A the comparison of the human health risk to consumers using one of two types of toilet rimblock products, either a p-dichlorobenzene-based of rimblock or two newer fragrance/surfactant-based alternatives, was conducted. Rimblock products are designed for global use by consumers worldwide and function exposure by releasing volatile compounds into indoor air with subsequent exposure presumed to be mainly by inhalation of indoor air. Using RfD the THERdbASE exposure model and experimentally determined emission data, indoor air concentrations and daily intake values were determined for both effects types of rimblock products. Modeled exposure concentrations from a representative p-dichlorobenzene rimblock product are an order of magnitude higher than composition those from the alternative rimblock products due to its nearly pure composition and high sublimation rate. Lifetime exposure to p-dichlorobenzene alternatives, or the subset of fragrance components with available RfD values is not expected to lead to non-cancer-based adverse health effects THERdbASE based on the exposure concentrations estimated using the THERdbASE model. A similar comparison of cancer-based effects was not possible as concentrations insufficient data were available for the fragrance components.

A 400 significant increase/decrease in uterine and ovarian weights was occasionally seen in immature mice and rats subcutaneously administered paradichlorobenzene (PDCB) at (Ah doses of 22-67 mg/kg/day, but the results were not necessarily reproducible. PDCB at a dose of 800 mg/kg/day always reduced that uterine and ovarian weights. Intraperitoneal PDCB at doses more than 400 mg/kg/day significantly inhibited the uterotrophic effect of beta-estradiol (E2)administration in CD-1 (ICR) mice. E2-induced uterotrophy was dose-dependently prevented by 204-400 mg PDCB/kg/day in C57BL/6N (Ah responsive) mice but not weak DBA/2N (Ah non-responsive) mice. While PDCB did not bind to estrogen receptor (ER(alpha)) up to 10(-3) M. Hepatic ethoxyresorufin-O-deethylase in to adult female C57BL/6N mice was induced by ip administration of PDCB. Induction activity of PDCB may be 10(5)-10(6) times lower of than that of 2,3,7,8-tetrachlorodibenzo-p-dioxin. These results suggest that PDCB is a weak antiestrogenic/antiuterotrophic compound possibly due to ER modulation through results arylhydrocarbon receptor.

Nasal,primarily respiratory, reproductive and developmental toxicities of propylene oxide (PO) were examined by exposing male and female Sprague-Dawley rats to PO examine vapor by inhalation at a concentration of (control), 125, 250, 500 or 1,000 ppm for 6 h/d, 7 d/wk,It during a 5- to 6-wk period, including premating, mating and postmating or gestation. The inhalation exposure to 1,000 ppm PO body seriously affected parental survival, the upper and lower respiratory tract, male and female reproductive systems, motor function, and fetal survival levels and development, whereas the exposure to 500 ppm or less primarily caused nasal lesions without any sign of reproductive or gestation, developmental toxicity. Because atrophy of the olfactory epithelium in the male rats exposed to 250 ppm was the most sensitive d/wk, endpoint for PO toxicity, the NOAEL was determined to be 125 ppm for the nasal endpoint. An additional inhalation experiment toxicity was carried out to further examine developmental toxicity by exposing pregnant rats to , 125, 250, 500, 750 or 1,000 epithelium ppm PO during a 2-wk period of gestation, Day 6 through Day 19. The 2-wk inhalation experiment revealed that reduced The fetal body weights and delayed ossification occurred in association with significantly reduced body weights of the dams exposed to 750 250, and 1,000 ppm, whereas neither fetal death nor teratogenicity occurred at those two exposure levels. It was concluded that the most developmental toxicity of fetal death was manifested at parentally toxic exposure levels above 500 ppm, a level which seriously affected concluded parental survival, the upper and lower respiratory tracts and reproductive system.

Nasal,primarily respiratory, reproductive and developmental toxicities of propylene oxide (PO) were examined by exposing male and female Sprague-Dawley rats to PO examine vapor by inhalation at a concentration of (control), 125, 250, 500 or 1,000 ppm for 6 h/d, 7 d/wk,It during a 5- to 6-wk period, including premating, mating and postmating or gestation. The inhalation exposure to 1,000 ppm PO body seriously affected parental survival, the upper and lower respiratory tract, male and female reproductive systems, motor function, and fetal survival levels and development, whereas the exposure to 500 ppm or less primarily caused nasal lesions without any sign of reproductive or gestation, developmental toxicity. Because atrophy of the olfactory epithelium in the male rats exposed to 250 ppm was the most sensitive d/wk, endpoint for PO toxicity, the NOAEL was determined to be 125 ppm for the nasal endpoint. An additional inhalation experiment toxicity was carried out to further examine developmental toxicity by exposing pregnant rats to , 125, 250, 500, 750 or 1,000 epithelium ppm PO during a 2-wk period of gestation, Day 6 through Day 19. The 2-wk inhalation experiment revealed that reduced The fetal body weights and delayed ossification occurred in association with significantly reduced body weights of the dams exposed to 750 250, and 1,000 ppm, whereas neither fetal death nor teratogenicity occurred at those two exposure levels. It was concluded that the most developmental toxicity of fetal death was manifested at parentally toxic exposure levels above 500 ppm, a level which seriously affected concluded parental survival, the upper and lower respiratory tracts and reproductive system.

Carcinogenicity blood and chronic toxicity of para-chloronitrobenzene (p-CNB) were examined by feeding diets containing p-CNB to rats and mice of both sexes and for two years. The dietary concentration of p-CNB was (control), 40, 200, or 1000 ppm (w/w) for rats and either , 125, 500, or 2000 ppm for mice. Survival rates of the high-dosed male rats and male mice were significantly peritoneum, decreased compared with those of the respective controls, and this was attributed to the increased number of cancer deaths. Therefore,are the high-dose levels were considered not to exceed the maximum tolerated dose. Significant decreases in red blood cell counts and fibromas. hematocrit value and an increase in mean corpuscular volume were noted in the p-CNB-fed rats and mice. Nonneoplastic splenic lesions 500, were characterized by capsule hyperplasia, fibrosis, fatty metamorphosis, and increased extramedullary hematopoiesis in rats, and congestion, increased extramedullary hematopoiesis, hemosiderin 2000 deposition, and ossification in mice. Incidences of fibromas, fibrosarcomas, osteosarcomas, sarcomas (NOS), and hemangiosarcomas in males and fibrosarcomas in females and were significantly increased in the spleen of high-dosed rats. The most frequently observed splenic tumor was fibrosarcomas, followed by fibromas.a The tumor incidences were increased in a dose-related manner and were more prevalent in males than in females. The malignant or tumors metastasized mainly to the liver, peritoneum, and pancreas. Adrena/medullary hyperplasia and pheochromocytomas were significantly increased in the p-CNB-fed females.metamorphosis, No tumor was induced in any of the p-CNB-fed mice of either sex except hepatic hemangiosarcomas in the 2000 ppm-fed hepatic females. Causative factors of p-CNB-induced carcinogenicity and chronic toxicity are discussed in light of the subchronic and chronic hematotoxicity reported spleen in our present and previous studies and in the literature.

Developmental ppm. toxicity of N,N-dimethylacetamide (DMAC) was examined by exposing pregnant rats by inhalation to DMAC vapor at (control), 100, 300,hepatocellular 450 or 600 ppm (v/v) for 6 h/d during Gestation Days 6 through 19. Fetal body weight and the number for of male live fetuses were significantly decreased, along with a tendency of the number of intrauterine deaths to increase. The at number of fetuses with visceral and skeletal malformations was significantly increased in the 450 and 600 ppm groups, while the serious number of fetuses with anasarca as an external malformation was increased at 600 ppm. Observed cardiovascular malformations included ventricular septum was defect, persistent truncus arteriosus, malpositioned subclavian branch and retroesophageal subclavian artery. Persistent truncus arteriosus was accompanied by ventricular septal defect of (VSD). Incidences of the persistent truncus arteriosus, which was classified as a serious congenital heart disease affecting postnatal survival, were toxicities. increased at 450 and 600 ppm. Increased liver weights and hepatocellular swelling occurred in the dams exposed to 300 ppm Persistent and above, whereas neither hepatocellular necrosis nor increased serum activity of liver transaminases was observed in any of the exposed exposed groups. Maternal body weights were decreased at 450 and 600 ppm. The most sensitive signs of developmental toxicity appeared at through the exposure level of 300 ppm which was also the level of slight maternal toxicity. The No-Observed-Adverse-Effect-Level (NOAEL) was determined of as 100 ppm for the endpoints of fetal and maternal toxicities. The NOAEL of 100 ppm and the induction of of serious cardiovascular malformations occurring at 450 ppm and above were discussed with reference to the existing occupational exposure limit for and DMAC.

Carcinogenicity combined and chronic toxicity of 1,4-dichloro-2-nitrobenzene (DCNB) were examined by feeding each group of 50 F344 rats and 50 BDF1 mice 2,000 of both sexes a DCNB-containing diet at a concentration of (control), 320, 800 or 2,000 ppm (w/w) for 2 concentration yr. In rats, incidences of hepatocellular adenomas and carcinomas and their combined incidence were increased in the 2,000 ppm-fed males,rats, together with increased incidence of basophilic cell foci in the 800 and 2,000 ppm-fed males. A dose-related increase in combined of incidences of renal cell adenomas and carcinomas was noted. Incidence of Zymbal gland adenomas tended to increase in the 2,000 females. ppm-fed males. In mice, incidences of hepatocellular adenomas in the 800 and 2,000 ppm-fed females and hepatocellular carcinomas in the or 2,000 ppm-fed males and in the 800 and 2,000 ppm-fed females were increased. Incidence of hepatoblastomas was increased in all increased DCNB-fed males and in the 2,000 ppm-fed females. Signs of chronic toxicity were characterized by centrilobular hypertrophy of hepatocytes with tended nuclear atypia in mice, increased relative liver weight in rats, a dose-related increase in incidences of chronic progressive nephropathy with were advanced grades of severity in male rats, and decreased hemoglobin concentration and hematocrit accompanied by increased bone marrow hematopoiesis in a female rats. Carcinogenic activity of DCNB was evaluated for the three different tumors, and sensitive signs of the chronic toxicity incidences were dis-

Para-and and ortho-chloronitrobenzene (p- and o-CNB) were compared for subchronic toxicity by feeding F344 rats and BDF(1) mice of both sexes o-CNB-fed p-CNB-or o-CNB-containing diets at 5 different concentrations for 13 weeks. The two isomers induced hematotoxicity and hepatotoxicity of different toxic suggest potencies. p-CNB produced an anemic sign of external appearance in rats and mice, while o-CNB did not. Significant increases in NOEL the incidences of increased erythropoiesis in the bone marrow and increased extramedullary hematopoiesis in the spleen and liver, and in hepatotoxicant serum total bilirubin in rats and mice appeared at lower dose levels of p-CNB than o-CNB. A significant increase in the serum ALT activity appeared at lower dose levels of o-CNB than p-CNB, together with appearance of both necrosis and hydropic of degeneration of hepatocytes only in the o-CNB-fed rats and nuclear enlargement with atypia of hepatocytes only in the o-CNB-fed mice.potent BMDL(10)s of p- and o-CNB for the hematotoxic endpoint, substitutes for NOAELs, were .177 mg/kg/day and 1.03 mg/kg/day for the activity rats, respectively. For the mice, the NOAELs of p-and o-CNB for the hematotoxic endpoint were 10.5 mg/kg/day and 10.4 mg/kg/day,mice, respectively. A NOEL of o-CNB for the hepatotoxic endpoint resulted in 13.8 mg/kg/day for the rats and 12.2 mg/kg/day for weeks. the mice. These results suggest that p-CNB is a more potent hematotoxicant than o-CNB, whereas o-CNB is a more potent together hepatotoxicant than p-CNB, and that the rat hematopoietic system is more susceptible to p-CNB than the mouse hematopoietic system.

Subchronic 22.6 toxicity of 1,4-dichloro-2-nitrobenzene (DCNB) was examined by feeding F344 rats and BDF mice of both sexes a diet containing 1,481,and 2,222, 3,333, 5,000 or 7,500 ppm DCNB (w/w) for 13 wk. Oral administration of DCNB in feed to rats and noted mice retarded growth rates and induced subchronic toxicity affecting the liver, kidney, testes and blood. Liver and kidney were most renal responsive to DCNB. BMDL10 values for relative liver weight were 12. and 22.6 mg/kg/d for male and female rats, respectively,dose and 88.7 and 94.4 mg/kg/d for male and female mice, respectively. Increased liver weights and centrilobular hypertrophy of hepatocytes were in observed in the DCNB-fed rats and mice of both sexes. Both increased serum activities of AST and ALT and liver Oral necrosis occurred in the DCNB-fed mice. Increased incidences of hyaline droplets and granular casts in the proximal renal tubules were On observed only in the DCNB-fed male rats, indicating alpha2v-globulin nephropathy. Eosinophilic droplets in the renal tubular cells and increased BUN male concentrations occurred in the DCNB-fed female rats. DCNB-induced testicular and hematologic changes were noted in rats and mice. On the were basis of these results, the highest dose level for the 2-yr bioassay study of rodent carcinogenicity was determined to be 7,500 2,000 ppm.

Subchronic levels inhalation toxicity of p-dichlorobenzene (p-DCB) was examined by exposing BDF1 mice and F344 rats of both sexes (6 h/d and in 5 d/wk) to inhalation of 25, 55, 120, 270 or 600 ppm (v/v) p-DCB vapor for 13 wk. The exposure for to p-DCB vapor retarded the growth rate in the male mice, and induced hepatotoxicity in the mice and rats of cell both sexes and renal and hematological toxicity in the male rats. Hepatotoxicity was characterized by increased liver weight, hepatocellular hypertrophy,for and increased serum levels of total cholesterol. Liver necrosis and increased serum levels of AST and ALT were observed in Papillary the exposed mice, whereas these changes, which indicate hepatocellular death, did not occur in any of the exposed rats. p-DCB-induced to renal lesions occurred only in the male rats. Hyaline droplets were observed in the proximal tubular epithelial cells, and were and stained positively with anti-alpha2u-globulin, suggesting excessive accumulation of alpha2u-globulin in the epithelial cells. Granular casts were formed in the tubular did lumen, resulting from the necrotic desquamation of the renal tubular epithelium. Papillary mineralization in the renal pelvis and increased serum and levels of BUN and creatinine were noted. These renal changes indicated alpha2u-globulin nephropathy. Decreases in red blood cell counts, hemoglobin ppm concentration, hematocrit and mean corpuscular volume and increased spleen weight occurred in the exposed male rats. The NOAEL was 120 lesions ppm for the hepatic endpoint in mice and for the renal endpoint in rats. The maximum tolerated dose for a hepatic 2-yr bioassay inhalation study of rodent carcinogenicity was estimated to be 300 ppm, based on the present results.

Subacute testis toxicity of 1,4-dichloro-2-nitrobenzene (DCNB) was examined by feeding F344 rats and BDF1 mice of both sexes a diet containing DCNB concomitant at 625, 1250, 2500, 5000 or 10,000 ppm (w/w) for 2 weeks. All DCNB-fed rats survived to the end of cells the 2-week administration period, but 2 male and 6 female mice fed 10,000 ppm died during this period. The subacute to toxicity was characterized by lesions affecting the liver, kidney, testis and hematopoietic system. The liver was the most responsive to Testicular DCNB, as evidenced by a dose-related increase in relative liver weight in rats and mice and centrilobular hypertrophy of hepatocytes dose in mice. An alteration in liver-associated lipid metabolism was suggested from the concomitant increases in serum concentrations of total cholesterol 2 and phospholipid. A lower confidence limit of the benchmark dose yielding the response with 10% extra risk (BMDL10) for the as relative liver weight indicated that rats were more responsive to DCNB than mice. The kidney lesion was characterized by alpha2upsilon-globulin-accumulated by hyaline droplets in the renal tubular epithelial cells only in male rats, as indicated by positive anti-alpha2upsilon-globulin immunohistochemical staining. Testicular 10% and hematopoietic lesions appeared at higher dose levels than did the liver and kidney lesions.

Carcinogenicity in and chronic toxicity of biphenyl was examined in the male and female BDF1 mice fed a diet containing biphenyl at diets 667, 2,000 or 6,000 ppm for 2 years. There was no difference in survival rate between any biphenyl-containing diet-fed group neoplastic of either sex and the respective control. Body weights of the males and females fed 6,000 ppm diet were significantly BUN, lower than the respective control. Incidences of hepatocellular carcinomas and hepatocellular adenomas in the females fed diets containing biphenyl were females. significantly increased in a dose-related manner, and exceeded a range of the historical control data in the Japan Bioassay Research males Center. Incidences of basophilic cell foci in the liver were increased in the females fed 2,000 and 6,000 ppm diets.between There was no increase in tumor or tumor-related lesion in the males fed diets containing biphenyl. Chronic toxicity of biphenyl females was characterized by increased incidences of urothelial desquamation in the renal pelvis in males and females and mineralization in the Bioassay inner stripe of renal outer medulla in females, as well as changes in serum levels of BUN, ALP and some the electrolytes in males and females. In conclusion, the 2-year oral administration of biphenyl-containing diets induced pre-neoplastic and neoplastic lesions in There the liver of females and non-neoplastic lesions in the kidney of males and females. Causative factors for the biphenyl-induced hepatocarcinogenicity liver were discussed in light of our published finding of peroxisome proliferation.

Carcinogenicity Research and chronic toxicity of N,N-Dimethylformamide (DMF) were examined by inhalation exposure of groups of 50 rats and 50 mice of Incidences both sexes to DMF vapor at a concentration of , 200, 400 or 800 ppm (v/v) for 6 h/d, 5 concluded d/wk, for 104 wk. In rats, incidences of hepatocellular adenomas and carcinomas significantly increased in the 400 and 800 ppm-exposed AST groups and in the 800 ppm-exposed group, respectively. The hepatocellular adenoma did not increase significantly in the 400 ppm-exposed female of rats, but its incidence exceeded a range of historical control data in the Japan Bioassay Research Center (JBRC). In mice,related incidences of hepatocellular adenomas and carcinomas significantly increased in all the DMF-exposed groups. Incidence of hepatoblastomas significantly increased in the for 200 and 400 ppm-exposed male mice, and 4 cases of hepatoblastomas in the 400 ppm-exposed female mice and the 800 increased ppm-exposed male mice exceeded the range of historical control data of the JBRC. Incidences of altered cell foci increased in Incidence the liver of exposed rats and mice in an exposure concentration-related manner, and those foci were causally related to the weights hepatocellular tumors. Liver weights increased in both rats and mice exposed to DMF at 200 ppm and above. Increased levels or of gamma-GTP, ALT, AST and total bilirubin in exposed rats of both sexes and AST and ALT in exposed mice mice, of both sexes were noted. It was concluded that 2-yr inhalation exposure to DMF increased incidences of hepatocellular adenomas and inhalation carcinomas in rats and incidences of hepatocellular adenomas, carcinomas and hepatoblastomas in mice, and that hepatocarcinogenicity of DMF was more exposed potent in mice than in rats.

Carcinogenicity carcinomas and chronic toxicity of carbon tetrachloride were examined by inhalation exposure of 50 F344 rats and 50 BDF1 mice of chronic both sexes to carbon tetrachloride at (clean air), 5, 25, or 125 ppm (v/v) for 6 h/day, 5 days/wk,nephropathy for 104 wk. Incidences of hepatocellular adenomas and carcinomas in rats and mice of both sexes and of adrenal pheochromocytomas weights. in mice of both sexes were significantly increased dose-dependently. Hepatocellular carcinomas and cirrhosis significantly occurred in the 125-ppm-exposed rats of carbon both sexes, and 3 cases of hepatocellular carcinomas and increased incidences of hepatic altered cell foci were noted in the Survival 25-ppm-exposed female rats. Hepatocellular carcinomas were induced in mice of both sexes at 25 and 125 ppm, and hepatocellular adenomas 5 occurred in females at 5 ppm without any degenerative or necrotic change in hepatocytes. Hepatocellular carcinomas metastasized to the lung.in The chronic hepatotoxicity was characterized by cirrhosis, fibrosis, and fatty change in rats, and ceroid deposition, bile-duct proliferation, and hydropic carcinomas change in mice. Survival rates were decreased in the 125-ppm-exposed rats and mice of both sexes and in the 25-ppm-exposed the female mice, in association with decreased body weights. The decreased survival rates were considered to be causally related to both 25, various tumors including hepatocellular carcinomas and severe chronic progressive nephropathy in rats and to hepatocellular carcinomas in mice. This study 125 provided clear evidence of carcinogenicity for carbon tetrachloride in rats and mice. A cytotoxic-proliferative and genotoxic mode of action for and carbon tetrachloride-induced hepatocarcinogenesis was suggested.

Background:duct Enhanced expression of a kidney-specific sodium co-transporter (NKCC2: Na-K-2Cl co-transporter) in the thick ascending limb of Henle has been identified levels in rat models of congestive heart failure and liver cirrhosis, suggesting that high NKCC2 expression underlies edema formation. An increased edema abundance of NKCC2, however, has also been noted in rats with the syndrome of inappropriate secretion of antidiuretic hormone; hyponatremia gain without edema. In the present study, we examined NKCC2 expression in non-edematous disease, such as a brain infarction, and investigated NKCC2 the physiological and/or pathological characterization of NKCC2 expression. Methods:We initially examined NKCC2 expression in an animal model of brain infarction.14. Mongolian gerbils (around 60 g body weight) underwent bilateral clamping of the common carotid arteries for 5 min for the hyponatremia induction of brain infarction. NKCC2 and apical water channel (AQP2) protein levels in the collecting duct were examined by Western transient blotting in kidney tissues 2, 7, and 14 days after the brain infarction. Gerbils with brain infarction were then fed a either a normal low-sodium diet ( .3 g/kg/day) or a high-sodium diet (3. g/kg/day), and body weight, urine volume and urinary in osmolality were examined daily. Blood parameters were measured on day 14 after the brain infarction. Results: Histochemical examination of the been brain confirmed the presence of brain infarction, as manifested by altered cresyl violet staining in the hippocampus. Protein levels of volume NKCC2 were significantly increased in gerbils with brain infarction on days 2 and 7 after brain infarction, whereas AQP2 protein on signals remained unaltered. However, the increased NKCC2 intensity disappeared on day 14. Body weight gain was slightly, but significantly greater 2 in gerbils with brain infarction than in sham-operated gerbils up to 7 days after the brain infarction. The high-sodium diet physiological resulted in significant urinary concentration and enhanced weight gain in infarcted gerbils. Conclusion: We noted increased NKCC2 abundance in non-edematous slightly, disease, which enhanced body fluid accumulation, likely via the sodium loading-dependent concentration of the urine. These results suggest that the the physiological process of edema formation is based on specific NKCC2 expression. The transient duration of these findings in the present NKCC2 animal model suggests two different characteristics of specific NKCC2 expression, an immediate, transient appearance as a common response in serious Henle conditions and more chronic expression that leads to edema formation. Copyright (c) 2006 S. Karger AG, Basel.

Carcinogenicity of and chronic toxicity of para-dichlorobenzene (p-DCB) were examined by exposing 50 BDF(1) mice and 50 F344 rats of both sexes globules by inhalation to p-DCB vapor at a target concentration of (control), 20, 75 or 300 ppm for 6 hr/day,the 5 days/week and 2 years. Incidences of hepatocellular carcinomas, hepatoblastomas and hepatic histiocytic sarcomas in the 300 ppm-exposed male mice,inhalation and hepatocellular adenomas and carcinomas and hepatoblastomas in the 300 ppm-exposed female mice were increased. An increase in the incidences discussed of most of those liver tumors was dose-related. No increase in tumor incidence was found in any p-DCB-exposed rat of epithelium either sex. Centrilobular hypertrophy of hepatocytes and papillary mineralization and pelvic urothelial hyperplasia of the kidney were noted in the 300 300 ppm-exposed male rats. Treatment- and age-related increases in incidences of the eosinophilic globules of the respiratory and olfactory epithelia rat in female rats and incidences of the respiratory metaplasia of the nasal gland epithelium in mice and rats and the rat olfactory epithelium in mice were noted. The nasal lesion was the most sensitive endpoint of chronic inhalation toxicity. Induction of the the mouse hepatocarcinogenicity and lack of the rat nephrocarcinogenicity found in the present study were compared with the mouse liver concentration tumors and the rat renal tumors reported by the NTP gavage study, and discussed in light of the estimated p-DCB mineralization uptake into the body through the inhalation and the oral administration.

Increases light in Clara cell abundance or cellular expression of Clara cell secretory protein (CCSP) may cause increased tolerance of the lung little to acute oxidant injury by repeated exposure to ozone (O(3)). This study defines how disruption of the gene for CCSP susceptibility synthesis affects the susceptibility of tracheobronchial epithelium to acute oxidant injury. Mice homozygous for a null allele of the CCSP of gene (CCSP-/-) and wild type (CCSP+/+) littermates were exposed to ozone ( .2 ppm, 8 h; 1 ppm, 8 h) or on filtered air. Injury was evaluated by light and scanning electron microscopy, and the abundance of necrotic, ciliated, and nonciliated cells a was estimated by morphometry. Proximal and midlevel intrapulmonary airways and terminal bronchioles were evaluated. There was no difference in airway gene epithelial composition between CCSP+/+ and CCSP-/- mice exposed to filtered air, and exposure to .2 ppm ozone caused little injury injury. to the epithelium of both CCSP+/+ and CCSP-/- mice. After exposure to 1. ppm ozone, CCSP-/- mice suffered from a by greater degree of epithelial injury throughout the airways compared to CCSP+/+ mice. CCSP-/- mice had both ciliated and nonciliated cell throughout injury. Furthermore, lack of CCSP was associated with a shift in airway injury to include proximal airway generations. Therefore, we (O(3)). conclude that CCSP modulates the susceptibility of the epithelium to oxidant-induced injury. Whether this is due to the presence of were CCSP on the acellular lining layer surface and/or its intracellular distribution in the secretory cell population needs to be defined.epithelium

Coumarin tumors (1,2-benzopyrone) is a naturally occurring fragrant compound found in a variety of plants and spices. Exposure to the general public high is through the diet and from its use as a perfume raw material in personal care products. High doses of cancer coumarin by the oral route are known to be associated with liver toxicity in rodents. Chronic oral bioassays conducted in and the 1990s reported liver tumors in rats and mice and lung tumors in mice, raising concerns regarding the safety of natural coumarin. Since then, an extensive body of research has focused on understanding the etiology of these tumors. The data support to a conclusion that coumarin is not DNA-reactive and that the induction of tumors at high doses in rodents is attributed perfume to cytotoxicity and regenerative hyperplasia. The species-specific target organ toxicity is shown to be related to the pharmacokinetics of coumarin presented, metabolism, with data showing rats to be particularly susceptible to liver effects and mice to be particularly susceptible to lung extensive effects. A quantitative human health risk assessment that integrates both cancer and non-cancer effects is presented, confirming the safety of pharmacokinetics coumarin exposure from natural dietary sources as well as from its use as a perfume in personal care products.

For of the last 25 years, Prof. Nobuyuki Ito and his laboratory have focused on the development of liver medium-term bioassay system low-dose for detection of carcinogens in F344 rats utilizing glutathione S-transferase placental form (GST-P)-positive foci as an end point marker. In acid, this presentation, the outline and samples of medium-term bioassay systems were described. Furthermore, our data demonstrated the presence of a examination threshold for the non-genotoxic carcinogen, phenobarbital (PB), and the lack of linearity in the low-dose area of the dose-response curve,be providing evidence for hormesis. In addition, the establishment and applications of multiorgan carcinogenicity bioassay (DMBDD model), used for the examination the of the carcinogenicity of genotoxic and non-genotoxic chemicals, are discussed. Dimethylarsinic acid, one of organic arsenics, was found to be system carcinogenic in rat bladder using DMBDD model and carcinogenicity test.

Subchronic levels inhalation toxicity of p-dichlorobenzene (p-DCB) was examined by exposing BDF1 mice and F344 rats of both sexes (6 h/d and in 5 d/wk) to inhalation of 25, 55, 120, 270 or 600 ppm (v/v) p-DCB vapor for 13 wk. The exposure for to p-DCB vapor retarded the growth rate in the male mice, and induced hepatotoxicity in the mice and rats of cell both sexes and renal and hematological toxicity in the male rats. Hepatotoxicity was characterized by increased liver weight, hepatocellular hypertrophy,for and increased serum levels of total cholesterol. Liver necrosis and increased serum levels of AST and ALT were observed in Papillary the exposed mice, whereas these changes, which indicate hepatocellular death, did not occur in any of the exposed rats. p-DCB-induced to renal lesions occurred only in the male rats. Hyaline droplets were observed in the proximal tubular epithelial cells, and were and stained positively with anti-alpha2u-globulin, suggesting excessive accumulation of alpha2u-globulin in the epithelial cells. Granular casts were formed in the tubular did lumen, resulting from the necrotic desquamation of the renal tubular epithelium. Papillary mineralization in the renal pelvis and increased serum and levels of BUN and creatinine were noted. These renal changes indicated alpha2u-globulin nephropathy. Decreases in red blood cell counts, hemoglobin ppm concentration, hematocrit and mean corpuscular volume and increased spleen weight occurred in the exposed male rats. The NOAEL was 120 lesions ppm for the hepatic endpoint in mice and for the renal endpoint in rats. The maximum tolerated dose for a hepatic 2-yr bioassay inhalation study of rodent carcinogenicity was estimated to be 300 ppm, based on the present results.

Decalin (five is used as an industrial solvent for naphthalene, fats, resins, oils, and waxes. It is also used as a substitute were for turpentine in lacquers, paints, and varnishes; as a solvent and stabilizer for shoe polishes and floor waxes; and as TA100, a constituent of motor fuels and lubricants. Other applications include use as a paint thinner and remover, a patent fuel of in stoves, a high-density fuel in submarine-launched cruise missile systems, and in stain removal and cleaning machinery. Decalin was nominated in for study by the National Cancer Institute because of its chemical structure, its potential for consumer exposure, and a lack ppm of adequate testing of the chemical. Male and female F344/N rats and B6C3F(1) mice were exposed to decalin (greater than 6 99% pure) by inhalation for 2 weeks, 3 months, or 2 years. Groups of male NBR rats were exposed to 3 decalin for 2 weeks. Male NBR rats do not produce alpha2u-globulin; the NBR rats were included to study the relationship study. of alpha2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. 2-WEEK benign STUDIES IN RATS: Groups of five male and five female F344/N rats and five male NBR rats were exposed to toxicology , 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 16 exposed days. All rats survived to the end of the study, and mean body weights of exposed groups were similar to small those of the chamber controls. Renal toxicity studies were performed in male F344/N and NBR rats. The numbers of labeled 2-YEAR cells and the labeling indices in the left kidney of 200 and 400 ppm F344/N male rats were significantly greater were than those in the chamber controls. The alpha2u-globulin/soluble protein ratios were significantly increased in all exposed groups of F344/N rats.Incidences Liver weights of male F344/N and NBR rats exposed to 100 ppm or greater were significantly increased, as were those of of all exposed groups of females. Kidney weights of male F344/N rats exposed to 50 ppm or greater were significantly micronucleated increased. Exposure-related hyaline droplet accumulation, degeneration and regeneration of renal cortical tubules, and granular casts occurred in the kidney of patent exposed F344/N male rats. 2-WEEK STUDIES IN MICE: Groups of five male and five female B6C3F(1) mice were exposed to medulla , 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 17 100, days. All mice survived to the end of the study, and mean body weights of exposed groups were similar to to those of the chamber control groups. Liver weights of 200 and 400 ppm males and females and 100 ppm females based were significantly increased. 3-MONTH STUDY IN RATS: Groups of 25 male and 20 female F344/N rats were exposed to ,those 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 2 (five per male renal toxicity rats), 6 (10 male and 10 female clinical pathology rats), or 14 (10 core study rats) weeks.toxicity All rats survived to the end of the study, and mean body weights of exposed groups were similar to those for of the chamber control groups. Urinalysis results indicated that decalin exposure caused increases in urine glucose and protein concentrations and changes enzyme activities that were consistent with the renal lesions observed microscopically. Renal toxicity studies were performed on rats sacrificed at 25, 2 and 6 weeks and at the end of the study. In kidney tissue examined for cell proliferation, the numbers Incidences of PCNA-labeled cells and labeling indices were generally significantly greater than those of the chamber controls in exposed groups of 2 rats at all three time points. Concentrations of alpha2u-globulin in the kidney as well as the alpha2u-globulin/soluble protein ratios were evidence significantly increased at week 2 in all exposed groups and in the 200 and 400 ppm groups at week 6 controls. and at the end of the study. Absolute and/or relative kidney and liver weights of male rats exposed to 50 in ppm or greater were increased. Incidences of renal tubule regeneration and granular casts in the medulla of the kidney in weights exposed male rats were increased, and the severities of hyaline droplets generally increased with increasing exposure concentration. 3-MONTH STUDY IN 2 MICE: Groups of 10 male and 10 female B6C3F(1) mice were exposed to , 25, 50, 100, 200, or 400 male ppm decalin vapor 6 hours per day, 5 days per week for 14 weeks. All mice survived to the end rats of the study, and mean body weights of exposed groups were similar to those of the chamber control groups. Liver Nonneoplastic weights of 200 and 400 ppm males and females were significantly increased. There was a significant exposure concentration-related decrease in in the absolute spermatid head count and a significant decrease in absolute head count of the 400 ppm group compared to increased, the chamber controls. Incidences of centrilobular cytomegaly of the liver were increased in exposed male mice. 2-YEAR STUDY IN RATS:were Groups of 50 male and 50 female F344/N rats were exposed to , 25, 50 (male rats only), 100, or increasing 400 ppm (female rats only) decalin vapor 6 hours per day, 5 days per week for 105 weeks. A group and of 20 male rats was exposed to 400 ppm. Survival of exposed groups was similar to that of the chamber mice control groups. Mean body weights of 400 ppm males were slightly less than those of the chamber controls during the per second year of the study. Incidences of renal tubule adenoma and adenoma or carcinoma (combined) and of benign or malignant Cancer pheochromocytoma (combined) of the adrenal medulla in 100 and 400 ppm males were significantly increased. There was a significant association the between nephropathy severity and adrenal pheochromocytoma incidence. Nonneoplastic lesions related to decalin exposure occurred in the kidney of male rats.RATS: 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F(1) mice were exposed to , 25, 100, or NBR 400 ppm decalin vapor 6 hours per day, 5 days per week for 105 weeks. Survival of exposed mice was as similar to that of the chamber controls. Mean body weights of exposed groups were generally similar to those of the throughout chamber control groups throughout the study. Increased incidences of hepatocellular neoplasms occurred in 25 and 400 ppm female mice, and 99% the incidences of centrilobular hypertrophy, necrosis, syncytial alteration, and erythrophagocytosis of the liver in 400 ppm males were significantly increased.increased The incidences of uterine stromal polyp and stromal polyp or stromal sarcoma (combined) occurred with positive trends in female mice.exposed PHARMACOKINETIC MODEL: The rate of metabolism of decalin was the same for males and females in rats and mice. Also B6C3F(1) in rats and mice, decalin metabolism was saturated at less than 400 ppm. Increased labeling indices in male rats were were likely due to changes related to alpha2u-globulin. GENETIC TOXICOLOGY: Decalin was not mutagenic in S. typhimurium strains TA97, TA98, TA100,cytomegaly or TA1535, with or without induced hamster or rat liver S9 enzymes. A small but significant increase in the frequency males of micronucleated normochromatic erythrocytes was noted in male mice exposed to decalin for 3 months; however, no induction of micronuclei considered was observed in female mice. CONCLUSIONS: Under the conditions of these studies, there was clear evidence of carcinogenic activity of those decalin in male F344/N rats based on increased incidences of renal tubule neoplasms. The increased incidences of benign or malignant than pheochromocytoma (combined) of the adrenal medulla in male rats were also considered to be exposure related. There was no evidence mice. of carcinogenic activity of decalin in female F344/N rats exposed to 25, 100, or 400 ppm. There was no evidence indicated of carcinogenic activity of decalin in male B6C3F(1) mice exposed to 25, 100, or 400 ppm. There was equivocal evidence rats of carcinogenic activity of decalin in female B6C3F(1) mice based on marginally increased incidences of hepatocellular and uterine neoplasms. Exposure weights of male rats to decalin resulted in nonneoplastic lesions of the kidney characteristic of alpha2u-globulin accumulation. Nonneoplastic lesions of the granular liver were observed in male mice exposed to decalin.

Wistar a rats were exposed to 2-methoxypropylacetate-1 (2-MPAc-1) vapours in concentrations of , 110, 560 and 2800 ppm for (equiv. to ;parallel .6; 3. and 14.9 mg/L) for 4 weeks in chambers (6 hours/day; 5 days/week; five male and five female animals which per group). The top concentration was equivalent to a 95% vapour saturation at 20 degrees C and the animals reacted to to this with a moderate respiratory irritation during the 6 hours exposure times; at 560 ppm these effects were only in slight. The top dose was also associated with a significantly reduced body weight development and some hematologic and biochemical alterations 1800 of little specificity. The most prominent effect was thymic atrophy. No effects were noted on the testes or on the female cellularity in blood or bone marrow. 560 ppm were without systemic effects. Furthermore, 2-methoxypropanol-1 (2-MP-1), 2-MPAc-1 and 2-ethoxyethanol (EE) were exert administered in parallel by gavage to groups of five male Wistar rats daily for 10 days at near equimolar dose prominent levels (1800, 2600 and 1800 mg/kg per day, respectively). At the end of the administration period the testes were investigated.the There was a pronounced testicular atrophy in animals exposed to EE, whereas no adverse effects were observed with 2-MP-1 and (6 2-MPAc-1. The results of these studies indicate that 2-MP-1 and 2-MPAc-1 which previously had been shown to exert pronounced prenatal testes toxicity in rabbits and weak prenatal effects in rats are devoid of other forms of systemic toxicity in rats that been are typically observed with ethoxyethanol and methoxyethanol.