Immune Function and Host Defense in Rodents Exposed to 60-Hz Magnetic Fields

This study was conducted to evaluate the influence of sub-chronicexposure to pure, linearly polarized 60-Hz magnetic fields (MF)on the host immune response in mice. The experimental designwas as follows: three groups were exposed continuously (18.5hr/day) to MF at field strengths of 0.02, 2, or 10 gauss (G),one group was exposed intermittently (1 hr on/l hr off) to MFat a field strength of 10 G, and one group served as a shamcontrol. Experimental endpoints included spleen and thymus weightsand cellularity, antibody-forming cell (AFC) response, delayed-typehypersensitivity (DTH) response, splenic lymphocyte subset analysis, susceptibility to infection with Listeria monocytogenes,and natural killer (NK) cell activity. No differences in bodyweight, lymphoid organ weight, or lymphoid organ cellularitywere ob served in any MF-exposed group in comparison to shamcontrols. Likewise, no statistically significant differenceswere found in com parisons of AFC responses. Isolated statisticallysignificant differ ences from control were observed in MF-exposedmice in the DTH assay, although no clear dose-related patternof altered activity was seen. Splenic lymphocyte subset parametersexamined were within normal limits in all groups, and no differencesbetween control and MF-exposed mice were found. Host resistanceto bacterial infection was not altered at any MF exposure examinedin this study. Finally, although apparently dose-related, statisticallysignificant alterations were observed in an initial study ofNK cell function, repeat studies failed to demonstrate a consistentpattern of alteration.     

Exposure to 60-Hz magnetic fields and proliferation of human astrocytoma cells in vitro

Epidemiological studies have suggested that exposure to electric and magnetic fields (EMF) may be associated with an increased incidence of brain tumors, most notably astrocytomas. However, potential cellular or molecular mechanisms involved in these effects of EMF are not known. In this study we investigated whether exposure to 60-Hz sinusoidal magnetic fields (0.3-1.2 G for 3-72 h) would cause proliferation of human astrocytoma cells. Sixty-Hertz magnetic fields (MF) caused a time- and dose-dependent increase in proliferation of astrocytoma cells, measured by (3)H-thymidine incorporation and by flow cytometry, and strongly potentiated the effect of two agonists (the muscarinic agonist carbachol and the phorbol ester PMA). However, MF had no effect on DNA synthesis of rat cortical astrocytes, i.e., of similar, nontransformed cells. To determine the amount of heating induced by MF, temperatures were also recorded in the medium. Both 1.2 G MF and a sham exposure caused a 0.7 degrees C temperature increase in the medium; however, (3)H-thymidine incorporation induced by sham exposure was significantly less than that caused by MF. GF 109203X, a rather specific protein kinase C (PKC) inhibitor, and down-regulation of PKC inhibited the effect of MF on basal and on agonist-stimulated (3)H-thymidine incorporation. These data indicate that MF can increase the proliferation of human astrocytoma cells and strongly potentiate the effects of two agonists. These findings may provide a biological basis for the observed epidemiological associations between MF exposure and brain tumors.     

Influence of Chronic Exposure to Uranium on Male Reproduction in Mice

Influence of Chronic Exposure to Uranium on Male Reproductionin Mice. Llobet, J. M., Sirvent, J. J., Ortega, A., and Domingo,J. L. (1991). Fundam Appl. Toxicol. 16, 821–829. Relativelyfew data are available concerning the reproductive and developmentaltoxicity of uranium. The present study was designed to evaluatethe reproductive effects of this metal in male Swiss mice. Theanimals were treated with uranyl acetate dihydrate at dosesof 0, 10, 20, 40, and 80 mg/kg/day given in the drinking waterfor 64 days. To evaluate the fertility of the uraniumtreatedmales, mice were mated with untreated females for 4 days. Therewas a significant but non-dose-related decrease in the pregnancyrate of these animals. Body weights were significantly depressedonly in the 80 mg/kg/day group. Testicular function/spermatogenesiswas not affected by uranium at any dose, as evidenced by normaltestes and epididymis weights and normal spermatogenesis, whereasinterstitial alterations and vacuolization of Leydig cells wereseen at 80 mg/kg/day. The results of this investigation indicatethat uranium does not cause any adverse effect on testicularfunction in mice at the concentrations usually ingested in thediet and drinking water, with a safety factor of more than 1000.However, although spermatogenesis was not affected by uraniumadministration, uranium produces a significant decrease in thepregnancy rate at 10, 20, 40, or 80 mg/kg/day.     

Prenatal Exposure of Rats to Diphenhydramine: Effects of Physical Development, Open Field, and Gonadal Hormone Levels in Adults

Diphenhydramine (DPH), a classical H₁ receptor antagonist, has been used in pregnancy for the treatment of allergies, nausea, and vomiting. It has been reported that 10-20% of pregnant women take antihistamine-containing preparations at some point during pregnancy. The present study analyzed the influence of prenatal exposure to DPH of rats on: 1) maternal behavior and milk production of dams; 2) physical and reflexologic development of offspring; and 3) long-term effects on open field behaviors and gonadal hormone levels in offspring. Female pregnant rats were injected SC, daily, with 20 mg/kg DPH or saline from embryonic day (E) 0 to 21. After delivery, maternal behavior was assessed and offspring physical and reflexologic development was examined. Open field activity of male and female rats was measured at 21 and 75 days of age and plasma hormone levels were evaluated in both sexes at 120 days of age. Neither maternal behavior nor milk production was affected by DPH treatment. Treated offspring showed an accelerated pinna unfolding, eye opening, and a delay of testes descent and vaginal opening. Both righting reflex and negative geotaxis development were accelerated, but prenatal exposure to DPH did not modify offspring locomotor activity. When tested as adults, a lack of sexual dimorphism in the open field activity of males and females was observed. No differences were observed between gonadal hormone levels of control and experimental groups of either sex. The findings suggest that prenatal DPH exposure influences physical and reflex development of rat pups.     

Prenatal Exposure of Rats to Diphenhydramine: Effects on Physical Development, Open Field, and Gonadal Hormone Levels in Adults

Diphenhydramine (DPH), a classical H₁ receptor antagonist, has been used in pregnancy for the treatment of allergies, nausea, and vomiting. It has been reported that 10–20% of pregnant women take antihistamine-containing preparations at some point during pregnancy. The present study analyzed the influence of prenatal exposure to DPH of rats on: 1) maternal behavior and milk production of dams; 2) physical and reflexologic development of offspring; and 3) long-term effects on open field behaviors and gonadal hormone levels in offspring. Female pregnant rats were injected SC, daily, with 20 mg/kg DPH or saline from embryonic day (E) 0 to 21. After delivery, maternal behavior was assessed and offspring physical and reflexologic development was examined. Open field activity of male and female rats was measured at 21 and 75 days of age and plasma hormone levels were evaluated in both sexes at 120 days of age. Neither maternal behavior nor milk production was affected by DPH treatement. Treated offspring showed an accelerated pinna unfolding, eye opening, and a delay of testes descent and vaginal opening. Both righting reflex and negative geotaxis development were accelerated, but prenatal exposure to DPH did not modify offspring locomotor activity. When tested as adults, a lack of sexual dimorphism in the open field activity of males and females was observed. No differences were observed between gonadal hormone levels of control and experimental groups of either sex. The findings suggest that prenatal DPH exposure influences physical and reflex development of rat pups.     

Chronic Corticosterone Exposure during Adolescence Reduces Impulsive Action but Increases Impulsive Choice and Sensitivity to Yohimbine in Male Sprague-Dawley Rats

Chronic stress during adolescence is associated with an increased risk for alcoholism and addictive disorders. Addiction is also associated with increased impulsivity, and stress during adolescence could alter cortical circuits responsible for response inhibition. Therefore, the present study determined the effect of chronic exposure to the stress hormone corticosterone (CORT) during adolescence on tests of impulsivity in adulthood and examined possible biochemical mechanisms. Male Sprague-Dawley rats were exposed to CORT by their drinking water during adolescence (post-natal day 30–50). The rats were then tested in adulthood to assess behavior on the 5-choice serial reaction time task (5CSRTT), stop-signal reaction time task (SSRTT), and the delay-discounting task, which differentially assess attention, impulsive action, and impulsive choice. Yohimbine-induced impulsivity on the 5CSRTT and biochemical analysis of the lateral orbital frontal cortex (lOFC) was also assessed owing to the ability of yohimbine to activate the hypothalamic-pituitary-adrenal axis and influence impulsivity. Adolescent CORT-treated rats were found to behave largely like controls on the 5CSRTT, but did show reduced premature responses when the intertrial interval was increased. Nevertheless, the CORT-treated rats tended to have more yohimbine-induced impulsive responses at low doses on this task, which was not found to be due to increased pCREB in the lOFC, but could be related to a higher expression/activity of the AMPA receptor subunit GluR1. Adolescent CORT-treated rats performed more accurately on the SSRTT, but showed greater impulsivity on the delay-discounting task, as indicated by steeper discounting functions. Therefore, adolescent CORT exposure reduced impulsive action but increased impulsive choice, indicating that chronic stress hormone exposure in adolescence can have long-term consequences on behavior.     

Ozone Adaptation in Rats after Chronic Exposure to a Simulated Urban Profile of Ozone

Studies in both humans and rats have indicated that certainpulmonary responses induced by exposure to an acute provocativeconcentration of ozone (O₃) will eventually attenuate if theexposure is repeated on a daily basis. This phenomenon is commonlyreferred to as O₃ adaptation. Whether or not a "state" of adaptationdevelops due to long-term low level O₃ exposure is unknown.Two human studies have reported adaptation in subjects livingin Los Angeles during periods when ambient O₃ concentrationshave been relatively high. At present, however, we are not awareof comparable information from rats. This study assessed O₃adaptation in rats following chronic (12 or 18 months) exposureand after a 4-month recovery period. A chronic exposure pattern,similar to that found in an urban area during the summer (0.06ppm O₃ for 13 hr/day, 7 days/week; Monday–Friday, peakto 0.25 ppm O₃, over 9 hr), was used. To assess whether adaptationhad occurred and/or persisted, awake rats were challenged withhigh provocative concentrations of O₃ for up to 2 hr. Duringa challenge, rats were monitored for typical O₃-induced alterationsin spontaneous breathing parameters (e.g., increase in breathingfrequency and decrease in tidal volume). Adaptation was definedas attenuation of breathing response during the challenge inrats chronically exposed to O₃ as compared to that in "control"rats (chronically exposed to air). Adaptation was found in therats within 8 hr following the chronic O₃ exposure but not afterthe 4-month recovery period. Spontaneous breathing parametersthat were significantly attenuated in the chronically exposedrats were breathing frequency, tidal volume, inspiratory andexpiratory times, and maximum expiratory flow. We conclude thatrats demonstrated adaptation to O₃ after long-term exposureto an urban-type O₃ profile and that the adaptation was notseen 4 months postexpo-sure. These results suggest that exposureto environmental O₃ in Los Angeles air may have been responsiblefor the adaptation found in residential subjects.     

The Use of Feed Additives to Reduce the Effects of Aflatoxin and Deoxynivalenol on Pig Growth,Organ Health and Immune Status during Chronic Exposure

Three feed additives were tested to improve the growth and health of pigs chronically challenged with aflatoxin (AF) and deoxynivalenol (DON). Gilts (n = 225, 8.8 ± 0.4 kg) were allotted to five treatments: CON (uncontaminated control); MT (contaminated with 150 µg/kg AF and 1100 µg/kg DON); A (MT + a clay additive); B (MT + a clay and dried yeast additive); and C (MT + a clay and yeast culture additive). Average daily gain (ADG) and feed intake (ADFI) were recorded for 42 days, blood collected for immune analysis and tissue samples to measure damage. Feeding mycotoxins tended to decrease ADG and altered the immune system through a tendency to increase monocytes and immunoglobulins. Mycotoxins caused tissue damage in the form of liver bile ductule hyperplasia and karyomegaly. The additives in diets A and B reduced mycotoxin effects on the immune system and the liver and showed some ability to improve growth. The diet C additive played a role in reducing liver damage. Collectively, we conclude that AF and DON can be harmful to the growth and health of pigs consuming mycotoxins chronically. The selected feed additives improved pig health and may play a role in pig growth.     

Chronic Exposure to Low Doses of Mercury Impairs Sperm Quality and Induces Oxidative Stress in Rats

Mercury (Hg) is a widespread environmental pollutant that adversely affects the male reproductive system. The precise mechanisms underlying mercuric chloride (HgCl₂)-induced toxicity are not fully understood; however, evidence indicates that oxidative stress may be involved in this process. Although the adverse effects of high levels of inorganic Hg on the male reproductive system have been investigated, the effects of low levels of exposure are unknown. Therefore, the aim of this study was to investigate the effects of chronic exposure to low concentrations of HgCl₂ on sperm parameters, lipid peroxidation, and antioxidant activity of male rats. Three-month-old male Wistar rats were treated for 30 d and divided into groups: control (saline, i.m.) and HgCl₂ group (i.m., first dose 4.6 μg/kg, subsequent doses 0.07 μg/kg/d). Sperm parameters (count, motility and morphology) and biomarkers of oxidative stress in testis, epididymis, prostate, and vas deferens were analyzed. Mercury treatment produced a reduction in sperm quantity (testis and epididymis) and daily sperm production, following by decrease in sperm motility and increase on head and tail morphologic abnormalities. HgCl₂ exposure was correlated with enhanced oxidative stress in reproductive organs, represented not only by augmented lipid peroxidation but also by changes in antioxidant enzymes activity superoxide dismutase (SOD) and catalase (CAT) and nonprotein thiol levels. In conclusion, chronic exposure to low doses of Hg impaired sperm quality and adversely affected male reproductive functions, which may be due, at least in part, to enhanced oxidative stress.     

Enhanced Inflammatory Response to Acute Ozone Exposure in Rats during Pregnancy and Lactation

Experimental evidence from several studies suggests that pregnantanimals and women are more susceptible to oxidants than nonpregnantcontrols. In the study reported here, we sought to determinewhether pregnant rats are more sensitive than age-matched virginfemales to the inflammatory effects of ozone, a gaseous oxidantof considerable environmental significance. Rats at severalstages of pregnancy and lactation, as well as age-matched virginfemales, were exposed to 1 ppm ozone for 6 hr. Controls weresham-exposed to pure air for an identical period of time. Bronchoalveolarlavage was performed 24 hr after the beginning of exposure,and components of the lavage fluid considered to be indicatorsof inflammation were used to assess the severity of pulmonaryinflammation. The results of this experiment showed that significantlyenhanced sensitivity to ozone-induced pulmonary inflammationdevelops during pregnancy, is maintained during lactation, anddisappears following lactation. Implicit in this pattern ofdifferential sensitivity in rats is the possibility of a similarpattern of inflammatory response in analogous groups of humansas well as the potential for applicability to other oxidativepollutants.     

Chronic Inhalation Exposure of Wistar Rats and two Different Strains of Mice to Diesel Engine Exhaust,Carbon Black,and Titanium Dioxide

Abstract

Wistar rats were exposed for 2 yr to diesel engine exhaust, carbon black (Printex 90, Degussa, FR. G), and ultraline TiO₂ (P25, Degussa, FRG) and were subsequently kept in clean air for 6 mo. Particle exposure concentration was increased during the course of the experiment for carbon black and TiO₂ to reach particle lung loads similar to those found in the diesel soot-exposed rats. The average particle exposure concentrations for diesel soot, carbon black, and TiO₂ were 7, 11.6, and 10 mg/m³, respectively. Lung tumor rates in these rats increased with increasing cumulative particle exposure (mg/m³ x h) independent of the type of particle employed. The exposure to 2.5 mg/m¹ diesel soot also induced a significantly increased lung tumor rate, but 0.8 mg/m³ diesel soot did not. With this study, it could be demonstrated that the carbon core of diesel soot is mainly responsible for the occurrence of diesel engine exhaust-related lung tumors; the role of diesel soot-attached polycyclic aromatic hydrocarbons (PAH) and NO₂-PAH is probably of minor importance in the rat lung. Agglomerates of ultrafine carbon and TiO₂ particles seem particularly suited to exert toxic effects primarily on alveolar macrophages and alveolar lung particle clearance. Although such lung toxic effects were also seen with the lowest diesel soot exposure concentration (0.8 mg/m³) used, no increased lung tumor rate was detected in this group of rats. Whether this result implies a threshold for the particle-related lung tumor induction mechanism as already discussed by Vostal (1986) or whether the tumor effect was simply not observed because of statistical reasons needs further research on the possible mode of action of ultra-fine insoluble particles in the lung. NMR. I mice that were kept in the same exposure atmospheres (high diesel soot, carbon black, TiO₂) as the rats did not show an increased lung tumor rate. Furthermore, there was no treatment-related tumor response in NMRI nor in C57BL/6N mice exposed to diesel exhaust containing 4.5 mg/m³ diesel soot or to the same exhaust dilution but devoid of soot particles. C57BU6N mice were exposed for 24 mo and were subsequently kept in clean air for another 6 mo. Not only the average survival time but also the particle load per gram lung wet weight of the C57BU6N mice was very similar to rats exposed to 7 mg/m³ diesel soot.     

Chronic Toxicity/Oncogenicity of Dimethylacetamide in Rats and Mice Following Inhalation Exposure

The potential chronic toxicity and oncogenicity of dimethylacetamide(DMAC) was evaluated by exposing male and female rats and miceto 0, 25, 100, or 350 ppm DMAC for 6 hr/day, 5 days/week for18 months (mice) or 2 years (rats). Clinical pathology was evaluatedat 3, 6, 12, 18, and 24 (rats only) months. An interim euthanizationfor rats occurred at 12 months and hepatic cell proliferationin rats and mice was examined at 2 weeks and 3 and 12 months.No compound-related effects on survival were observed. Ratsexposed to 350 ppm had lower body weight and/or body weightgain. There were no compound-related effects on body weightor weight gain in mice at any concentration. There were no compound-relatedadverse effects on the incidence of clinical signs of toxicityin rats or mice. No hematologic changes were observed in eitherspecies. Serum sorbitol dehydrogenase activity was increasedin rats exposed to 350 ppm. Serum cholesterol and glucose concentrationswere significantly higher in 100 and 350 ppm female rats. Compound-relatedmorphological changes were observed in the liver. In rats, exposureto 100 or 350 ppm produced increased absolute and/or relativeliver weights, hepatic focal cystic degeneration, hepatic peliosis,biliary hyperplasia (350 ppm only), and lipofuscin/hemosiderinaccumulation in Kupffer cells. In mice, exposure to 100 or 350ppm produced increased absolute and relative liver weights (350ppm females only), accumulation of lipofuscin/hemosiderin inKupifer cells, and centrilobular single cell necrosis. Malerats exposed to 350 ppm also had significantly higher absoluteand relative kidney weights which correlated with the grossand microscopic changes resulting from a compound-related increasein severity of chronic progressive nephropathy. Female miceexposed to 350 ppm had an increased incidence of bilateral,diffuse retinal atrophy. No increase in hepatic cell proliferationwas seen in mice or rats at any exposure concentration. DMACwas not oncogenic under these experimental conditions in eitherthe rat or mouse. The NOAEL for male and female rats and miceis 25 ppm.     

Chronic Toxicity/Oncogenicity of Dimethylformamide in Rats and Mice Following Inhalation Exposure

The potential chronic toxicity and oncogenicity of dimethylformamide(DMF) was evaluated by exposing male and female rats and miceto 0, 25, 100, or 400 ppm DMF for 6 hr/day, 5 days/week for18 months (mice) or 2 years (rats). Clinical pathology was evaluatedat 3, 6, 12, 18, and 24 (rats only) months. An interim euthanasiafor rats occurred at 12 months and hepatic cell proliferationin rats and mice was examined at 2 weeks, 3 months, and 12 months.No compound-related effects on clinical observations or survivalwere observed. Body weights of rats exposed to 100 (males only)and 400 ppm were reduced. Conversely, body weights were increasedin 400 ppm mice. No hematologic changes were observed in eitherspecies. Serum sorbitol dehydrogenase activity was increasedin rats exposed to 100 or 400 ppm. There were no compound-relatedeffects on the estrous cycle of rats or mice at any concentration.Compound-related morphological changes were observed only inthe liver. In rats, exposure to 100 and 400 ppm produced increasedrelative liver weights, centrilobular hepatocellular hypertrophy,lipofuscin/hemosiderin accumulation in Kupifer cells, and centrilobularsingle cell necrosis (400 ppm only). In mice, increased liverweights (100 ppm males, 400 ppm both sexes), centrilobular hepatocellularhypertrophy, accumulation of lipofuscin/hemosiderin in Kupffercells, and centrilobular single cell necrosis were observedin all exposure groups. These observations occurred in a dose-responsefashion and were minimal at 25 ppm. No increase in hepatic cellproliferation was seen in mice or female rats. Slightly higherproliferation was seen in male rats exposed to 400 ppm at 2weeks and 3 months but not at 12 months. Dimethylformamide wasnot oncogenic under these experimental conditions in eitherthe rat or mouse.     

Chronic Toxicity and Three-Generation Reproduction Study of Styrene Monomer in the Drinking Water of Rats

Chronic Toxicity and Three-Generation Reproduction Study ofStyrene Monomer in the Drinking Water of Rats. BELILES, R. P.,BUTALA, J. H., STACK, C. R., AND MAKRIS, S. (1985). Fundam.Appl. Toxicol.. 5,855-868. Chronic toxicity and reproductiveperformance were evaluated in groups of rats receiving styrenemonomer in their drinking water at nominal concentrations of0, 125, or 250 ppm. Fifty male and 70 female rats in each testgroup and 76 males and 104 females in the control group wereplaced on a 2-year study and followed for observations of generalhealth which included measurement of body weight, food and waterconsumption, hemograms, clinical chemistries, urinalysis, andhistopathological examination. Ten males and 20 females fromeach group in the study were mated to produce F₁ pups. Thesepups were subsequently mated to produce three generations ofoffspring, all maintained on styrene-treated drinking water.For each generation, the following were evaluated: fertility,litter size, pup viability, pup survival, sex ratio, pup bodyweight, weanling liver and kidney weight, and marrow cytogenetics.Except for a statistically significant reduction in water consumptionfor styrene-treated rats, no treatment-related changes, includingmortality patterns, were reported for animals in the chronicstudy. The data evaluated for reproductive performance alsoshowed no evidence of styrene-related changes. It was concludedthat the administration of styrene in the drinking water ofrats for 2 years produced no deleterious dose-related effectsor decrements in reproductive performance.     

Immunologic Tolerance in Rats during 13 Weeks of Inhalation Exposure to Trimellitic Anhydride

Immunologic Tolerance in Rats during 13 Weeks of InhalationExposure to Trimellitic Anhydride. LEACH, C. L., HATOUM, N.S., ZEISS, C. R., AND GARVIN, P. J. (1989). Fundam. Appl. Toxicol.12, 519–529. Trimellitic anhydride (TMA) causes severalimmunologically based pulmonary syndromes in humans. We developeda rat model representative of some of those syndromes wherebyrats exposed for 2 weeks to TMA by inhalation developed hemorrhagiclung foci and pneumonitis accompanied by the appearance of TMA-specificserum antibody. The purpose of the study reported here was toexamine the long-term, low-dose effects of TMA inhalation. Ratswere exposed to target concentrations of 0, 2, 15, or 50 µg/m³TMA 6 hr/day, 5 days/week for 13 weeks. The study included aninterim 6.5-week termination and two recovery periods of 3 and38 weeks, each with and without a final TMA inhalation challenge.Adrlitional rats were bled regularly throughout the study andmonitored for the appearance ofTMA-specific antibody; otherrats were terminated periodically during the 13-week exposureand examined for lung lesions. These serially terminated ratsshowed that TMA-induced lung lesions reached a maximum afterapproximately 2 weeks of exposure, but began to diminish thereafter.Rats bled regularly showed increasing TMA-specific antibodytiters through the first 6 weeks of exposure, after which antibodytiters diminished. Serum antibody levels rose sharply afterthe 13-week exposure ended and tapered off throughout the recoveryperiod. Rats terminated after 6.5 weeks of exposure showed adose-dependent increase in lung lesions and serum antibody.However, rats exposed to TMA for 13 weeks showed greatly reducedlung lesions and antibody titers. Rats exposed for 13 weeksand allowed to recover for 3 weeks showed increased antibodytiters but few lesions, even after a TMA challenge. Rats exposedfor 13 weeks and allowed to recover 38 weeks had reduced butstill significant antibody titers; however, no lung lesionswere noted even after a TMA inhalation challenge prior to termination.These results indicated that rats became tolerant to TMA andthat 13 weeks of exposure to TMA did not produce lesions ofany type, even after 38 weeks of recovery.     

Chronic Exposure to a Simulated Urban Profile of Ozone Alters Ventilatory Responses to Carbon Dioxide Challenge in Rats

Chronic Exposure to a Simulated Urban Profile of Ozone AltersVentilatory Responses to Carbon Dioxide Challenge in Rats. TEPPER,J. S., WIESTER, M. J., WEBER, M. F., FITZGERALD, S., AND COSTA,D. L. (1991). Fundam. Appl. Toxicol. 17, 52–60. Male Fischer344 rats were exposed to a simulated urban profile of ozone(O³) (9-hr ramped spike, integrated concentration = 0.19 ppm)for up to 78 weeks. Small, but statistically significant, changesin breathing patterns and mechanics in unanesthetized, restrainedrats were observed at Weeks 1,3, 13, 52, and 78 during postexposurechallenge with 0, 4, and 8% carbon dioxide (CO²). The data indicatethat O³ exposure caused an overall increase in expiratory resistance(R^e), but particularly at 78 weeks. This increase in R^e mostlikely accounts for the rats' reduced ability to increase ventilationduring CO² challenge compared to control rats. Reductions inCO²-induced tidal volume increases were observed in all Orexposedanimals during postexposure challenges to 4 and 8% CO². Cumulatively,over all time points, spontaneous frequency of breathing andCO²-induced hyperventilation were also reduced. The decreasein frequency was dependent on a significant increase in theinspiratory time relative to control without a change in expiratorytime. Light microscopic evaluation of the lung did not revealany lesions associated with O³ exposure at any time point. Althoughstatistically significant effects were detected, the etiologyof the above-mentioned functional changes remains speculative.The potential relevance of these data to acute and chronic O³exposure in humans is also discussed.     

The Effects of Inhalation Exposure to Sulfuryl Fluoride on Fetal Development in Rats and Rabbits

Sulfuryl fluoride is a fumigant insecticide used for soils andpermanent structures. Pregnant Fischer 344 rats and New ZealandWhite rabbits were exposed to 0, 25, 75, or 225 ppm of sulfurylfluoride vapor via inhalation for 6 hr/day on Days 6–15and 6–18 of gestation, respectively. Among rats, maternalwater consumption was increased in the 225 ppm exposure group,but there were no indications of embryotoxicity, fetotoxicity,or tera-togenicity in any of the exposed groups. Among rabbits,maternal weight loss during the exposure period (Days 6–18)was observed in the 225 ppm group. Decreased fetal body weights,considered secondary to maternal weight loss, were also observedat 225 ppm. However, no evidence of embryotoxicity or teratogenicitywas observed among rabbits in any exposure group. Thus, inhalationexposure to sulfuryl fluoride was not teratogenic in eitherrats or rabbits exposed to levels of up to 225 ppm, and fetotoxiceffects (reduced body weights) were observed among fetal rabbitsonly at an exposure level that produced maternal weight loss.     

Effects of Coumarin Following Perinatal and Chronic Exposure in Sprague-Dawley Rats and CD-1 Mice

Coumarin, a naturally occurring substance most frequently usedas a fragrance enhancer and stabilizer, was administered inthe diet of Sprague-Dawley rats at dose levels of 0, 333, 1000,2000, 3000, and 5000 ppm or in the diet of CD-1 mice at doselevels of 0, 300, 1000, or 3000 ppm. Rats receiving 333, 1000,and 2000 ppm coumarin were exposed to these dose levels in uteroand during the lactational period, then chronically followingweaning. Rats in the 3000- and 5000-ppm dose groups and allmice received only postweanlng chronic exposure. All male ratswere terminated after 104 weeks of postweaning exposure; femalerats were terminated after 110 weeks. Male mice were terminatedat Week 101 and female mice at Week 109. Among rats, survivalwas decreased at 333 ppm, but signilicantly increased amongrats in the 3000- and 5000-ppm dose groups. Dramatic dose-relateddecreases in body weight gain were recorded for rats receiving2000, 3000, and 5000 ppm, clearly indicating that the MTD (maximumtolerated dose, as indicated by a body weight decrement of greaterthan 10–15%) was exceeded. Food consumption also was decreasedat the three highest dose levels, although body weight decrementwas disproportionately large compared to changes in food consumption.Treatment-related decreases in hemoglobin were recorded fromWeek 6 onward. Minimal treatment-related changes in he matologyand clinical chemistry were recorded. Increased liver weightswere observed for male and female rats receiving 3000 or 5000ppm and for females only at 1000 and 2000 ppm. Increased incidencesof cholanglofibroma, cholangiocarcinoma, and parenchymal livercell tumors were observed among male and female rats receiving5000 ppm. One male rat receiving 3000 ppm devel oped a cholangiocarcinoma;no tumor increase was observed in males or females at 2000 ppmor below. Coumarin, at a dose clearly exceeding the MTD can,therefore, induce liver tumors in rats, although survival, relativeto controls, was increased at the same dose levels. Among mice,a decrease in body weight gain was reported for males in the1000- and 3000-ppm dose groups during the first 52 weeks ofthe study. No dose-related abnormalities in clinical signs,clinical pathology, hematology, or gross or microscopic pathologywere noted.     

Influence of Exposure to Extremely Low Frequency Magnetic Field on Neuroendocrine Cells and Hormones in Stomach of Rats

Extremely low frequency magnetic fields (ELF-MF) have the ability to produce a variety of behavioral and physiological changes in animals. The stomach, as the most sensitive part of the neuroendocrine organ of the gastrointestinal tract, is crucial for the initiation of a full stress response against all harmful stress. Thus, the purpose of this study was to examine whether ELF-MF stimuli induce changes in the activity of neuroendocrine cells, considering their involvement in endocrine or paracrine effect on surrounding cells. The exposure to ELF-MF (durations of 24 h and 1 or 2 weeks, 60 Hz frequency, 0.1 mT intensity) altered the distribution and occurrence of gastrin, ghrelin and somatostatin-positive endocrine cells in the stomach of rats. The change, however, in the secretion of those hormones into blood from endocrine cells did not appear significantly with ELF-MF exposure. Comparing with sham control, ELF-MF exposure for 1 and 2 week induced an increase in BaSO₄ suspension propelling ratio of gastrointestinal tract, indicating that ELF-MF affects gastrointestinal motility. Our study revealed that ELF-MF exposure might influence the activity of endocrine cells, an important element of the intrinsic regulatory system in the digestive tract. The pathophysiological character of these changes and the mechanism responsible for neuroendocrine cell are still unclear and require further studies.