor characteristics including size, histological grade, margin status, lymph node status, surgical TNM staging, and postoperative adjuvant therapy. The primary outcome variable analyzed was survival. RESULTS: A total of 116 patients had complete follow-up and were included in the final analysis. The median survival after surgery was 16 months. The 1-, 3-, 5-, and 7-yr survival rates for all 116 patients were 60%, 23%, 19%, and 11%, respectively. The 1-, 3-, 5-, and 7-yr survival rates for patients who received adjuvant therapy were 69%, 28%, 23%, and 18% compared with 20% and 0% in patients who did not receive adjuvant therapy (p < 0.0001). The 1-, 3-, 5-, and 7-yr survival rates for patients with negative lymph nodes were 73%, 38%, 26%, and 22% compared with survival rates of 52%, 14%, 14%, and 9% in patients with positive lymph nodes (p = 0.01). In multivariate analyses, adjuvant therapy was the only feature found to be strongly associated with survival (hazards ratio = 0.26, 95% CI = 0.15-0.44). CONCLUSIONS: The overall 5- and 7-yr survival rates of 19% and 11% in our study further validate that surgical resection in patients with pancreatic adenocarcinoma can result in long term survival, particularly when performed in association with adjuvant chemoradiation.

Sensory-nerve-mediated nasal vasodilatory response to inspired acetaldehyde and acetic acid vapors.

This study was designed to characterize the acute nasal vasodilatory responses to the sensory irritants acetaldehyde and acetic acid. For this purpose, the upper respiratory tract of the urethane-anesthetized male F344 rat was isolated by insertion of an endotracheal cannula, and irritant-laden air was drawn continuously through that site at a flow rate of 100 ml/min for 50 min. Vascular function was monitored by measuring inert vapor (acetone) uptake throughout the exposure. Both acetaldehyde and acetic acid induced an immediate concentration-dependent vasodilation as indicated by increased steady-state acetone uptake rates. This response was observed at exposure concentrations of 25 ppm or 130 ppm or higher for acetaldehyde or acetic acid, respectively. The response to either vapor was significantly diminished in rats pretreated with the sensory nerve toxin capsaicin (50 mg/kg, 7 days prior to exposure), providing evidence that sensory nerves play a role in the response. Acetaldehyde is metabolized by aldehyde dehydrogenase to acetic acid. Pretreatment with the aldehyde dehydrogenase inhibitor cyanamide (10 mg/kg, 1 h prior to exposure) reduced the vasodilatory response to 200 ppm but not to 50 ppm acetaldehyde. These results suggest that formation of acetic acid is important in the sensory nerve-mediated vasodilatory response to high, but perhaps not to low, concentrations of acetaldehyde.

Effect of prolonged selective intramesenteric arterial vasodilator therapy on intestinal viability after acute segmental mesenteric vascular occlusion.

OBJECTIVE: To evaluate the effect of selective intramesenteric artery vasodilator infusion on intestinal viability in a rat model of acute segmental mesenteric vascular occlusion. SUMMARY BACKGROUND DATA: Although intramesenteric arterial vasodilator infusion may be an effective treatment for nonocclusive mesenteric ischemia, it has also been advocated to increase collateral blood flow after mesenteric vascular occlusion. However, the authors have previously found that intraarterial vasodilators actually reduce collateral blood flow acutely, by preferentially dilating the vasculature of adjacent, nonischemic mesenteric vascular beds, a phenomenon well established in other organs. METHODS: A segment of rat ileum was acutely devascularized, with blood flow provided only by collateral arterial vessels from adjacent, nonischemic bowel. Papaverine (30 or 40 microg/kg/min), isoproterenol (0.06 microg/kg/min), norepinephrine (0.1 or 0.2 microg/kg/min), or vehicle saline was continuously infused into the cranial (superior) mesenteric artery for 48 hours. Viability was then assessed using previously established, objective gross and microscopic criteria. RESULTS: Although papaverine increased total mesenteric blood flow in normally vascularized rats, it not only failed to improve but actually significantly reduced the length of the devascularized segment maintained viable by collateral blood flow after 48 hours. Isoproterenol had a similar effect. Norepinephrine infusion decreased both normal mesenteric blood flow and viable segment length. CONCLUSIONS: These findings suggest that intraarterial vasodilator therapy fails to improve intestinal viability after segmental mesenteric vascular occlusion.

Overview of upper respiratory tract vapor uptake studies.

This review is aimed at highlighting toxicologically relevant physiological and biochemical factors that influence the delivery of inhaled vapors to nasal tissues. Numerous experiments in rodents have shown that vapor uptake efficiencies are dependent on vapor solubility (as measured by blood:air partition coefficient) and inspiratory flow rate. Nasal tissues are rich in xenobiotic metabolizing enzymes, and it has been shown experimentally through the use of metabolic inhibitors that inspired vapors are metabolized in nasal tissue and that this process serves to enhance inspired vapor uptake efficiency in that site. Metabolism-based species differences in vapor uptake have been observed among rodent species. Concentration-dependent changes in vapor uptake have also been observed and related to saturation of local metabolic pathways at high exposure concentrations. Therefore, appropriate consideration of local metabolism is necessary for comprehensive high- to low-dose or species extrapolations of nasal toxicity data. Recent studies have provided evidence of sensory nerve-mediated reflex responses that alter nasal vascular function and may alter nasal inspired vapor dosimetric relationships. In toto, these studies also indicate the need to define uptake behavior for a vapor of interest over a wide range of exposure concentrations due to the possibility of nonlinear metabolism kinetics or the induction of nasal reflex and/or toxic responses. Such data are required for the formulation of a robust nasal dosimetry model.

A hybrid computational fluid dynamics and physiologically based pharmacokinetic model for comparison of predicted tissue concentrations of acrylic acid and other vapors in the rat and human nasal cavities following inhalation exposure.

To assist in interspecies dosimetry comparisons for risk assessment of the nasal effects of organic acids, a hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of inhaled vapors in the rat and human nasal cavity. Application to a specific vapor would involve the incorporation of the chemical-specific reactivity, metabolism, partition coefficients, and diffusivity (in both air and tissue phases) of the vapor. This report describes the structure of the CFD-PBPK model and its application to a representative acidic vapor, acrylic acid, for interspecies tissue concentration comparisons to assist in risk assessment. By using the results from a series of short-term in vivo studies combined with computer modeling, regional nasal tissue dose estimates were developed and comparisons of tissue doses between species were conducted. To make these comparisons, the assumption was made that the susceptibilities of human and rat olfactory epithelium to the cytotoxic effects of organic acids were similar, based on similar histological structure and common mode of action considerations. Interspecies differences in response were therefore assumed to be driven primarily by differences in nasal tissue concentrations that result from regional differences in nasal air flow patterns relative to the species-specific distribution of olfactory epithelium in the nasal cavity. The results of simulations with the seven-compartment CFD-PBPK model suggested that the olfactory epithelium of the human nasal cavity would be exposed to tissue concentrations of acrylic acid similar to that of the rat nasal cavity when the exposure conditions are the same. Similar analysis of CFD data and CFD-PBPK model simulations with a simpler one-compartment model of the whole nasal cavities of rats and humans provides comparable results to averaging over the compartments of the seven-compartment model. These results indicate that the general structure of the hybrid CFD-PBPK model applied in this assessment would be useful for target tissue dosimetry and interspecies dose comparisons for a wide variety of vapors. Because of its flexibility, this CFD-PBPK model is envisioned to be a platform for the construction of case-specific inhalation dosimetry models to simulate in vivo exposures that do not involve significant histopathological damage to the nasal cavity.

Endosonography is superior to angiography in the preoperative assessment of vascular involvement among patients with pancreatic carcinoma.

Surgical exploration in patients with pancreatic carcinoma without adequate preoperative attempts to determine resectability results in resection in only a minority of patients. Besides distant metastases, involvement of the major vessels is the most important parameter for determining resectability in patients with pancreatic adenocarcinoma. Angiography has been an integral part of pancreatic cancer staging. Lately, endoscopic ultrasound (EUS) has emerged as a more accurate tool in the diagnosis and staging of pancreatic cancer. We hypothesize that EUS is more accurate than selective venous angiography (SVA) for assessing resectability of pancreatic adenocarcinoma based on preoperative evaluation of vascular involvement. Twenty-one patients who met the inclusion criteria were prospectively evaluated with both EUS and SVA before undergoing surgical exploration for attempted curative resection. Vascular involvement was determined by EUS and SVA using previously described criteria. The sensitivity, specificity, and overall accuracy of EUS and SVA in assessing vascular involvement were compared, using surgical exploration as the gold standard. Endoscopic ultrasound had a higher sensitivity than SVA for detecting vascular involvement (86% vs. 21%, respectively; p = 0.0018). The specificity and accuracy of EUS for detecting vascular involvement was 71% and 81%, respectively. In contrast, the specificity and accuracy of SVA for detecting vascular involvement was 71% and 38%, respectively. Endoscopic ultrasound is significantly more sensitive than angiography for detecting vascu lar involvement in patients with pancreatic adenocarcinoma and, thus, may improve patient selection for attempted curative resection.

Detection and measurement of middle-distillate fuel vapors by use of tunable diode lasers.

A sensor for the rapid (10-ms response time) measurement of vapors from the hydrocarbon-based fuels JP-8, DF-2, and gasoline is described. The sensor is based on a previously reported laser-mixing technique that uses two tunable diode lasers emitting in the near-infrared spectral region [Appl. Opt. 39, 5006 (2000)] to measure concentrations of gases that have unstructured absorption spectra. The fiber-mixed laser beam consists of two wavelengths: one that is absorbed by the fuel vapor and one that is not absorbed. Sinusoidally modulating the power of the two lasers at the same frequency but 180 degrees out of phase allows a sinusoidal signal to be generated at the detector (when the target gas is present in the line of sight). The signal amplitude, measured by use of standard phase-sensitive detection techniques, is proportional to the fuel-vapor concentration. Limits of detection at room temperature are reported for the vapors of the three fuels studied. Improvements to be incorporated into the next generation of the sensor are discussed.

EUS in preoperative staging of pancreatic cancer.

BACKGROUND: Endoscopic ultrasound (EUS) is believed to be highly accurate in the local (T) and nodal (N) staging of pancreatic cancer. However, there are scant data concerning the predictive value of EUS for resectability of pancreatic adenocarcinoma. This study was performed to determine the accuracy of TNM staging by EUS in patients with pancreatic adenocarcinoma and to evaluate the role of preoperative TNM staging by EUS for determining resectability in patients with pancreatic adenocarcinoma. METHODS: This is a retrospective review of a cohort of 89 patients evaluated preoperatively with EUS for pancreatic adenocarcinoma between January 1995 and December 1997. Preoperative TNM classification by EUS was compared with surgical and histopathologic TNM staging. Resectability rates were determined and compared with the preoperative TNM staging by EUS. RESULTS: The overall accuracy of EUS for T and N staging was found to be 69% and 54%, respectively. The overall proportion of tumors that were deemed resectable by EUS and were actually found to be resectable during surgical exploration was 46%. The proportion of tumors staged as T4 N1, T4 N0, T3 N1 and T3 N0 by EUS that were found to be resectable during surgical exploration was 45%, 37%, 44% and 62%, respectively. CONCLUSIONS: In a tertiary referral patient population, EUS is not as accurate as previously reported in the T and N staging of pancreatic cancer. EUS is also not predictive of resectability in stage T3 or T4 pancreatic cancer.

Outcome of invasive pneumococcal disease: a UK based study. Oxford Pneumococcal Surveillance Group.

METHODS: The records of 106 children aged less than 5 years with invasive disease caused by Streptococcus pneumoniae were reviewed. RESULTS: The clinical manifestations were meningitis (37%), upper respiratory tract infection (24%), pneumonia (19%), and occult bacteraemia (18%). One child died and seven had persisting neurological impairment. Five serotypes caused 83% of disease and 92% of the serotypes are included in the seven valent conjugate vaccines which are undergoing trials. CONCLUSIONS: These data suggest that S pneumoniae infection is associated with a low case fatality rate but substantial morbidity in the UK.

Thrombin stimulation of platelets causes an increase in phosphatidylinositol 5-phosphate revealed by mass assay.

Phosphatidylinositol 5-phosphate (PtdIns5P), a novel inositol lipid, has been shown to be the major substrate for the type II PtdInsP kinases (PIPkins) ¿Rameh et al. (1997) Nature 390, 192-196. A PtdInsP fraction was prepared from cell extracts by neomycin chromatography, using a protocol devised to eliminate the interaction of acidic solvents with plasticware, since this was found to inhibit the enzyme. The PtdIns5P in this fraction was measured by incubating with ¿gamma-(32)PATP and recombinant PIPkin IIalpha, and quantifying the radiolabelled PtdInsP(2) formed. This assay was used on platelets to show that during 10 min stimulation with thrombin, the mass level of PtdIns5P increases, implying the existence of an agonist-stimulated synthetic mechanism.

Uptake of styrene in the upper respiratory tract of the CD mouse and Sprague-Dawley rat.

Inspired styrene is an olfactory toxicant in the mouse and rat. To provide nasal dosimetric information, upper respiratory tract (URT) uptake efficiency (UE) of styrene was measured in the surgically isolated URT of the urethane-anesthetized CD mouse and Sprague Dawley rat throughout a 45-min exposure. In the first studies, the effect of inspiratory flow rate on styrene UE was examined. At flows of 12-, 24-, or 70-ml/min average UE of 17, 9.8, and 4.1%, respectively, were observed in the mouse. For the rat, UE averaged 14, 9.1 and 5.7% at flow rates of 70, 150, and 400 ml/min, respectively. In the second study, UE was measured at inspired concentrations of 5, 10, 25, 50, 100, or 200 ppm at a flow rate of 12 ml/min in the mouse and 70 ml/min in the rat in both naive and metyrapone (150 mg/kg sc) pretreated animals. In the rat, steady state UE decreased with increasing exposure concentration, averaging between 24 and 10% efficiency at 5 to 200 ppm (p < 0.0001). Metyrapone pretreatment resulted in statistically significant reductions in UE with steady-state UE averaging 10-14% at 5-200 ppm. Metyrapone pretreatment abolished the concentration dependence. In naive mice, styrene UE did not maintain a steady state, but steadily declined during exposure. The mechanisms of the non-steady state behavior are not known, but they appear to be due to a styrene metabolite, as evidenced by the fact that steady-state UE was observed in metyrapone-pretreated mice. In the mouse, UE averaged between 42 and 10% efficiency at 5 to 200 ppm (p < 0.0001). Metyrapone pretreatment resulted in statistically significant reductions in UE, with steady state UE averaging 20-10% at 5-200 ppm. As in the rat, metyrapone pretreatment abolished the concentration dependence. In toto, these data provide strong evidence that inspired styrene is metabolized in nasal tissues in the rat and mouse and that a metabolic basis exists for the observed inspired concentration dependence of UE.

Type I phosphatidylinositol 4-phosphate 5-kinase directly interacts with ADP-ribosylation factor 1 and is responsible for phosphatidylinositol 4,5-bisphosphate synthesis in the golgi compartment.

Phosphatidylinositol (PtdIns) 4,5-bisphosphate is involved in many aspects of membrane traffic, but the regulation of its synthesis is only partially understood. Golgi membranes contain PI 4-kinase activity and a pool of phosphatidylinositol phosphate (PIP), which is further increased by ADP-ribosylation factor 1 (ARF1). COS7 cells were transfected with alpha and beta forms of PI 4-kinase, and only membranes from COS7 cells transfected with PI 4-kinase beta increased their content of PIP when incubated with ARF1. PtdIns(4, 5)P(2) content in Golgi membranes was nonexistent but could be increased to a small extent upon adding either cytosol or Type I or Type II PIP kinases. However, when ARF1 was present, PtdIns(4,5)P(2) levels increased dramatically when membranes were incubated in the presence of cytosol or Type I, but not Type II, PIP kinase. To examine whether ARF1 could directly activate Type I PIP 5-kinase, we used an in vitro assay consisting of phosphatidycholine-containing liposomes, ARF1, and PIP 5-kinase. ARF1 increased Type I PIP 5-kinase activity in a guanine nucleotide-dependent manner, identifying this enzyme as a direct effector for ARF1.

The long-term results of resection and multiple resections in Crohn's disease.

Crohn's disease is a panenteric, transmural inflammatory disease of unknown origin. Although primarily managed medically, 70% to 90% of patients will require surgical intervention. Surgery for small bowel Crohn's is usually necessary for unrelenting stenotic complications of the disease. Fistula, abscess, and perforation can also necessitate surgical intervention. Most patients benefit from resection or strictureplasty with an improved quality of life and remission of disease, but recurrence is common and 33% to 82% of patients will need a second operation, and 22% to 33% will require more than two resections. Short-bowel syndrome is unavoidable in a small percentage of Crohn's patients because of recurrent resection of affected small bowel and inflammatory destruction of the remaining mucosa. Although previously a lethal and unrelenting disease with death caused by malnutrition, patients with short-bowel syndrome today can lead productive lives with maintenance on total parenteral nutrition (TPN). This lifestyle, however, does not come without a price. Severe TPN-related complications, such as sepsis of indwelling central venous catheters and liver failure, do occur. Future developments will focus on more powerful and effective anti-inflammatory medication specifically targeting the immune mechanisms responsible for Crohn's disease. Successful medical management of the disease will alleviate the need for surgical resection and reduce the frequency of short-bowel syndrome. Improving the efficacy of immunosuppression and the understanding of tolerance induction should increase the safety and applicability of small-bowel transplant for those with short gut. Tissue engineering offers the potential to avoid immunosuppression altogether and supplement intestinal length using the patient's own tissues.

Sensory nerve-mediated immediate nasal responses to inspired acrolein.

To investigate the role of sensory C-fiber stimulation and tachykinin release in the immediate nasal responses to the sensory irritant acrolein, the upper respiratory tract of the urethan-anesthetized male Fischer 344 rat was isolated via insertion of an endotracheal tube, and acrolein-laden air [2, 5, 10, or 20 parts/million (ppm)] was drawn continuously through that site at a flow rate of 100 ml/min for 50 min. Uptake of the inert vapor acetone was measured throughout the exposure to assess nasal vascular function. Plasma protein extravasation into nasal tissue and nasal lavage fluid was also assessed via injection of Evans blue dye. At 20 ppm, acrolein induced 1) a twofold increase in acetone uptake, indicative of vasodilation, followed by a progressive decline toward basal levels and 2) increased plasma protein extravasation, as indicated by dye leakage into nasal tissue and nasal lavage. These responses were inhibited by capsaicin pretreatment and the neurokinin type 1 antagonist N-acetyltrifluoromethyl tryptophan benzyl ester and were potentiated by the peptidase inhibitors phosphoramidon and captopril, suggesting that these responses were mediated by tachykinin. At lower exposure concentrations, acrolein was without effect on dye leakage but produced vasodilation, as indicated by increased acetone uptake. The responses at the lower concentrations were inhibited by capsaicin pretreatment, implicating nasal sensory C-fiber involvement, but were not influenced by N-acetyltrifluoromethyl tryptophan benzyl ester, phosphoramidon, or captopril, suggesting the involvement of a mediator other than the tachykinins substance P and neurokinin A.

A method for measuring upper respiratory tract vapor uptake and its applicability to quantitative inhalation risk assessment.

A thorough understanding of the toxicity of any substance requires knowledge of the relationships between exposure concentration and dose delivered to the critical target site. This is particularly true for inhalation exposures because inspired particles and vapors do not deposit uniformly in the respiratory tract. The current report describes in detail a methodology for measuring upper respiratory tract (URT) uptake of vapors in the rat. A urethane-anesthetized animal model is utilized in which two endotracheal tubes are inserted: one leading toward the lung to facilitate respiration, and the other toward the nose to allow air sampling through the nasal passages. The animal is placed in a nose-only exposure chamber and test vapor is drawn through the nose for periods up to 1 h. Uptake efficiency is calculated from the difference in vapor concentration between the inspired (chamber) air and air exiting the URT. Uptake data are provided for acetaldehyde and nicotine vapors, and a suggested experimental design that includes multiple air flow regimes and inspired concentrations is described. The data obtained by this methodology are not necessarily reflective of uptake efficiencies in normally breathing animals due to the nonphysiologic airflow regimes and the invasiveness of the procedure. The data so obtained are best utilized to support and validate state-of-the-art mathematical simulation models of regional vapor uptake. These models increase scientific rigor and reduce uncertainty in quantitative risk assessments for inhaled materials.

The effect of inhibition of aldehyde dehydrogenase on nasal uptake of inspired acetaldehyde.

At exposure concentrations of 750 ppm or more, acetaldehyde is a rodent inhalation carcinogen that induces nasal tumors. Aldehyde dehydrogenase (ALDH) is thought to be an important detoxifying enzyme for aldehydes. Although nasal tissues express ALDH, the importance of this enzyme relative to delivered dosage rates at high-inspired concentrations is not well defined. To provide such information, uptake of inspired acetaldehyde was measured at an inspiratory flow rate that approximated the minute ventilation rate in the surgically isolated nasal cavity of F 344 rats pretreated with either saline (control) or the ALDH inhibitor, cyanamide (10 mg/kg s.c.). ALDH activities (substrate concentration 3 times the K(m)) in anterior (respiratory mucosa) and posterior (olfactory mucosa) nasal tissues averaged 160 and 210 nmol/min), respectively, in control animals (total activity 370 nmol/min), compared to 60 and 80 nmol/min, respectively, in cyanamide-pretreated rats (p < 0.05), indicating that approximately 60% inhibition was obtained. Nasal uptake was measured at 3 inspired concentrations: 10, 300, and 1500 ppm. At these concentrations, acetaldehyde uptake efficiency averaged 54, 37, and 34% in saline-pretreated rats, respectively (p < 0.05). In absolute terms, the delivered dosage rates at these exposure concentrations averaged 21, 420, and 1990 nmol/min. The concentration dependence on uptake suggests a saturable process was involved. At inspired concentrations of 300 ppm or more, the delivered dosage rates exceeded the measured specific activity for nasal ALDH of 370 nmol/min. Cyanamide pretreatment abolished the concentration dependence. Specifically, uptake efficiencies in cyanamide-pretreated rats averaged 30, 27, and 31% at inspired concentrations of 10, 300, and 1500 ppm, respectively (p > 0.05); delivered dosage rates were 12, 310, and 1780 nmol/min. Thus, cyanamide pretreatment reduced nasal-delivered dosage rates at inspired concentrations of 10, 300, and 1500 ppm, respectively by 9, 110, and 210 nmol/min, values that correspond well with the total nasal ALDH activity of 370 nmol/min. In toto, these results suggest that inspired acetaldehyde is metabolized in situ by ALDH, but at exposure concentrations of 300 ppm or greater, the delivered dosage rate may equal or exceed the capacity of this enzyme.