Chronic marijuana smoke alters alveolar macrophage morphology and protein expression.

Male rhesus monkeys were subjected to chronic exposure to marijuana smoke. High dose animals (HI) were exposed 7 days/week to 1 MJ cigarette/day; low dose animals (LO) were exposed on 2 consecutive weekend days to 1 MJ cigarette/day; placebo animals (EM) were exposed to 1 ethanol-extracted MJ cigarette/day for 7 days/week; sham animals (SH) were exposed to sham smoking conditions 7 days/week. This regimen was maintained for 1 year and was followed by a 7 month rest period. Alveolar macrophages of animals exposed to the LO and HI dose smoking regimens exhibited irregular cell surface morphology, increased vacuolization, and a spherical conformation upon adherence to plastic. Gel protein profiles of purified macrophages from HI and LO animals showed marked differences in both constitutive and bacterial lipopolysaccharide-elicited protein expression when compared with those of macrophages from the EM or SH animals. These results indicate that chronic THC exposure alters macrophage morphology and protein expression to external stimuli even after a 7 month rest period.     

The Inhalation Toxicity of Two Commercial Dyes: Solvent Yellow 33 and Solvent Green 3

The Inhalation Toxicity of Two Commercial Dyes: Solvent Yellow33 and Solvent Green 3. Sun, J. D., HENDERSON, R. F., MARSHALL,T. C., CHENG, Y.-S., DUTCHER, J. S., PICKRELL, J. A., MAUDERLY,J. L., HAHN, F. F., BANAS, D. A., SEILER, F. A., AND HOBBS,C. H. (1987) Fundam. Appl. Toxicol. 8, 358–371. The quinolinedye 2-(2'-quinolyl)-l,3-indandione or Solvent Yellow 33 (SY)and the anthraquinone dye 1,4-di-p-toluidinoanthraquinone orSolvent Green 3 (SG) are used in many manufactured productsincluding military smoke grenades. During manufacturing, SYor a combination of both SY and SG can be released into theair, exposing factory workers by inhalation to these dye compounds.The potential inhalation toxicity of these compounds was testedby exposing F344/N rats to different concentrations of SY orSY/SG dye mixture (30:70 w/w) for 6 hr/day, 5 days/week for4 or 13 weeks. In the 4-week studies, rats were exposed to SYaerosols at average concentrations of 10 ± 5, 51 ±10, or 230 ± 30 mg/m³ ( ± SD) or SY/SG aerosolsat average concentrations of 11 ± 5, 49 ± 11,or 210 ± 50 mg/m³ ( ± SD). Rats exposed to thehighest concentration of SY or SY/SG had body weights that were8% or 7% less, respectively, than their controls after exposure.Rats exposed to the highest concentration of SY/SG for 4 weeksalso had reduced pulmonary gas exchange efficiency, airflowobstruction, mild pulmonary inflammation, slight Type II pulmonaryepithelial cell hyperplasia, and proliferation of vacuolatedalveolar macrophages. In the 13-week studies, rats were exposedto SY aerosols at average concentrations of 1.0 ± 0.2,10.8 ± 1.8, or 100 ± 17 mg/m3 ( ± SD) orSY/SG aerosols at average concentrations of 1.1 ± 0.5,10.2 ± 3.1, or 101 ± 23 mg/m3 ( ± SD).Animals exposed to the highest concentration of SY or SY/SGfor 13 weeks had body weights that were 5 or 9% less, respectively,than their controls after exposure and had accumulation of vacuolatedalveolar macrophages in lungs. Rats exposed to the highest concentrationof SY/SG dye mixture for 13 weeks also had indications of mildpulmonary inflammation and slight Type II pulmonary epithelialcell hyperplasia. Very little SY was found in lungs after anyexposures, indicating its clearance from lungs was at a rapidrate. However, significant amounts of the SG component of theSY/SG mixture were detected in lungs after each exposure. Lungclearance half-times of SG from the 13-week exposure were estimatedto be 280 days. In summary, neither test material appeared tobe highly toxic following inhalation. However, the slightlyhigher toxicity observed for SY/SG over SY alone is probablyrelated to the longer lung retention of the SG component ofthe dye mixture.     

No increase in carcinogen-DNA adducts in the lungs of monkeys exposed chronically to marijuana smoke.

Rhesus monkeys exposed to marijuana smoke either 7 or 2 days/weeks (HI and LO groups, respectively), or ethanol-extracted marijuana smoke for 7 days/week (EM) or sham treatment (SH) for 1 year were sacrificed 7 months following the last exposure. Pulmonary levels of carcinogen-DNA adducts were determined. Although mean or median adduct levels were not statistically different, 15 of 22 adduct measures were highest in the EM group and lowest 12 of 22 times in the SH group. The levels of aromatic carcinogen-DNA adducts seem no higher in the lungs of animals exposed to marijuana smoke than in untreated animals. Ethanol-extracted marijuana may have effects greater than marijuana itself.     

An Immunotoxicological Evaluation of {gamma}-Chlordane

An Immunotoxicological Evaluation of -Chlordane. JOHNSON, K.W., HOLSAPPLE, M. P., AND MUNSON, A. E. (1986). Fundam. Appl.Toxicol. 6, 317–326. Various toxicological and immunologicalparameters were assessed after exposure of female B6C3F1 miceto 0.1, 1.0. 4.0. and 8.0 mg/kg -chlordane for 14 days via oralgavage. Variables evaluated included periodic body weights,terminal organ weights, hematology including leukocyte differentials,antibody response to sheep red blood cells (SRBC), lymphoproliferativeresponses to the mitogens phytohemagglutinin (PHA), concanavalinA (Con A), and lipopolysaccharide (LPS) and allogeneic cells,and the delayed hypersensitivity response (DHR) to keyhole limpethemocyanin (KLH). When compared to the corn oil (vehicle) controls,chlordane produced a significant, dose-related increase in liverweight. Total leukocytes were significantly increased in chlordane-treatedgroups and seemed to be due to a significant increase in thelymphocyte population. Humoral immunity (HI), as assessed byenumeration of SRBC-specific immunoglobulin M (IgM) antibodyforming cells (AFC) and proliferation of LPS-stimulated spleencells, was not significantly altered in mice exposed to chlordane.In vitro evaluation of cell-mediated immunity (CMI), as measuredby proliferation of Con A and PHA-stimulated spleen cells fromchlordane-treated animals, indicated a significant and dose-relatedincrease. The response to allogeneic cells was also enhanced.Results from an in vivo indicator of cell-mediated immune status,the delayed hypersensitivity response to KLH, did not supportchlordane-enhanced T cell function suggested by mitogen andmixed lymphocyte responses. Therefore, a potent cyclodiene insecticideof environmental concern produced an enhancement of certainindicators of CMI. The expression of a DHR in vivo and the antibodyresponse to SRBC was unaltered in mice exposed to the chemical.These results suggest that -chlordane, at the concentrationsutilized, does not produce a biologically significant alterationof the immunocompetence of intact animals.     

Comparative Skin Phototoxicity in Mice with Two Photosensitizing Drugs: Benzoporphyrin Derivative Monoacid Ring A and Porfimer Sodium (Photofrin)

Benzoporphyrin derivative monoacid ring A (BPD-MA) and Photofrin(porfimer sodium) are photodynamic anticancer agents. The chemicalstructures of the two regioisomers of BPD-MA are 9-methyl trans-{±)-18-ethenyl-4,4-dihydro-3,4-bis(methoxycarbonyl)-4,8,14,19-tetramethyl-4,4-dihydro-3,4-bis (methoxycarbonyl)-4, 8,14,19-tetramethyl-23H, 25H-benzo(b)porphine-9,13-dipropanoateand 13-methyl-trans-(±)-18-ethenyl-4,4-dihydro-3,4-bis(methoxycarbonyl)-4,8,14,19-tetramethyl-23H,25H-benzo(b)porphine-9,13-dipropanoate.Photofrin (a registered trademark of American Cyanamid Co.)is a polyporphrin oligomer containing ester and ether linkages.The ability of BPD-MA or Photofrin to cause skin phototoxicitywas investigated in mice exposed to simulated sunlight (light)3, 24, or 48 hr after receiving a single intravenous injectionof vehicle or 2, 10, or 20 mg/kg of BPD-MA or Photofrin. Thedata were from two studies conducted using male and female CD1mice (7 weeks old). The hair of the dorsal thoracic area wasclipped 24 hr prior to exposure to light. Mice were exposedto light for 5 min. The clipped area of skin was the primarysite for the evaluation of phototoxicity. Mice were observedfor 2 weeks after treatment. There were no significant findingsin controls or in mice given 2 mg/kg of BPD-MA. When mice wereexposed to light 3 hr after dosing, both BPD-MA (10 or 20 mg/kg)and Photofrin (2, 10 or 20 mg/kg) caused phototoxicity. Deathoccurred in all mice given 20 mg/kg of BPD-MA or Photofrin,and in the majority of mice given 10 mg/kg of Photofrin. Insurviving mice, the skin of the back reacted by forming a largearea of eschar (scab). When mice were exposed to light 24 or48 hr after administration of BPD-MA or Photofrin, significantphototoxicity (browned skin and eschar formation) was observedonly in the mice given Photofrin. The data suggest that in miceBPD-MA causes substantial tissue injury when photoactivated3 hr after administration, but that the potential for phototoxicityis essentially gone after 24 hr. In contrast, phototoxicitywas elicited in the skin of mice exposed to simulated sunlight3, 24, and 48 hr after injection of Photofrin.     

Development of Fish Peritoneal Macrophages as a Model for Higher Vertebrates in Immunotoxicological Studies: I. Characterization of Trout Macrophage Morphological, Functional, and Biochemical Properties

Development of Fish Peritoneal Macrophages as a Model for HigherVertebrates in Immunotoxicological Studies. I. Characterizationof Trout Macrophage Morphological, Functional, and BiochemicalProperties. ZELIKOFF, J. T., ENANE, N. A., BOWSER, D., SQUIBB,K. S., AND FRENKEL, K. (1991). Fundam. Appl. Toxicol. 16, 576–589.The immune defense mechanisms of fish are not as well characterizedas those of mammals but seem to be related and similarly competent.Because of this, there is an increased interest in the immuneresponses of fish as models for higher vertebrates in immunotoxicologicalstudies. Prior to such studies, baseline criteria for specificcomponents of the immune response needed to be established.For this study, we have examined trout macrophage morphologyusing light and scanning electron microscopy, phagocytic activity,random and stimulus-directed migration, and superoxide anionradical (^{dot}) production for resident and lipopolysacharide (LPS) or Aeromonas salmonicidae-elicited rainbowtrout (Oncorhynchus mykiss) peritoneal macrophages (M). Followingperitoneal lavage, >89% of the cells were M as determinedby differential counts and nonspecific esterase staining. Immunizationwith LPS and A. salmonicidae increased M number {small tilde}5and 13-fold, respectively, and overall size. Trout M were phagocyticallyactive engulfing serum opsonized latex particles and were mobile,migrating both randomly and in a directed fashion towards formyl-methionine-L-leucine-L-phenylalanine(FMLP) and trout serum-derived complement fragment C5a. Concentrationsof FMLP (100 nM) and C5a (0.01–1%) effective for attractingtrout M are the same as those used to attract rabbit M. Residenttrout M produced negligable quantities of-(^{dot}) following stimulation with 1 µg/ml phorbol myristate acetate;Aeromonas-elicited M produced (^{dot}) in a time-dependen manner which peaked after 60 min at 2.9 nmolper 2 ? 10₅ cells and then declined. The results of this studyprovide a data base for future toxicological studies with troutperitoneal M and indicate the usefulness of this system forimmunotoxicological studies.     

Organ-Specific Hematopoietic Changes Induced by a Recombinant Human Interferon-{alpha} in Mice

Organ-Specific Hematopoietic Changes Induced by a RecombinantHuman Interferon- in Mice. ROSENTHAL, G. J., STRANAHAN, R. P.,ILL, THOMPSON, M., BLAIR, P., GERMOLEC, D. R., COMMENT, C. E.,SCHWAB, K., AND LUSTER, M. I. (1990). Fundam. Appl. Toxicol.14, 666–675. Interferon-a (IFN-) is a naturally occurringcytokine that mediates numerous biological activities and hasdemonstrated therapeutic potential in a variety of malignancies.Encouraging activity against HIV-1 replication has also beenobserved with IFN- in the treatment of AIDS, although hematotoxicityhas been a frequently observed side effect. In addition, invitro studies have suggested that IFN- may function as a down-regulatorof myelopoiesis. A recombinant hybrid of subtypes of human IFN-,rHuIFN-A/D, has antiviral activity in mu-rine cells in vitroand In vivo. This study examines the effect of acute and subchronicexposure to rHuIFN-A/D on hemopoietic and immune parametersin C57B1/6 mice. IFN-a was administered ip at 0, 1000, 10,000,and 100,000 units/day for either 1 or 10 consecutive days. Manyof the known effects of IFN- in humans such as anemia, leukopenia,and thrombocytopenia were observed in mice following subchronicexposure, with the latter two effects also manifested followingacute exposure. Further analysis showed that this leukopeniawas not selective. Both splenic and bone marrow cells were examinedfollowing 10 days of dosing with the high dose of IFN-. Lymphocyteswere reduced in both compartments, while granulocytes were increasedin both compartments. Bone marrow cells programmed to differentiateinto granulocytes (CFU-G) were suppressed, while macrophageprogenitors (CFU-M) were stimulated. Erythroid cells decreasedin the marrow but increased in the spleen, suggesting that themicroenvironmerit may play a significant role in the effectof IFN-. The proliferative capacity of both B and T spleniclymphocytes was significantly suppressed in a dose-related fashionfollowing multiple exposure to IFN-a. Clinically, IFN-a is mostoften given in multiple doses and the present data suggest thatsuch a regimen is toxic to both erythroid and myeloid cells,as well as being immunotoxic to splenic B and T lymphocytes.     

Modulation of Pulmonary Eicosanoid Metabolism following Exposure to Sulfuric Acid

Modulation of Pulmonary Eicosanoid Metabolism following Exposureto Sulfuric Acid. SCHLESINGER, R. B., GUNNISON, A. F., AND ZELIKOFF,J. T. (1990). Fundam. Appl. Toxicol. 15, 151–162. Eicosanoids(arachidonic acid metabolites) are potent biological mediators.Modulation of their metabolism by air pollutants may be a possiblefactor in the pathogenesis of environmentally related lung disease.Sulfuric acid (H₂SO₄) aerosols are components of ambient airin many areas. Rabbits were exposed to H₂SO₄ (0.3 µm)at 250, 500, or 1000 µg/m³ for 1 hr/ day for 5 days. Theywere then euthanized, the lungs lavaged, and eicosanoid analysesperformed by radioimmunoassay of acellular lavage fluid. Anexposure-concentration-dependent decrease in levels of prostaglandinsE₂ and F₂ and thromboxane B₂ was found; no change in leukotrieneB₄ was observed. Tracheal explants exposed to acidic environmentsin vitro also showed reduced production of PGE₂, PGF₂, and TxB₂.Incubation with sodium sulfate (Na₂SO₄ showed no effect of thesulfate ion (SO₄^2–). This study, the first to examineeicosanoid production after in vivo exposure to pure H₂SO₄ droplets,indicates that such exposure can modulate arachidonic acid metabolism,and that this is likely due to the deposition of hydrogen ion(H⁺ on target issue.     

Comparison of the physiological and morphological effects of cigarette smoke exposure at comparable weekly doses on Sprague-Dawley rats

A variety of dose x duration exposure regimens have been used in inhalation toxicity studies using rodents. We evaluated the effects of differences in smoke concentration and daily exposure duration under similar weekly cumulative exposures in rats to determine potential variation in type and severity of adverse effects in 13-week exposure studies. The weekly cumulative dosages were 2100 and 4200?μg wet total particle matter (WTPM)/L, and the daily exposure durations were 1 and 6?h. Weekly exposure duration was 5 or 7 days/week for groups exposed 1?h/day and 7 days/week for groups exposed 6?h/day. Recovery duration was 6 and 13 weeks. Mainstream smoke exposure suppressed body weight (BW) gain in both regimens. Lower dose groups exposed 1?h/day had a consistently greater of BW gain compared with corresponding 6?h/day groups. Respiratory rate, tidal volume, and minute volume (MV) were suppressed in a dose-dependent manner in both regimens. Higher MV in rats exposed for 6?h/day compared with rats exposed 1?h/day suggested that a lower concentration for longer duration resulted in a greater total inhaled mass (TIM) in rats exposed 6?h/day. Groups exposed for 6?h/day had lower blood carboxyhemoglobin and plasma nicotine levels than groups exposed 1?h/day, reflecting the lower carbon monoxide (CO) and WTPM concentrations in the 6?h/day groups. Data from examination of bronchoalveolar lavage fluids (BALF) and respiratory tract tissues indicated comparable effects between both regimens. Exposure-induced histopathological changes regressed similarly for both regimens after the recovery periods.     

Endometriosis in Rhesus Monkeys (Macaca mulatta) Following Chronic Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Endometriosis in Rhesus Monkeys (Macaca mulatta) Following ChronicExposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin. RIER, S. E.,MARTIN, D. C., BOWMAN, R. E., DMOWSKI, W. P., AND BECKER, J.L. (1993). Fundam. Appl. Toxicol. 21, 433–441. The incidence of the reproductive disease endometriosis wasdetermined in a colony of rhesus monkeys chronically exposedto 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) fora period of 4 years. Ten years after termination of dioxin treatment,the presence of endometriosis was documented by surgical laparoscopyand the severity of disease was assessed. The incidence of endometriosiswas directly correlated with dioxin exposure and the severityof disease was dependent upon the dose administered (p <0.001). Three of 7 animals exposed to 5 ppt dioxin (43%) and5 of 7 animals exposed to 25 ppt dioxin (71%) had moderate tosevere endometriosis. In contrast, the frequency of diseasein the control group was 33%, similar to an overall prevalenceof 30% in 304 rhesus monkeys housed at The Harlow Primate Centerwith no dioxin exposure. This 15-year study indicates that latentfemale reproductive abnormalities may be associated with dioxinexposure in the rhesus. Therefore, the effects of this toxinmay be more diverse than previously recognized.     

Prechronic Inhalation Toxicity Studies of Isobutyl Nitrite

Isobutyl nitrite (IBN) is a volatile liquid that has becomeincreasingly popular as an inhaled recreational drug. To investigateshort-term toxic effects and establish exposure parameters forchronic inhalation studies, F344/N rats and B6C3F1 mice wereexposed to IBN vapors on a 6 hr/day + t90, 5 days/week schedule.Twelve exposures were administered at concentrations of 0, 100,200, 400, 600, and 800 ppm IBN. This exposure series resultedmortality in rats exposed to 600 ppm and mice exposed to 800ppm. Animals exposed at the lower concentrations developed hyperplasiaof the bronchiolar and nasal turbinate epithelium (rats andmice) and lymphocytic atrophy in the spleen and thymus (mice).Longer term, 13-week, subchronic exposures were conducted atconcentrations of 0, 10, 25, 75, 150, and 300 ppm IBN. Exposureto 300 ppm IBN reduced the body weight gains in both sexes ofrats and in female mice. IBN-related clinical pathology changesincluded reduced RBC counts accompanied by moderate increasesin mean corpuscular volume and reticulocyte counts, increasedWBC counts, and mildly increased methemoglobin concentration.Bone marrow hyperplasia was observed in all groups of IBN-exposedrats, while in mice only females at l50 ppm IBN displayed thischange. Excessive splenic pulp hematopoiesis was noted in miceat all IBN exposure levels. Respiratory system changes includedincreased lung weights in rats and female mice at 300 ppm, hyperplasiaof the nasal mucosa (male rats at 75 ppm and female rats at150 ppm), and hyperplasia of the lung epithelium (male miceat 150 ppm and female mice at 75 ppm). The results suggestedthat a concentration of 150 ppm could be used as the highestexposure level for subsequent chronic inhalation tests.     

Influence of Low-Level Exposure to Fusarium Mycotoxins on Selected Immunological and Hematological Parameters in Young Swine

The effects of low dietary concentrations of Fusarium myco toxins(deoxynivalenol (DON), 1 5-acetyl-DON, and zearalenone) on growth,immunological, and hematological parameters were determinedin young pigs during a 28-day feeding experiment. Clean andnaturally contaminated corn were incorporated into basal dietsformulated to contain 0.00, 0.75, 1.50, and 3.00 mg DON/kg diet.A pair-fed control animal was used for comparison with eachanimal receiving the highest level of contamination (diet 4).Skin temperature, measured during the first week of the experiment,decreased linearly as the dietary mycotoxin concentration increased.Several other linear effects were observed: depressed feed intakethroughout the experiment, reduction in thyroid size (absolute/relative),and changes in the appearance of the esophageal region of thestomach (thicker and higher degree of folding with increasingtoxin concentration). Serum T₄ (thyroxine) levels increasedquadratically after 7 and 28 days of exposure compared to controlanimals. This change coincided with an increase in albumin levels,a decrease in -globulin levels, and an overall increase in albumin/globulinratio as the level of contamination increased. After immunizationwith sheep red blood cells (SRBC), animals fed contaminateddiets showed a delayed response in peak titers. At the end ofthe experiment an increase in the segmented neutrophil countwas observed. The following observations were made for ani malsconsuming diet 4 as compared to the pair-fed controls: lowerskin temperature, better feed efficiency, more corrugated stomachs,reduced -globulin levels, and lower antibody titers to SRBC.The study showed a physiobiochemical adaptation response ofanimals exposed to mycotoxin-contaminated diets. Although mostchanges seem to be related to the nutritional status of theanimal, others such as reduced skin temperature, altered stomachcondition, and reduced -globulin levels suggest specific effectsdue to the Fusarium toxins. The pair-feeding treatment was importantin reaching these conclusions, but it is also evident that thetreatment itself introduces changes in response to a reducedfeed intake.     

The Enhancing Effect of Spawning on Elimination of a Persistent Polychlorinated Biphenyl from Female Yellow Perch

The Enhancing Effect of Spawning on Elimination of a PersistentPolychlorinated Biphenyl from Female Yellow Perch. VODICNIK,M. J., AND PETERSON, R. E. (1985). Fundam. Appl. Toxicol. 5,770–776. Distribution and elimination of 2,5,2',5'-tetrachloro[¹⁴C]biphenyl.(4-CB) were studied for 6 months after exposing sexually maturefemale yellow perch to the compound in water and transferringthem to flowing 4-CB-free water. Perch that were exposed inJanuary spawned in May, and the study was terminated in June.During the first 4 months after exposure, the t for whole-bodyelimination was 22 weeks, primarily by elimination of 4-CB fromthe viscera and carcass. During spawning, enhanced elimination(t < 0.7 weeks) was due to the voiding of eggs containing4-CB. After spawning, whole-body elimination returned to a slowerrate (t = 16.3 weeks). Prior to the enhancement in 4-CB eliminationrate during spawning, there was a redistribution of 4-CB residueswithin the body of the perch which was characterized by a transferof 4-CB residues from primarily the carcass and viscera to eggs.Two weeks after exposure, 30% of the initial 4-CB body burdenwas distributed to the eggs, whereas just prior to spawning,about 50% was present in this tissue. These findings demonstratethat egg maturation and spawning result in a significant reductionin the body burden of a persistent polychlorinated biphenylin a lean-fish species.     

The Effects of in Vitro and Aerosol Exposures to Cadmium on Phagocytosis by Rat Pulmonary Macrophages

The Effects of in Vitro and Aerosol Exposures to Cadmium onPhagocytosis by Rat Pulmonary Macrophages. GREENSPAN, B. J.,and MORROW, P. E (1984). Fundam. Appl. Toxicol. 4, 48–57.Aerosol exposures of rats were performed to assess the in vivoeffects of cadmium on the phagocytosis of latex particles bypulmonary macrophages. An in vitro assay for particle uptakewas devised which allowed quantification of phagocytosis byadhering and nonadhering macrophages. In vitro exposure to CdCl₂caused dose-dependent decreases in viability (trypan blue exclusion),percentage cells with particles, total number of particles phagocytized,and the ability of the macrophages to adhere to a siliconizedglass surface. In vivo effects were studied following 30-minaerosol exposures to 1.5 mg/m³ Cd (MMAD = 0.35 µm, _g =1.45) or 5.0 mg/m³ Cd (MMAD = 0.45 µm, _g = 1.60) as CdCl₂.Phagocytic activity in the in vitro test system was increasedimmediately and at Day 1 in the low exposure group. However,following exposure to 5.0 mg/m³ Cd, phagocytic activity wasdepressed until 8 days postexposure. The results show that cadmiumis capable of modifying the phagocytic ability of macrophagesin vivo as well as in vitro. Determinations of the total numberof particles phagocytized were found to be more sensitive thanpercentage cells phagocytizing in detecting the effects of cadmiumexposure.     

A Subchronic Dermal Exposure Study of Diethylene Glycol Monomethyl Ether and Ethylene Glycol Monomethyl Ether in the Male Guinea Pig

A Subchronic Dermal Exposure Study of Diethylene Glycol MonomethylEther and Ethylene Glycol Monomethyl Ether in the Male GuineaPig. HOBSON, D. W., D'ADDARIO, A. P., BRUNER, R. H., AND UDDIN,D. E. (1986). Fundam. Appl. Toxicol 6, 339–348. Diethyleneglycol monomethyl ether (DEGME) has been selected as a replacementanti-icing additive for ethylene glycol monomethyl ether (EGME)in Navy jet aircraft fuel. This experiment was performed todetermine whether DEGME produced similar toxicity to EGME followingdermal exposure. Male guinea pigs were dermally exposed to 1.00,0.20, 0.04, or 0 (control) g/kg/day EGME for 13 weeks, 5 days/week,6 hr/day. Another group of animals was similarly exposed to1.00 g/kg/day EGME. Body weights as well as testicular and splenicweights were reduced as a result of exposure to EGME. DEGME-exposedanimals exhibited decreased splenic weight in the high- andmediumdose (1.00 and 0.20 g/kg/day) exposure groups only. Hematologicchanges in EGME-exposed animals included mild anemia with increasederythrocytic mean corpuscular volumes and a lymphopenia withincreased neutrophils. Similar hematological changes were notobserved in any animals exposed to DEGME. Serum creatine kinaseactivity was increased in animals exposed to EGME, and serumlactate dehydrogenase activity was increased in EGME and 1.00g/kg/day DEGME-exposed animals. In general, DEGME produced minimaltoxicological changes following dermal exposure, whereas thetoxicological changes observed following similar exposure toEGME were much more profound.     

NCI-Black-Reiter (NBR) Male Rats Fail to Develop Renal Disease following Exposure to Agents That Induce {alpha}-2u-Globulin ({alpha}2u) Nephropathy

NCI-Black-Reiler (NBR) Male Rats Fail to Develop Renal Diseasefollowing Exposure to Agents That Induce _2u-Globulin (_2u) Nephropathy.Dietrich, D. R., and Swenberg, J. A. (1991). Fundam. Appl. Toxicol16, 749–762. The NCI-Black-Reiter (NBR) rat is the onlystrain of male rat known not to synthesize the hepatic formof the low molecular weight protein, _2u-globulin. In previousstudies, NBR rats were shown not to develop renal disease whenexposed to decalin, a compound known to induce _2u-globulin nephropathyin other rat strains. The objective of this study was to showthat the presence of _2u-globulin (_2u-) is essential for thedevelopment of this syndrome in rats exposed to 2,2,4-trimethylpentane(TMP), 1,4-dichlorobenzene (DCB), isopho-rone (IP), PS-6 unleadedgasoline (UG), and d-limonene (d-L). The induction of _2u-nephropathyin F344 male rats with lindane was used as a positive controland this response was contrasted to male NBR and female F344rats treated with lindane. Five to seven 11-week-old male NBRrats were exposed to TMP (500 mg/kg/day), DCB (500 mg/kg/day),IP (1000 mg/kg/day), UG (500 mg/kg/day), d-L (1650 mg/kg/day),or lindane (10 mg/kg/day) and five 11-week-old male and femaleF344 rats were exposed to lindane (10 mg/kg/day) by oral gavageon 4 consecutive days. NBR male and F344 male and female ratsgavaged with corn oil were incorporated in the study as vehiclecontrols. The presence of hyaline droplets was assessed in perfusion-fixedkidneys by staining paraffin sections with Mallory-Heidenheinstain and in GMA sections with Lee's methylene basic blue fuchsinstain. Paraffin sections were also analyzed immunohistochemicallyfor the presence of _2u-. Under exposure conditions that clearlyinduce _2u-nephropathy in male F344 rats, no lesions, hyalinedroplets, or _2u- were detectable in treated or control maleNBR and female F344 rats. It is thus concluded that the presenceof _2u is causal to the development of renal disease in ratsexposed to TMP, DCB, IP, UG, d-L, and lindane.     

Evaluation of the impact of waterpipe tobacco smoke exposure on the activity and expression of rat hepatic CYP450: a pharmacokinetic study

Abstract

Waterpipe smoke contains many toxic constituents that can alter drug pharmacokinetics. This study assessed the effect of waterpipe smoke exposure on the activity and expression of CYP450 enzymes in rats. Animals (n?=?10/group) were exposed to either waterpipe smoke or side-stream cigarette smoke for 1?h/day (6 days/week) for 31 days, or fresh air (control). An intragastric cocktail solution containing three probe drugs, phenacetin, chlorzoxazone and testosterone was administered to assess the activity of CYP1A2, CYP2E1 and CYP3A, respectively. Serum concentrations were determined using LC-MS/MS and the pharmacokinetic parameters were calculated. The mRNA expression of hepatic enzymes was also quantified. Waterpipe and cigarette smoke exposure did not significantly alter the pharmacokinetics of phenacetin, chlorzoxazone and testosterone. For example, the clearance and drug exposure values were comparable among groups for all probe drugs. Additionally, there was no significant effect of waterpipe and cigarette smoke on mRNA expression of hepatic CYP1A2, CYP2E1 and CYP3A2. The results demonstrate that waterpipe smoke exposure had no effect on the functional expression of three key CYP450 isoforms in rats. Future research is required with longer exposure periods to waterpipe smoke. Such work serves to enhance current understanding of effect of waterpipe smoke exposure on pharmacokinetics.     

Reproduction in Fischer-344 Rats Exposed to Methyl Chloride by Inhalation For Two Generations

Reproduction in Fischer-344 Rats Exposed to Methyl Chlorideby Inhalation For Two Generations. HAMM, T. E., JR., RAYNOR,T. H., PHELPS, M. C, AUMAN, C. D., ADAMS, W. T., PROCTOR, J.E., AND WOLKOWSKI-TYL, R. (1985) Fund. Appl. Toxicol. 5, 568–577.Male and female Fischer-344 rats were exposed to methyl chlorideby inhalation (0, 150, 475, or 1500 ppm, 6 hr/day, 5 days/week,40 males and 80 females per group). The only treatment-relatedclinical signs were a 10 to 20% body weight gain depression(BWGD) in both males and females exposed to 1500 ppm at allweekly weighings after 2 weeks of exposure and a 5–7%BWGD in 475-ppm exposed animals after Day 57. After 10 weeksthe exposure schedule was changed to 6 hr/day, 7 days/week andeach male was mated to two exposed females. The mating periodwas ended after 2 weeks, at which point 10 males/group werenecropsied. The only tratment-related lesions Found were severebilateral testicular degeneration (10/10) and granulomas inthe epididymis (3/10) in the 1500-ppm males. The remaining 30males per group were then removed from exposure and mated duringa 2-week period with 60 unexposed females. The exposed femaleswere continued on exposure from the start of mating to PostnatalDay 28 (6 hr/day, 7 days/week). The females were not exposedfrom Gestation Day 18 to Postnatal Day 4, and the pups werenever directly exposed prior to weaning. There were no significantdifferences between groups in the number of exposed or unexposedfemales that mated, as evidenced by copulation plugs. No litterswere born to exposed or unexposed females mated to the 1500-ppmmales. There was no significant difference in the number oflitters produced by the 150-ppm groups when compared to thecontrol groups. Fewer litters were born in the 475-ppm groupsthan in the control groups. No differences in litter size, sexratio, pup viability, or pup growth were Found among the 475-ppm,150-ppm, or control F₀ groups. When bred 10 weeks after thecessation of exposures, 5 to 20 1500-ppm F₀ males had regainedthe ability to sire normal litters. The same number of 475-ppmF₀ males proved as fertile (15/ 20) as control F₀ males (13/20).After weaning, F₁ pups from the 475-, 150-, and 0-ppm groupswere exposed to the same concentrations of methyl chloride For10 weeks and then mated. A trend toward decreased fertilitywas Found in the 475-ppm F₁ group     

Pulmonary Immunotoxicity of Inhaled Ammonium Metavanadate in Fisher 344 Rats

Male Fisher 344 rats were exposed to 2 mg vanadium(V)/m³ (asammonium metavanadate NH⁴VO³, 0.32 µm MMD) atmospheresfor 8 hr/day for 4 days in a nose-only exposure system. In exposedrats, lung V burdens increased in a time-dependent fashion.Analysis of lung cells and lavage fluid 24 hr after the finalexposure suggested that tissue damage and a strong inflammatoryresponse was elicited; numbers of neutrophil and small macrophages(M), as well as levels of lavageable protein and lactate dehydrogenase,were significantly elevated as compared with levels observedwith air-exposed rats. Vanadium also affected pulmonary alveolarM (PAM) capacities to produce and respond to immunoregulatingcytokines. Inducible PAM production of tumor necrosis factor-awas significantly inhibited, as was the ability to increasecell surface Class II/I-A molecule expression in response tointerferon- (rFN-). PAM from V-exposed hosts were also inhibitedin their ability to be primed by EFN- to produce superorideanion and hydrogen peroxide in response to stimulation withopsonized zy-mosan. These studies indicate that short-term repeatedexposure of rats to atmospheric V, at levels encountered inan occupational setting, can alter host pulmonary immunomocompetence,with one major effect occurring at the level of cytokine-relatedfunctions. These alterations may be underlying mechanisms forthe well-documented increases in bronchopulmonary infectionsand cancers in workers chronically exposed to V-containing atmospheres.