Age-Dependent Effect of Ozone on Pulmonary Eicosanoid Metabolism in Rabbits and Rats

Age-Dependent Effect of Ozone on Pulmonary Eicosanoid Metabolismin Rabbits and Rats. GUNNISON, A. F., FINKELSTEIN, I., WEIDEMAN,P., SU, W.-Y., SOBO, M., AND SCHLESINGER, R. B. (1990). Fundam.Appl Toxicol. 15, 779–790. Acute exposures to ozone havepreviously been shown to cause quantitative changes in the spectrumof arachidonic acid (AA) metabolites in lung lavage fluid. Sinceage appears to be an important variable in the toxicity of inhaledozone, we investigated its effect on ozone-induced changes inpulmonary eicosanoid metabolism. Rats and rabbits ranging inage from neonates to young adults were exposed either to airor to 1 ppm ozone for 2 hr. Lung lavage fluid was collectedwithin 1 hr following exposure and analyzed for its contentof selected eicosanoids. In both species, there was a pronouncedeffect of age on ozone-induced pulmonary eicosanoid metabolism.Ozone-exposed animals at the youngest ages examined had severalfoldgreater amounts of two products of the cyclooxygenase pathway,prostaglandin E₂ (PGE₂) and prostaglandin F_2a (PGF_2a), thandid age-matched controls. This effect lessened and eventuallydisappeared as the animals grew toward adulthood. In rabbits,ozone also induced increases in 6-keto-prostaglandin F_1a andthromboxane B₂, but these changes were of lesser magnitude andevident only in the youngest rabbits exposed. There was no observedeffect of ozone on lung lavage content of leukothriene B₄. Indicesof nonspecific pulmonary damage, i.e., protein concentrationin lung lavage fluid and total number and viability of lavagedlung cells, were affected by ozone exposure, but not in an age-dependentmanner that correlated with changes in pulmonary eicosanoidmetabolism. In vitro ozone exposure of lung macrophages fromnaive rabbits of the same age range as those exposed in vivodemonstrated that ozone is capable of stimulating the elaborationof PGF_2a and especially PGE₂. However, the increase in lavagefluid PGE₂ and PGF_2a caused by ozone inhalation could not beattributed to macrophage metabolism conclusively since elaborationof PGE₂ and PGF_2a by cultured macrophages was not enhanced byprior in vivo ozone exposure. In an ancillary study it was shownthat 15-hydroxyprostaglandin dehydrogenase (PGDH) activity inrabbit lung homogenates was not affected by prior exposure toozone, indicating that the increase in lung lavage fluid eicosanoidsthat occurred in these animals could not be explained by inhibitionof PGDH.     

Effects of Phosgene Exposure on Lung Arachidonic Acid Metabolism

Abstract

Phosgene can acylate macromolecules and may react with and affect enzymes involved in arachidonic acid metabolism. We examined the effects of an acute phosgene exposure in vivo and in vitro on lung arachidonic acid metabolism. Fischer 344 rats were exposed either to air or to phosgene (0.05–7.0 ppm) for 4 h and the lungs were lavaged at 0, 4, 20, and 44 h postexposure. Leukotriene B, (LTBJ, peptide leuko-trienes C₄ D₄ and E₄ (LTC₄/D/E₄, and prostaglandin E₂ (PCE₂) were measured in la-vage fluid by radioimmunoassay Phosgene exposure in vivo (0.7–7.0 ppm for 4 b) produced significant decreases in concentrations of PGE, (maximal decrease of 74%), LTB, (maximal decrease of 59%), and LTC₄/D₄/E₄ (maximal decrease of 97%) measured in rat lavage fluid immediately postexposure. Associated with this decrease in eicosa-noid production was a decrease in the number of alveolar macrophages and an increased number of neutrophils recovered in the lavage fluid of phosgene-exposed rats. Lung lavage eicosanoid concentrations in rats exposed to either 0.7 or 0.25 ppm phosgene returned to or exceeded air control values by 44 h postexposure. However, rats exposed to 0.5 or 7.0 ppm phosgene had a persistent decrease in the concentration of PGE, and LTC₄/D₄/E₄ at44h after the exposure. Phosgene exposure in vitro (7.0 ppm for 4 h) of rat or human alveolar macrophages induced a 56% decrease in the production of LTB₄ in the rat macrophages and a 31% nonsignificant decrease in the formation of LTB₄ in human alveolar macrophages. Production of PCE, and the LTC₄/D₄/E₄ by the rat macrophages, and PCE₂ by the human macrophages, was not different from air-exposed culture values. These data suggested that phosgene exposure altered arachidonic acid metabolism in rat lungs after in vivo exposure and in rat and human alveolar macrophages after exposure in vitro. These changes in lung mac-rophage arachidonic acid metabolism may be involved in some of the lung responses to phosgene exposure.     

Functional Assessment of Rabbit Alveolar Macrophages following Intermittent Inhalation Exposures to Sulfuric Acid Mist

Functional Assessment of Rabbit Alveolar Macrophages followingIntermittent Inhalation Exposures to Sulfuric Acid Mist. SCHLESINGER,R. B. (1987). Fundam. Appl. Toxicol. 8, 328–334. Sulfuricacid (H₂SO₄) aerosols are common in both ambient and occupationalenvironments. This study examined the numbers and selected invitro functional properties of alveolar macrophages recoveredfrom rabbits undergoing inhalation exposure to 0.5 mg/m³ submicrometer(0.3 µm) H₂SO₄ for 2 hr/day. Bronchoalveolar lavage wasperformed on Days 3, 7, and 14 during the exposure period (specifically,24 hr after either 2, 6, or 13 exposures). Total cell numbersand macrophage counts were increased on Day 3, but returnedto control levels by Day 7; no change in polymorphonuclear leukocyteswas observed at any time point. Macrophage substrate attachmentwas not affected by exposures to H₂SO₄, but random mobilitywas severely depressed at Days 7 and 14. The numbers of phagocyticallyactive macrophages and the level of such activity were increasedon Day 3, but became depressed by Day 14. These results demonstratesignificant alterations in important functional properties ofalveolar macrophages due to short-term intermittent exposuresto H₂SO₄ aerosols; these changes have implications for the abilityof the lungs to maintain adequate defense against depositedviable and nonviable particles.     

Mercapturic Acid Excretion by Rats following Inhalation Exposure to m1,3-Dichloropropene

Mercapturic Acid Excretion by Rats following Acute InhalationExposure to 1,3-Dichloro-propcne. Fisher, G. D., and Kjlgore,W. W. (1988). Fundam Appl. Toxicol. 11, 300–307. Ratswere exposed to 1,3-dichloropropene (DCP), a commonly used agriculturalnematicide, by inhalation to assess the relationship betweenDCP concentration and the urinary excretion of the mercapturicacid of cis-DCP (3C-NAC). The nose-only exposure system thatwas used for simultaneously exposing up to four rodents is described.This apparatus provided for generation and monitoring of relativehumidity and test vapor concentration. Animals were exposedfor 1 hr to concentrations of up to 789 ppm DCP. Urine was collectedfor 24 hr after exposure. The quantity of 3C-NAC contained inthe urine collections exhibited an exposure concentration-dependentincrease from 0 to 284 ppm DCP. However, the amount of 3C-NACwas no greater for animals exposed to 398 or 789 ppm DCP thanfor animals exposed to 284 ppm DCP. C 1988 Society of Toxicology     

A Novel System for the in Vitro Exposure of Pulmonary Cells to Acid Sulfate Aerosols

While ambient acid aerosols are considered a potential respiratoryhealth hazard, the mechanism by which they induce responsesin the lungs is not known. Attempts to ascertain these mechanismsusing inhalation exposures are complicated by a number of technicaldifficulties, chief among which are neutralization of inhaledacids by endogenous ammonia and variations in deposition withinhaled particle size. To control for these variables, a novelin vitro exposure system allowing experimental evaluation offactors which influence biologic responses to acid sulfate particleswas developed. The system consists of two subunits, a generation/deliverycomponent and a cell exposure component. Sulfuric acid aerosolsare generated by nebulizing dilute acid solutions. Particleslarger than a specified size of interest (based upon the specificexposure conditions desired) are removed, and particles at thedesired size and mass concentration are uniformly deliveredonto a target cell monolayer. The system is capable of deliveringacid particles larger than 0.7 µm (mass median diameter),yet at constant particle mass concentrations. This paper describesthe design of the exposure system and its performance characteristicsand presents initial results of some biological responses obtainedusing it. In conjunction with inhalation studies, this exposuresystem may provide additional insights into mechanisms by whichacid aerosols adversely affect the respiratory tract and intothe physical characteristics of acid particles which modulatetoxicity.     

Changes in Carbohydrate Metabolism in Various Organs of the Snail,Lymnaea acuminata following Exposure to Trichlorfon

Abstract: Several aspects of carbohydrate metabolism following 24 hr and 48 hr treatment with 10 and 20 mg/l of trichlorfon, were studied in hepatopancreas, mantle, intestine and foot of the snail, Lymnaea acuminata. Following treatment with the pesticide, the rate of oxygen consumption and concentration of glycogen were reduced, while the levels of lactic acid and reducing sugars were enhanced. Withdrawal of pesticide for 7 days following trichlorfon treatment (10 mg/l for 48 hrs) could not reverse these changes.     

Effects of Cyclosporin on Kidney Glutathione Metabolism and Cytochrome P-450 in the Rabbit: Possible Implication of Eicosanoid Metabolism

ABSTRACT

This study was designed to assess Cyclosporin A (CsA) nephrotoxicity in the rabbit - possibly a more sensitive species than the rat - and to explore the mechanism of this toxicity with special attention to glutathione metabolism disturbances and cytochrome P-450 level in the kidney. CsA given for three days at a daily dose of 50 mg/kg (s.c.) induced nephrotoxicity as assessed by histological abnormalities and by a significant increase in blood urea nitrogen and urinary enzyme activities : N-acetyl-β-D-glucosaminidase and L-gamma-glutamyl-transferase. This observed renal injury was of the same order as that obtained in the rat.

In addition, there was a significant increase in oxidized glutathione content (40%) while reduced glutathione level remained unchanged. Concurrently, there was a significant decrease in renal cortex glutathione reductase (49%) and to a lesser extent in glutathione peroxidase activities (16%) whereas that of glutathione-S-transferase was not modified. A significant increase in renal cortex cytochrome P-450 (3-fold versus controls) was also observed. The mechanism of CsA nephrotoxicity is to be related to a cytochrome P-450 induction. This event could induce the observed impairments in renal glutathione metabolism and Na⁺K ⁺-ATPase activity, via a possible increase in eicosanoid metabolism.     

Exposure to Bisphenol A Affects Lipid Metabolism in Drosophila melanogaster

Exposure to bisphenol A (BPA) in rodents was shown to induce obesity, yet the mechanism by which BPA might induce obesity is still unclear. We employed the genetically tractable model organism, Drosophila melanogaster, to test the effects of raising them on food containing various concentrations of BPA. Of note, raising males on food containing BPA were susceptible to starvation, possibly by inhibiting their ability to perform lipolysis during starvation, leading to significantly increased lipid content after 24 hr of fasting. Furthermore, feeding males with BPA significantly inhibited the expression of insulin‐like peptides. From these results, we conclude that BPA may inhibit lipid recruitment during starvation in Drosophila.     

Pulmonary Response to Toner upon Chronic Inhalation Exposure in Rats

Pulmonary Response to Toner upon Chronic Inhalation Exposurein Rats. MUHLE, H., BELLMANN, B., CREUTZENBERG, O., DASENBROCK,C., ERNST, H., KILPPER, R., MACKENZIE, J. C., MORROW, P., MOHR,U., TAKENAKA, S., AND MERMELSTEIN, R., Fundam. Appl. Toxicol.17, 280–299. A chronic inhalation study of a test tonerwas conducted by exposure of groups of F-344 rats for 6 hr/day,5 days/week for 24 months The test toner was a special Xerox9000 type xerographic toner, enriched in respirable-sized particlescompared to commercial toner, such that it was about 35% respirableaccording to the ACGlH criteria. The target test aerosol exposureconcentrations were 0, 1.0 (low), 4.0 (medium), and 16.0 (high)mg/m³. Titamum dioxide (5 mg/m³) and crystalline silicon dioxide(1 mg/m³), used as negative and pasitive controls for fibrogenicity,were also evaluated. Inhalation of the test toner or the controlmaterials showed no signs of overt toxicity. Body weight, clinicalchemistry values, food consumption, and organ weights were normalin the toner- and TiO₂-exposed groups, except for a 40% increasein lung weight in the toner highexposure group. All of the changesin the toner-exposed groups were restricted to the lungs orassociated lymph nodes. A chronic inflammatory response wasevident from the bronchoalveolar lavage parameters for the tonerhigh-exposure group. The incidence of primary lung tumors wascomparable among the three toner-exposed groups and the TiO²-exposed,and air-only controls, as well as consistent with historicalbackground levels A mild to moderate degree of lung fibrosiswas observed in 92% of the rats in the toner high-exposure group,and a minimal to mild degree of fibrosis was noted in 22% ofthe animals in the toner high-exposure group. The pulmonarychanges in the toner high-exposure group were smaller in magnitudethan those found in the crystalline silica-exposed group. Thecomparative fibrogenic potency of TiO², toner, and SiO² wasestimated to be 1:5:418 using a dasimetric model and assuminga common mechanistic basis. There were no pulmonary changesof any type at the toncr low-exposure level, which is most relevantin regard to potential human exposures The lung alterationsin the toner high-exposure group are interpreted in terms of"lung overloading," a generic response of the respiratory systemto saturation of its detoxification capacity. The maximum tolerateddose (MTD) criterion was met at the toner high (16 mg/m³)-exposurelevel.     

Effects of Sulfuric Acid on Ferret Respiratory Tract Clearance

Abstract

This study was performed to assess the effects of sulfuric acid inhalation, and partly to examine the potential suitability of the laboratory ferret as a respiratory tract clearance model. Separate groups of ferrets were first exposed nose-only to purified air, 0.5 mg/m³ ofsulfuric acid aerosol, and 1.0 mg/m³ ofsulfuric acid aerosol for 4 h. Following the deposition of radiolabeled tracer microspheres, the clearance rates from the head and chest regions were monitored using collimated radiation detection equipment. The results indicate that (1) neither of the acid atmospheres produced a statistically significant effect on the clearance rate of the head region; (2) the high-acid atmosphere produced a significant acceleration in the clearance rate of the lung region; and (3) the long-term lung clearance rate of the purified air-exposed ferrets was very close to that observed with humans. Also, the ferrets were docile and easy to handle, and seemed to be well suited to this type of study.     

Exposure to cyanide following a meal of cassava food

Exposure to cyanide from gari, a popular cassava food in West Africa, is implicated in the causation of ataxic polyneuropathy and amblyopia, but this has been questioned because cyanide was not detected in gari in a study. This study was carried out to determine if gari is a source of exposure to cyanide. Gari (150 g) containing cyanohydrin, from which 128 micromol of cyanide ions could be released, was dissolved in 500 ml of cold water for each of the 12 healthy subjects to drink. Concentrations of cyanide in plasma and erythrocytes were determined at baseline and following the meal at 30 min, 1 h, hourly for 4 h and two hourly for 12 h. The mean concentrations of cyanide in the plasma were 6 micromol/l (95% CI 2-10) at baseline, 12 micromol/l (95% CI 6-17) at peak and 6 micromol/l (95% CI 2-10) on return to baseline. The mean amount of cyanide absorbed into the plasma was 13 micromol (S.D. 12), while the transit time of absorbed cyanide was 7.3 h (S.D. 2.1). This study shows that exposure to cyanide follows consumption of gari, but the amount of cyanide absorbed into the plasma from a single meal is small and unlikely to cause acute intoxication. The long transit time of absorbed cyanide in the plasma suggests that frequent intake of gari could cause cyanide to accumulate in the plasma.     

Pulmonary Host Defenses and Resistance to Infection Following Subchronic Exposure to Phosgene

Abstract

Acute exposure to phosgene, a toxic gas widely used in industrial processes, decreases resistance to bacteria in mice and rats and enhances susceptibility to B16 tumor cell challenge in mice. These effects appear to be due to impaired alveolar macrophage and natural killer (NK) cell activity, respectively. In this study effects of repeated phosgene exposures on bacterial infection and NK activity were determined. Rats were exposed for 4 or 12 wk, 6 h/day, 5 days/wk, to 0.1 or 0.2 ppm phosgene or 2 days/wk to 0.5 ppm and infected by aerosol with Streptococcus zooepidemicus immediately after the last exposure. An additional group was also infected after 4 wk of recovery following the 12-wk exposure regimens. Bronchoalveolar lavage (BAL) fluid was assessed 0, 6, and 24 h postinfection for bacteria and inflammatory cells. Differential cell counts in BAL and pulmonary NK activity were also determined in uninfected rats 18 Is after the last exposure. All phosgene exposures impaired clearance of bacteria from the lungs and caused an increase in polymorphonuclear leukocytes (PMNs) in BAL of infected rats. Effects in the 0.5 ppm exposure group were greatest, and were significantly different from those in the 0.2 ppm exposure group, although the product of concentration × time was the same. BAL cell counts and bacterial clearance were normal in rats assessed 4 wk after the 12-wk phosgene exposures. Bacterial clearance and the PMN response to infection following repeated exposure were similar to those observed after a single exposure; that is, for these endpoints, effects due to repetitive exposure were neither additive nor attenuated. In contrast, NK activity was suppressed only at the 0.5 ppm level, and the magnitude of suppression was much less than that following acute exposure, suggesting that attenuation of this effect did occur with repeated exposure. The data indicate that susceptibility to streptococcal infection is a sensitive endpoint for phosgene toxicity following subchronic exposure.     

Determination of Mercapturic Acid Excretions in Exposure Control to Toxicants

Abstract

Toxicants can be converted in vivo by a variety of biotransformation reactions into substances that are more, equally, or less noxious than the parent compound. Although conjugation with glutathione is a process that usually results in less harmful products, these products might subsequently form new metabolites that exert more toxicity than the parent compound. These conjugation reactions are catalyzed by several classes of glutathione-S-transferase isoenzymes and thus result in the urinary or biliary excretion of N-acetyl-L-cysteine-S-conjugates (mercapturic acids). Inasmuch as GSH-S-transferase activity varies among different tissues, urinary excretion of mercapturic acids might reflect tissue-specific toxicity. Urinary mercapturic acids are biomarkers of internal and, in some cases, effective dose. The utility of these markers is, however, limited to times shortly after exposure. Studies on possible human deficiencies in some GSH-S-transferases might help us better understand interindividual variations in susceptibility to different toxicants and thus the differences in the pathway of mercapturic acid excretion pattern.     

Pulmonary tolerance to cadmium following cadmium aerosol pretreatment

Male Lewis rats pretreated by inhalation of an atmosphere containing 1.6 mg Cd/m3 for 4 weeks (3 hr/day, 5 days/week) exhibited pulmonary tolerance when challenged with a single 3-hr acute exposure to 8.4 mg Cd/m3. Tolerance in prior-exposed animals was suggested by (a) bronchoalveolar lavage fluid analysis showing a reduction in the number of inflammatory cells and decreased release of lactic dehydrogenase, alkaline and acid phosphatase, and protein into the alveolar space and (b) an earlier resolution in lung histopathology following Cd challenge compared to sham air control animals. Multiple defense mechanisms appear to be involved in the development of pulmonary tolerance to Cd. Metallothionein (MT) content in lungs of prior-exposed animals was 50-fold higher than that in untreated animals. The amount of Cd retained in the lungs after the challenge dose was the same regardless of whether the animals had been pretreated with Cd. However, the Cd/thionein ratio was considerably lower in treated animals and did not increase upon challenge, suggesting that synthesis of MT was keeping abreast with the amount of accumulated Cd. Pretreatment of animals with Cd aerosols also led to an increase in the number of type II alveolar cells which may, in turn, be responsible for increasing nonprotein sulfhydryl groups and antioxidant enzymes in the lung.     

Pulmonary toxicity following exposure to waterproofing grout sealer

Introduction

We report a large number of cases of pulmonary toxicity from 6 regional poison control centers associated with the use of a waterproofing-grout sealer. The identification of this illness occurred by means of the poison control center (PCC) national automated toxicosurveillance.

Materials and Methods

This is a retrospective case review of all cases of pulmonary toxicity following exposure to a waterproofing grout sealer from 6 regional PCCs including Michigan, Kentucky, Utah, Maine, Arizona, and Nebraska. The study period extended from June 1, 2005 to December 1, 2005.

Results

The vast majority of patients used the product at home (80%). Over half the patients presented within 3 hours of exposure. The most common presenting symptoms were shortness of breath (63%), cough (60%), and chest pain (44%). Wheezing (33%) and rales (23%) were the most common signs of clinical toxicity. One patient required endotracheal intubation. Thirty-seven percent of patients had signs of acute pneumonitis on initial chest x-ray. The mean presenting oxygen saturation was 89.5%. The most common treatment measures used were supplemental oxygen, bronchodilator therapy, oral steroids, and antibiotics. Over half of the study group required hospital admission.

Conclusion

The majority of patients in this study were adults using the product at home. Over one-third of patients had an abnormal x-ray upon presentation. Over half of the study group required hospital admission following exposure to this product. Medical professionals should be aware of the potential for pulmonary toxicity due to waterproofing aerosols.     

Metabolism of Acrylic Acid to Carbon Dioxide in Mouse Tissues

Acrylic acid (AA) is acutely irritating at sites of initialcontact but causes little systemic toxicity probably due toits rapid metabolism to CO₂ and acetyl-CoA via a secondary pathwayof propionic acid catabolism. In this study, the rate of AAoxidation in 13 tissues of C3H mice was measured by incubatingtissue slices with [1-¹⁴C]AA and collecting ¹⁴CO₂. Oxidationof AA followed pseudo-Michaelis-Menten kinetics in the liver,kidney, and skin. Pseudo-K_m values were similar among thesetissues and averaged 0.67 mM. The maximal rate of AA oxidationin kidney, liver, and skin was 2890±436 (mean±SE,N=3), 616±62, and 47.9±5.8 nmol/hr/g, respectively.The remaining organs oxidized AA at rates less than 40% of therate in liver. Rates of metabolism in tissues from male andfemale mice were similar. 3-Hydroxypropionic acid was the onlymetabolite detected by high-performance liquid chromatographicanalysis following incubation of tissues with [1-¹⁴C]AA. Kidneyand liver also oxidized [2,3-¹⁴C]AA and [1-¹⁴C]acetate well,thus providing for the complete metabolism of AA carbons toCO₂. These results demonstrate that the rate of AA metabolismvaries significantly among mouse tissues and suggest that thekidneys and liver are major sites of detoxification of AA.     

Increased Endobiotic Fatty Acid Methyl Esters Following Exposure to Methanol

Human exposure to methanol is likely to increase in the futuredue to its proposed use as an alternate automobile fuel. Sincealcohols are known to esteri1 the fatty acids in the body andsome of those esterifled esters are toxic, we studied the formationof fatty acid esters of methanol in Long-Evans male rats givena single oral dose of 3.5 g/kg body weight of methanol in saline.Animals given an equal volume of saline served as control. Threerats were euthanized at 1, 3, 6, 12, and 24 hr following thetreatment. Fatty acid methyl esters, extracted from whole blood,liver, pancreas, and brown fat were separated by thin-layerchromatography and quantitated by gas chromatography (GC). Theiridentity was then confirmed by GC-mass spectrometry. Averagelevels as high as 596, 5293, 2239, 1106, 9665, 7728, 562, and2792 µg/g (wet weight basis) of 14:0, 16:0, 16:1, 18:0,18:1, 18:2, 18:3, and 20:4 fatty acid methyl esters, respectively,were found in the pancreas of methanol-treated rats. The averageconcentration of total fatty acid methyl esters was computedto be 4513, 29594, 22871, 18956, 17014, and 9702 µg/gin the pancreas compared to 1.9, 25.4, 36.8, 18.5, 18.9, and14.2 µg/g in the liver at 0, 1, 3, 6, 12, and 24 hr, respectively,following methanol exposure. On dry lipid weight basis, thelevels were significantly higher again in pancreas followedby brown fat and liver. In whole blood, only low levels of 16:0,18:0, and 20:4 fatty acid methyl esters could be detected atall time points. The highest concentration of total fatty acidmethyl esters in the pancreas, liver, and brown fat was detectedat 1, 3, and 24 hr, respectively. Most of the fatty acid methylesters found in the liver and pancreas decreased after 6 hrof methanol exposure. The fatty acid methyl esters of higherconcentrations were 16:0 in the whole blood, 18:0, 18:1, 18:2,and 20:4 in liver, 18:1, and 18:2 in pancreas and 16:0, 18:1,and 18:2 in brown fat. These fatty acid methyl esters were alsodetected in the tissues of control rats indicating their endogenousformation. Significant increase in methylation of the fattyacids during methanol exposure, as found in this study, mayserve as a defense mechanism for preventing available methanolfrom oxidative metabolism to render toxicity. However, the biologicalsignificance of these fatty acid methyl esters is yet to beunderstood.     

Pulmonary First-Pass and Steady-State Metabolism of Phenols

Purpose. To study (A) the effect of the administration route (i.v. and i.t.) on pre- and post-absorptive metabolism of phenol and 1-naphthol by the lung and (B) pulmonary extraction of phenol at steady-state. Methods. Phenols were administered intra-arterially, intravenously and intratracheally and the pre- and post-absorptive metabolism assessed by comparing the AUCs in arterial blood. Phenol was infused to steady-state and the pulmonary extraction assessed by measuring jugular vein and carotid artery blood concentrations. Results. In contrast to previously published data (e.g., Mistry and Houston, Drug Metab. Dispos. 13:740–745 (1985)) we could not detect pulmonary first-pass metabolism of the phenols; reasons for this disparity are discussed. An apparent negative pulmonary extraction of phenol at steady-state was observed, probably as a consequence of extraction by organs which are in series, and not parallel, with the lungs (e.g. liver, kidneys and GIT). Conclusions. (A) Phenol and 1-naphthol do not undergo pulmonary first-pass metabolism. (B) Traditional methods of assessing organ extraction and clearance at steady-state cannot be utilised when metabolising organs are in series.     

Modulation of serum complement levels following exposure to polychlorinated dibenzo-p-dioxins

Subchronic 14-day exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed serum total hemolytic complement activity (CH50) in female B6C3F1 mice at doses of 0.01, 0.05, 0.1, 0.5, 1.0, and 2.0 micrograms/kg. Serum levels of complement component C3 were also suppressed at doses of 0.5, 1.0, and 2.0 micrograms/kg. Another dioxin isomer, 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HCDD), also produced dose-dependent suppression of complement activity at doses of 0.1, 1.0, and 10 micrograms/kg with decreased C3 levels at 10 micrograms/kg. Both TCDD and HCDD enhanced susceptibility to Streptococcus pneumoniae, a bacterial pathogen whose host defense is complement mediated. Recovery studies demonstrated that complement activity in TCDD (1 microgram/kg) and HCDD (10 micrograms/kg)-treated animals was suppressed until 50 days post-treatment, while low doses of HCDD (0.1 and 1.0 micrograms/kg) elevated CH50 levels. Acute exposure to TCDD (14 micrograms/kg) also suppressed complement CH50 and C3 levels. These studies demonstrate that the complement system and innate immunity represent potential target sites for polychlorinated dibenzo-p-dioxins.     

Pulmonary Response to Perfluoropolymer Fume and Particles Generated under Various Exposure Condotions

Pulmonary Response to Perfluoropolymer Fume and Particles Generatedunder Various Exposure Conditions. LEE, K. P., AND SEIDEL W.C. (1991). Fundam Appl. Toxicol. 17, 254–269. Combustion-producttoxicity of perfluorinated polymers in small-scale tests variedmarkedly under various exposure conditions. The toxicity ofperfluoropolymer fumes is associated with submicron pyrolysispartides (0.03–0.15 µm ) in the fumes The toxicityof pyrolysis products was not observed in rats exposed to thefumes filtered to remove the particles. The particles in thefume were agglomerated by aging or a water-treatment process,and the toxicity of particles was markedly reduced when ratswere exposed to aged or water-treatd fumes. Some agglomeratedparticles showed chain-aggregation and ultimately attained nonrespirablesize. The reduced toxicity of pyrolysis fume is believed tobe due to a decreased number of toxic particles resulting fromparticle agglomeration. Aged particle agglomerate was not toxicwhen instilled intratracheally into the rats. However, the particleagglomerate became toxic when rats were exposed by the inhalationto fumes evolved from the reheated agglomerate. The fumes containednumerous toxic submicron particles evolved from thermal dacompositionof agglomerates by reheating. Rats exposed to the pyrolysisfumes died with pulmonary edema and hemorrhage due to Type Ipneymoqte damage. The edematous lungs revealed some agglomeratedparticles, but it was difficult to distinguish small pyrolysisparticles from contaminating dust or cellular debris.