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Vanadium pentoxide (V2O5) is a slightly soluble compound found in airborne particle emissions from metallurgical works and oil and coal burning. Because the carcinogenic potential of V2O5 was not known, F344/N rats and B6C3F1 mice (N = 50/sex/species) were exposed to V205at concentrations of 0, 0.5 (rats only), 1, 2, or 4 (mice only) mg/m3, by whole-body inhalation for 2 years. The survival and body weights of rats were minimally affected by exposure to V2O5. The survival and body weights of male mice exposed to 4 mg/m3and body weights of all exposed groups of female mice were lower than the controls. Alveolar/bronchiolar (A/B) neoplasms occurred in male rats exposed to 0.5 and 2 mg/m3 at incidences exceeding the National Toxicology Program (NTP) historical control ranges. A marginal increase in A/B neoplasms was also observed in female rats exposed to 0.5 mg/m3. Increases in chronic inflammation, interstitial fibrosis, and alveolar and bronchiolar hyperplasia/metaplasia and squamous metaplasia were observed in exposed male and female rats. A/B neoplasms were significantly increased in all groups of exposed mice. As with rats, increases in chronic inflammation, interstitial fibrosis, and alveolar and bronchiolar epithelial hyperplasia were observed in mice exposed to V205. Thus, V205 exposure was a pulmonary carcinogen in male rats and male and female mice. The marginal tumor response in the lungs of female rats could not be attributed conclusively to exposure to V205. These responses were noted at and slightly above the OSHA permissible occupational exposure limit of 0.5 mg/m3 (dust) (National Institute for Occupational Safety and Health,NIOSH Pocket Guide to Chemical Hazards, U.S. Department of Health and Human Services, Washington, DC, 1997, p. 328). [ABSTRACT FROM AUTHOR]

Groups of F344 rats and B6C3F 1 mice were exposed to furfuryl alcohol vapor for 6 hours per day, 5 days per week for 14 days (0, 16, 31, 63, 125, 250 ppm) or 13 weeks (0, 2, 4, 8, 16, 32 ppm). Reduced survival was observed in the 14-day study at 250 ppm. Final mean body weights of rats and mice exposed to 125 ppm and of female mice exposed to 63 ppm were lower than controls at the end of the 14-daystudy; there were no significant differences in mean body weight among chemical-exposed and control groups in the 13-week study. Exposureto furfuryl alcohol had no toxicologically significant effect on organ weights in either rats or mice, and did not cause any adverse changes in hematology or serum chemistry parameters evaluated in rats in the 13-week study. Microscopic lesions associated with exposure to furfuryl alcohol were present in the nose of both rats and mice at all exposure concentrations in both the 14-day and 13-week studies. Lesions observed in the 14-day study consisted of inflammation of the nasal turbinates accompanied by necrosis and squamous metaplasia of the respiratory epithelium and necrosis and degeneration of the olfactory epithelium. Similar lesions were observed in both rats and mice in the 13-week study. In addition, squamous metaplasia and goblet cell hyperplasia of the respiratory epithelium, squamous metaplasia of the transitional epithelium and degeneration, hyperplasia and some respiratory metaplasia of the olfactory epithelium were also observed in ratsin the 13-week study, and hyaline droplets in the respiratory epithelium and chronic inflammation and respiratory metaplasia in the olfactory epithelium were observed in mice in the 13-week study. Ir general the nasal passages of mice appeared less sensitive than those of rats at the concentrations used in the 13-week study; a no-observable-effect level was not achieved in either the 14-day or the 13-week study. [ABSTRACT FROM AUTHOR]

Researchers strive to design and implement high-quality surveys to maximize the utility of the data collected. The definitions of quality and usefulness, however, vary from survey to survey and depend on the analytic needs. Survey teams must evaluate the trade-offs of various decisions, such as when results are needed and their required level of precision, in addition to practical constraints like budget, before finalizing the design. Characteristics within the concept of fit for purpose (FfP) can provide the framework for considering the trade-offs. Furthermore, this tool can enable an evaluation of quality for the resulting estimates. Implementation of a FfP framework in this context, however, is not straightforward. In this article, we provide the reader with a glimpse of a FfP framework in action for obtaining estimates on early season influenza vaccination coverage estimates and on knowledge, attitudes, behaviors, and barriers related to influenza and influenza prevention among civilian noninstitutionalized adults aged 18 years and older in the United States. The result is the National Internet Flu Survey (NIFS), an annual, two-week internet survey sponsored by the US Centers for Disease Control and Prevention. In addition to critical design decisions, we use the established NIFS FfP framework to discuss the quality of the NIFS in meeting the intended objectives. We highlight aspects that work well and other survey traits requiring further evaluation. Differences found in comparing the NIFS to the National Flu Survey, the National Health Interview Survey, and Behavioral Risk Factor Surveillance System are discussed via their respective FfP characteristics. The findings presented here highlight the importance of the FfP framework for designing surveys, defining data quality, and providing a set a metrics used to advertise the intended use of the survey data and results.

Background: Annual vaccination is the most effective strategy for preventing influenza. We assessed trends and demographic and access-to-care characteristics associated with place of vaccination in recent years., Methods: Data from the 2014-2018 National Internet Flu Survey were analyzed to assess trends in place of early-season influenza vaccination during the 2014-15 through 2018-19 seasons. Multivariable logistic regression was conducted to identify factors independently associated with vaccination settings in the 2018-19 season., Results: Among vaccinated adults, the proportion vaccinated in medical (range: 49%-53%) versus nonmedical settings (range: 47%-51%) during the 2014-15 through 2018-19 seasons were similar. Among adults aged ≥18 years vaccinated early in the 2018-19 influenza season, a doctor's office was the most common place (34.4%), followed by pharmacies or stores (32.3%), and workplaces (15.0%). Characteristics significantly associated with an increased likelihood of receipt of vaccination in nonmedical settings among adults included household income ≥$50,000, having no doctor visits since July 1, 2018, or having a doctor visit but not receiving an influenza vaccination recommendation from the medical professional., Conclusions: Place of early-season influenza vaccination among adults who reported receiving influenza vaccination was stable over 5 recent seasons. Both medical and nonmedical settings were important places for influenza vaccination. Increasing access to vaccination services in medical and nonmedical settings should be considered as an important strategy for improving vaccination coverage., (Published by Elsevier Inc.)

Previous research has shown that increasing the size of incentives can increase response rates for probability-based, cross-sectional surveys. However, the effects of incentives on web panels have not been extensively studied. We sought to answer the question: What is the effect of larger, postpaid incentives on (1) response, (2) data quality, and (3) nonresponse bias for individuals in a web panel? We analyzed data from the 2015 and 2016 National Internet Flu Survey, a survey that uses the GfK KnowledgePanel ® as its sampling frame. We compare panel members who received a postpaid, standard 1,000-point (the equivalent of US$1) incentive in 2015 to panelists who received a larger, 5,000-point (the equivalent of US$5) incentive in 2016. We found that larger incentives were associated with increased interview completion rates with minimal impact on data quality or bias., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Influenza vaccination has been recommended for all persons aged ≥6 months since 2010., Methods: Data from the 2016 National Internet Flu Survey were analyzed to assess provider vaccination recommendations and early influenza vaccination during the 2016-17 season among adults aged ≥18 years. Predictive marginals from a multivariable logistic regression model were used to identify factors independently associated with early vaccine uptake by provider vaccination recommendation status., Results: Overall, 24.0% visited a provider who both recommended and offered influenza vaccination, 9.0% visited a provider who only recommended but did not offer, 25.1% visited a provider who neither recommended nor offered, and 41.9% did not visit a doctor from July 1 through date of interview. Adults who reported that a provider both recommended and offered vaccine had significantly higher vaccination coverage (66.6%) compared with those who reported that a provider only recommended but did not offer (48.4%), those who neither received recommendation nor offer (32.0%), and those who did not visit a doctor during the vaccination period (28.8%). Results of multivariable logistic regression indicated that having received a provider recommendation, with or without an offer for vaccination, was significantly associated with higher vaccination coverage after controlling for demographic and access-to-care factors., Conclusions: Provider recommendation was significantly associated with influenza vaccination. However, overall, 67.0% of adults did not visit a doctor during the vaccination period or did visit a doctor but did not receive a provider recommendation. Evidence-based strategies such as client reminder/recall, standing orders, provider reminders, or health systems interventions in combination should be undertaken to improve provider recommendation and influenza vaccination coverage. Other factors significantly associated with a higher level of influenza vaccination included age ≥50 years, being Hispanic, having a college or higher education, having a usual place for medical care, and having public health insurance., (Published by Elsevier Ltd.)

Chromium picolinate monohydrate (CPM) is a synthetic compound heavily marketed to consumers in the United States for use as a dietary supplement for muscle building and weight loss. The National Toxicology Program (NTP) tested the toxicity of this compound based on the potential for widespread consumer exposure and lack of information about its toxicity. Groups of 10 male and 10 female F344/N rats and B6C3F(1) mice were exposed to 0, 80, 240, 2000, 10,000, or 50,000 ppm CPM in feed for 13 weeks. CPM administration produced no effect on body weight gain or survival of rats or mice. Organ weights and organ/body weight ratios in exposed animals were generally unaffected by CPM. No compound-related changes in hematology and clinical chemistry parameters were observed. There were no histopathological lesions attributed to CPM in rats or mice.

Propylene glycol mono-t-butyl ether (PGMBE) is a widely used solvent in industry and in consumer products, posing a potential for human exposure via inhalation or dermal routes. Toxicokinetic studies were conducted on F344/N rats and B6C3F1 mice of both sexes to evaluate single or repeated dose, species, and/or sex differences in PGMBE elimination kinetics following intravenous or inhalation exposure. In the first study, rats and mice received a single intravenous dose of 15 or 200 mg PGMBE/kg and serial blood samples were collected and analyzed for PGMBE. In the second study, rats and mice received a single 6-h whole-body inhalation exposure to 75, 300, or 1200 ppm PGMBE and serial blood samples were collected and analyzed for PGMBE. In the third study, rats and mice received whole-body inhalation exposures to 75, 300, or 1200 ppm PGMBE for 6 h/day, 5 days/wk for 14 (rats) or 16 (mice) wk. Serial blood samples were analyzed for PGMBE after 2, 6, 14 (rats), and 16 (mice) wk on study. Urine samples were also collected for 16 h postexposure and analyzed for creatinine and PGMBE sulfate and PGMBE glucuronide conjugates. These studies revealed that: (1) PGMBE was eliminated from blood following concentration-dependent nonlinear kinetics in both species; (2) saturable Michaelis-Menten kinetics were clearly exhibited following a single inhalation exposure at 1200 ppm, but were less obvious following repeated exposures; (3) mice were more efficient in eliminating PGMBE from blood at lower exposure concentrations (i.e., < or = 300 ppm), but at exposure concentrations potentially exceeding their elimination capacity, mice had a greater concentration-dependent decrease in PGMBE elimination than rats; (4) there were minimal but consistent sex differences in PGMBE elimination profiles for rats, with females having higher blood concentrations at all exposure concentrations and sampling times; and (5) sex differences in PGMBE elimination were in part associated with differences in urinary excretion of PGMBE metabolites., (Copyright Taylor & Francis Inc.)

Previous work showed a correlation between K-ras mutation and loss of heterozygosity (LOH) on chromosome 6 in the region of K-ras in lung carcinomas from B6C3F1 mice. We hypothesized that mitogen-activated protein kinase (MAPK) would be activated only in those lung neoplasms with both K-ras mutation and LOH. As MAPK activity can be correlated directly with signal detection using antibodies to phosphorylated MAPK, we were able to analyze lung carcinomas from B6C3F1 mice for the presence or absence of MAPK activity by western analysis. Vanadium pentoxide-induced mouse lung carcinomas, which had been shown to have a high frequency of K-ras mutations and LOH on chromosome 6 and for which frozen tumor tissue was available, were used for this study. Total MAPK expression levels were similar between normal lung and lung carcinomas. Phospho-MAPK was elevated in five of six lung carcinoma samples examined in which K-ras mutations and chromosome 6 LOH were identified and in four of five carcinomas with K-ras mutations that lacked LOH. Phospho-MAPK was undetectable or weakly expressed in seven carcinomas examined without K-ras mutations and in normal lung. By immunohistochemistry three K-ras positive/LOH negative samples exhibited multifocal areas of nuclear and cytoplasmic staining for phospho-MAPK. Large amounts of non-staining fibroblasts, lymphocytes and macrophages were also observed in these tumors. Two of these lung carcinomas were microdissected and chromosome 6 LOH was detected in regions of phospho-MAPK positive cells. These results suggest that MAPK is activated during vanadium pentoxide-induced B6C3F1 mouse lung tumorigenesis following K-ras mutation and loss of the wild-type K-ras allele.

Whole-body inhalation toxicology and carcinogenicity studies were performed with the widely used fixative and cold-sterilant glutaraldehyde. Groups of 50 male and female F344/N rats and B6C3F(1) mice were exposed to glutaraldehyde (rats: 0, 250, 500, or 750 ppb; mice: 0, 62.5, 125, or 250 ppb) 6 h/day, 5 days/week, for 104 weeks. Survival of 500- and 750-ppb female rats was less than that of controls. Mean body weights of all exposed groups of male rats, 500- and 750-ppb female rats, and 250-ppb female mice were generally less than those of controls. No exposure-related neoplastic lesions were observed in either rats or mice. Non-neoplastic lesions were limited primarily to the most anterior region of the nasal cavity. In rats, hyperplasia and inflammation of the squamous epithelium; hyperplasia, goblet cell hyperplasia, inflammation, and squamous metaplasia of the respiratory epithelium; and hyaline degeneration of the olfactory epithelium were observed. In mice, the nasal lesions were qualitatively similar to those in rats. Squamous metaplasia of the respiratory epithelium was observed in both sexes of mice while female mice also had inflammation and hyaline degeneration of the respiratory epithelium. In contrast to the nasal carcinogen formaldehyde, no neoplastic lesions were observed after inhalation exposure to glutaraldehyde. However, exposure to glutaraldehyde resulted in considerable non-neoplastic lesions in the noses of rats and mice.

Female Fischer 344 (F344)/N rats (10 per exposure group) were exposed to 2-butoxyethanol (BE) vapors (0, 31, 62.5, 125, 250, or 500 ppm 6 h/d, 5 d/wk, for 13 weeks) to characterize its prechronic toxicity. Dental lesions consisting of bilateral multifocal dental pulp thrombosis, pulp infarction, and odontoblast infarction were noted in the maxillary incisors of 3 of 4 rats from the 500-ppm group that were sacrificed when moribund during the first week of exposure. In addition, 1 rat from the 500-ppm group that was sacrificed on day 32 had similar unilateral incisor lesions but with additional findings consistent with a unilateral maxillary incisor fracture. In contrast, rats sacrificed after 13 weeks of exposure lacked dental lesions. In conclusion, BE has the potential to cause pulp thrombosis and odontoblast infarction in female rats. The apparent variability in response to BE noted in moribund sacrificed vs terminally sacrificed rats was attributed to development of tolerance to BE-induced hemolysis and subsequent incisor regeneration.

Cobalt sulfate is a water-soluble cobalt salt with a variety of industrial and agricultural uses. Several cobalt compounds have induced sarcomas at injection sites in animals, and reports have suggested that exposure to cobalt-containing materials may cause lung cancer in humans. The present studies were done because no adequate rodent carcinogenicity studies had been performed with a soluble cobalt salt using a route relevant to occupational exposures. Groups of 50 male and 50 female F344/N rats and B6C3F1 mice were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m3 cobalt sulfate hexahydrate, 6 h/day, 5 days/week, for 104 weeks. Survival and body weights of exposed rats and mice were generally unaffected by the exposures. In rats, proteinosis, alveolar epithelial metaplasia, granulomatous alveolar inflammation, and interstitial fibrosis were observed in the lung in all exposed groups. Nonneoplastic lesions of the nose and larynx were also attributed to exposure to all concentrations of cobalt sulfate. In 3.0 mg/m3 male rats and in female rats exposed to 1.0 or 3.0 mg/m3, the incidences of alveolar/bronchiolar neoplasms were increased over those in the control groups. Lung tumors occurred with significant positive trends in both sexes. The incidences of adrenal pheochromocytoma in 1.0 mg/m3 male rats and in 3.0 mg/m3 female rats were increased. Nonneoplastic lesions of the respiratory tract were less severe in mice than in rats. In mice, alveolar/bronchiolar neoplasms in 3.0 mg/m3 males and females were greater than those in the controls, and lung tumors occurred with significantly positive trends. Male mice had liver lesions consistent with a Helicobacter hepaticus infection. Incidences of liver hemangiosarcomas were increased in exposed groups of male mice; however, because of the infection, no conclusion could be reached concerning an association between liver hemangiosarcomas and cobalt sulfate. In summary, exposure to cobalt sulfate by inhalation resulted in increased incidence of alveolar/bronchiolar neoplasms and a spectrum of inflammatory, fibrotic, and proliferative lesions in the respiratory tracts of male and female rats and mice. Adrenal pheochromocytomas were increased in female rats, and possibly in male rats.

Groups of 10 male and 10 female F344/N rats were exposed to 0, 31, 62.5, 125, 250, and 500 ppm of 2-butoxyethanol (BE) by inhalation, 6 hr/day, 5 days/wk, for 13 wk. Four moribund female rats from the 500 ppm group were sacrificed during the first 4 days of exposure, and 1 moribund female from the same group was sacrificed during week 5. Dark irregular mottling and/or loss of the distal tail were noted in sacrificed moribund rats. Similar gross lesions were noted in the terminally sacrificed females exposed to 500 ppm BE. Histologic changes noted in the day 4 sacrificed moribund rats included disseminated thrombosis involving the coccygeal vertebrae, cardiac atrium, lungs, liver, pulp of the incisor teeth, and the submucosa of the anterior section of the nasal cavity. Alterations noted in coccygeal vertebrae from the 500 ppm sacrificed moribund rats included ischemic necrosis and/or degeneration of bone marrow cells, bone-lining cells, osteocytes (within cortical and trabecular bone), and chondrocytes (both articular and growth plate), changes that are consistent with an infarction process. The moribund female rat that was sacrificed during week 5 and those female rats treated with 500 ppm and sacrificed following 13 wk of treatment lacked thrombi, but they had coccygeal vertebral changes consistent with prior infarction and transient or complete bone growth arrest. No bone lesions or thrombi were noted in the male rats treated with the same doses of BE. In conclusion, exposure to 500 ppm BE vapors caused acute disseminated thrombosis and bone infarction in female rats. Possible pathogenic mechanisms are discussed.

2-Butoxyethanol (2BE) is used extensively in the production of cleaning agents and as a general solvent. It is primarily metabolized in the liver to 2-butoxyacetic acid (2BAA), which is excreted in urine. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model describing the toxicokinetic behavior of 2BE and 2BAA in different species following repeated, long-term exposures. The PBPK model was first developed for short-term 2BE exposure to male rats. Allometric scaling was employed to estimate physiological and biochemical model parameters based on body weight. To accommodate differences in 2BE toxicokinetics in female rats, a higher Vmax for 2BE metabolism to 2BAA, higher plasma protein binding sites for 2BAA, and lower Vmax for 2BAA excretion through the kidney were incorporated into the model. For mice, a higher Vmax for 2BE metabolism to 2BAA for both sexes and higher plasma protein binding sites for 2BAA for female mice were also incorporated into the model. Subsequently, the model was expanded to simulate 2BE and 2BAA toxicokinetics for long-term, repeated exposures by incorporating time-dependent changes in model parameters. To reflect physiological/biochemical changes in animals during a chronic exposure, parameters for cardiac output, body composition, metabolic capacity, protein binding, or capacity of renal excretion were adjusted over time depending on species and sex. Sensitivity analysis was performed to better understand how sensitive model responses were to uncertainties in input parameters. The resulting PBPK model was used to simulate toxicokinetic data acquired during a 2-year inhalation toxicity and carcinogenicity study in male and female F344/N rats and B6C3F1 mice., (Copyright 1998 Academic Press.)

2-Butoxyethanol (2BE) is used extensively in the production of cleaning agents and solvents. It is primarily metabolized in the liver to 2-butoxyacetic acid (2BAA), which is believed to be responsible for 2BE toxicities associated with hemolysis of red blood cells. The objective of the study was to characterize the systemic disposition of 2BE and 2BAA in rats and mice during 2-year 2BE inhalation toxicity studies. Male and female F344 rats and B6C3F1 mice (6-7 weeks old) were exposed to target 2BE concentrations of 0, 31.2, 62.5, or 125 ppm (rats), or 0, 62.5, 125, or 250 ppm (mice), by whole-body inhalation for 6 h/day, 5 days/week for up to 18 months. Postexposure blood samples were collected after 1 day, 2 weeks, and 3, 6, 12, and 18 months of exposure. Postexposure 16-h urine samples were collected after 2 weeks and 3, 6, 12, and 18 months of exposure. A separate set of mice was kept in the control chamber and exposed to 2BE for 3 weeks when they were approximately 19 months old. Postexposure blood samples were collected after 1 day and 3 weeks of exposure and 16-h urine samples were collected after 2 weeks of exposure from these aged mice. Blood samples were analyzed for both 2BE and 2BAA and urine samples were analyzed for 2BAA using GC/MS, and their kinetic parameters were estimated through the curve-fitting method using SAS. Systemically absorbed 2BE was rapidly cleared from blood (t1/2-RAT < 10 min; t1/2-MOUSE < 5 min after the 1-day exposure) independent of exposure concentration. Proportional increases in AUC2BE relative to increases in exposure concentration indicated linear 2BE kinetics. In contrast, the rate of 2BAA elimination from blood decreased as the exposure concentration increased. Nonproportional increases in AUC2BAA also indicated that 2BAA is eliminated following dose-dependent, nonlinear kinetics. Overall, mice eliminated both 2BE and 2BAA from blood faster than rats. Sex-related differences in 2BAA elimination were most significant with rats, in that females were less efficient in clearing 2BAA from the blood. Differences in renal excretion of 2BAA are possibly responsible for the sex-related difference in the 2BAA blood profiles in rats. As exposure continued, the rates of elimination for both 2BE and 2BAA decreased in both species, resulting in longer residence times in the blood. When 19-month-old naive mice were exposed to 125 ppm, 2BE was rapidly cleared from the systemic circulation, exhibiting clearance profiles similar to young mice. However, old mice eliminated 2BAA from blood > 10 times slower than young mice after 1-day of exposure. This delayed elimination of 2BAA in old mice was less obvious after 3 weeks of exposure, suggesting that there might be other factors in addition to the age of animals that could influence the apparent difference in 2BAA kinetics between old and young mice. It was concluded that the elimination kinetics of 2BE and 2BAA following repeated 2BE exposure appear to be dependent on species, sex, age, time of exposure, as well as the exposure concentration., (Copyright 1998 Academic Press.)

Tetrafluoroethylene (TFE) was evaluated for carcinogenicity in inhalation studies because of its high use in the production of Teflon. There was clear evidence of hepatocarcinogenic activity in B6C3F1 mice after 2 yr of TFE exposure. The present study was designed to characterize the mutation profiles of H- and K-ras oncogenes in liver neoplasms in mice after exposure to 0, 312, 625, or 1,250 ppm TFE. ras mutations were identified by restriction fragment length polymorphism, single-stranded conformation polymorphism analysis, and direct sequencing of polymerase chain reaction amplified-DNA isolated from frozen or paraffin-embedded liver neoplasms. A low frequency (15%, 9/59) of H-ras codon 61 mutations was detected in hepatocellular neoplasms when compared with the higher frequency (59% of this study and 56% of historical data) in spontaneously occurring liver neoplasms. There was no difference in the mutation frequency or spectrum among exposure groups or between benign and malignant hepatocellular neoplasms. K-ras mutations at codons 12, 13, and 61 and H-ras mutations at codon 117 were not detected in hepatocellular neoplasms. These data suggest that TFE-induced hepatocellular neoplasms are developed by pathways that are mostly independent of ras mutations. The ras mutation frequency and spectrum were similar to those of the structurally related chemical tetrachloroethylene.

Groups of F344 rats and B6C3F1 mice were exposed to furfuryl alcohol vapor for 6 hours per day, 5 days per week for 14 days (0, 16, 31, 63, 125, 250 ppm) or 13 weeks (0, 2, 4, 8, 16, 32 ppm). Reduced survival was observed in the 14-day study at 250 ppm. Final mean body weights of rats and mice exposed to 125 ppm and of female mice exposed to 63 ppm were lower than controls at the end of the 14-day study; there were no significant differences in mean body weight among chemical-exposed and control groups in the 13-week study. Exposure to furfuryl alcohol had no toxicologically significant effect on organ weights in either rats or mice, and did not cause any adverse changes in hematology or serum chemistry parameters evaluated in rates in the 13-week study. Microscopic lesions associated with exposure to furfuryl alcohol were present in the nose of both rats and mice at all exposure concentrations in both the 14-day and 13-week studies. Lesions observed in the 14-day study consisted of inflammation of the nasal turbinates accompanied by necrosis and squamous metaplasia of the respiratory epithelium and necrosis and degeneration of the olfactory epithelium. Similar lesions were observed in both rats and mice in the 13-week study. In addition, squamous metaplasia and goblet cell hyperplasia of the respiratory epithelium, squamous metaplasia of the transitional epithelium and degeneration, hyperplasia and some respiratory metaplasia of the olfactory epithelium were also observed in rats in the 13-week study, and hyaline droplets in the respiratory epithelium and chronic inflammation and respiratory metaplasia in the olfactory epithelium were observed in mice in the 13-week study. In general the nasal passages of mice appeared less sensitive than those of rats at the concentrations used in the 13-week study; a no-observable-effect level was not achieved in either the 14-day or the 13-week study.

On May 8-10, 1995, a workshop on chronic inhalation toxicity and carcinogenicity testing of respirable fibrous particles was held in Chapel Hill, North Carolina. The workshop was sponsored by the Office of Pollution Prevention and Toxics, U.S. Environmental Protection Agency (EPA), in collaboration with the National Institute of Environmental Health Sciences (NIEHS), the National Institute for Occupational Safety and Health (NIOSH), and the Occupational Safety and Health Administration (OSHA). The goal of the workshop was to obtain input from the scientific community on a number of issues related to fiber testing. Major issues for discussion were: (i) the optimal design and conduct of studies of the health effects of chronic inhalation exposure of animals to fibers; (ii) preliminary studies which would be useful guides in designing the chronic exposure study; (iii) mechanistic studies which would be important adjuncts to the chronic exposure study to enable better interpretation of study results and extrapolation of potential effects in exposed humans; and (iv) available screening tests which can be used to develop a minimum data set for (a) making decisions about the potential health hazard of the fibers and (b) prioritizing the need for further testing in a chronic inhalation study. After extensive discussion and debate of the workshop issues, the general consensus of the expert panel is that chronic inhalation studies of fibers in the rat are the most appropriate tests for predicting inhalation hazard and risk of fibers to humans. A number of guidances specific for the design and conduct of prechronic and chronic inhalation studies of fibers in rodents were recommended. For instance, it was recommended that along with other information (decrease in body weight, systemic toxicity, etc.), data should be obtained on lung burdens and bronchoalveolar lavage fluid analysis to assist in establishing the chronic exposure levels. Lung burden data are also important for quantifying aspects of risk assessment related to dosimetric adjustments before extrapolation. Although mechanistic studies are not recommended as part of the standard chronic inhalation studies, the expert panel stressed the need for obtaining mechanistic information as far as possible during the course of subchronic or chronic inhalation studies. At present, no single assay and battery of short-term assays can predict the outcome of a chronic inhalation bioassay with respect to carcinogenic effects. Meanwhile, several short-term in vitro and in vivo studies that may be useful to assess the relative potential of fibrous substances to cause lung toxicity/carcinogenicity have been identified.

As with 1,3-butadiene (BD), inhalation exposure of B6C3F1 mice to isoprene (2-methyl-1,3-butadiene) caused a macrocytic anemia; induced increases in sister chromatid exchanges in bone marrow cells and in levels of micronucleated erythrocytes in peripheral blood; and produced degeneration of the olfactory epithelium, forestomach epithelial hyperplasia, and testicular atrophy. Most notable was the finding that like BD, isoprene induced neoplasms in the liver, lung, Harderian gland, and forestomach of mice. The carcinogenic effects of isoprene were observed after a 26-week exposure (6 h/day, 5 days/week) of male mice to 700 ppm or higher concentrations of isoprene followed by a 26-week recovery period. Unlike BD, isoprene did not induce lymphomas or hemangiosarcomas of the heart in mice under these conditions nor did it induce chromosomal aberrations in mouse bone marrow cells. No toxicological effects were evident in rats exposed for 13 weeks to either isoprene or BD at concentrations up to 7000 ppm or 8000 ppm, respectively. Interstitial cell hyperplasia of the testis was observed in male F344 rats exposed to 7000 ppm isoprene for 26 weeks, and following a 26-week recovery period, there was a marginal increase in benign testicular interstitial cell tumors.

To evaluate the toxicity and carcinogenic potential of long-term exposure to ozone, B6C3F1 mice were exposed by whole-body inhalation to 0, 0.12, 0.5, or 1.0 ppm and 0, 0.5, or 1.0 ppm ozone for 24 or 30 mo (lifetime), respectively. The incidence of alveolar/ bronchiolar adenomas and carcinomas (combined) increased (p < 0.05) in female mice exposed to 1.0 ppm for 24 or 30 mo and marginally increased (p > 0.05) in male mice exposed to concentrations of 0.5 or 1.0 ppm. An increased incidence of nonneoplastic lesions were observed in the nasal cavities and in the centriacinar region of the lung of mice exposed to 0.5 or 1.0 ppm for 24 and 30 mo. Nasal cavity lesions were mild and included hyaline degeneration, hyperplasia, squamous metaplasia, fibrosis and suppurative inflammation of the transitional and respiratory epithelium of the lateral wall, and atrophy of the olfactory epithelium. Lung lesions included replacement of the epithelium of the alveolar ducts and adjacent alveolar septa with epithelium similar to that normally found in terminal bronchioles (metaplasia) and associated alveolar histiocytosis. Based on the results of these studies, we conclude that inhalation exposure of B6C3F1 mice to ozone for 24 or 30 mo (a) is carcinogenic in female B6C3F1 mice exposed to 1.0 ppm of ozone based on an increased incidence of alveolar/bronchiolar adenoma or carcinoma and (b) results in mild, site-specific, nonneoplastic lesions in the nasal cavity and centriacinar lung of male and female mice exposed to 0.5 or 1.0 ppm of ozone for 2 yrs, which persist with continued exposure to 30 mo. It is uncertain whether or not the marginal increase (p > 0.05) of alveolar/bronchiolar neoplasms in male B6C3F1 mice resulted from exposure to ozone.

Female B6C3F1 mice were exposed to isobutyl nitrite (IBN) by inhalation at 0, 37.5, 75, or 150 ppm for 6 hr per day, 5 days per week for 15 weeks. The potential of this compound to induce immunotoxicity was assessed during the 3rd, 13th, 14th, and 15th week of exposure and after 2 weeks of recovery following the 15 weeks of exposure. Both systemic and lung immune functions were examined, including body and lymphoid organs weights, pulmonary macrophage function and host defense, expression of splenic lymphocyte cell-surface markers, natural killer cell function, mixed lymphocyte reaction, and induction of specific antibody to a T-cell-dependent antigen. There was a dose-related suppression of T-cell-dependent antibody-forming cell responses in the spleen following IBN exposure; however, other measures of T-cell and nonspecific immunity were not significantly affected. A dose-related increase of H202 production by alveolar macrophages was present after 12 but not after 68 exposures to IBN. In contrast, pulmonary host defense mechanisms against Klebsiella pneumoniae were unaffected. These results suggest that in the absence of changes in host resistance, IBN may have selective and partially reversible effects on the immune system.

Isoprene, the 2-methyl analogue of 1,3-butadiene, is a high production chemical used largely in the manufacture of synthetic rubber and is the major endogenous hydrocarbon exhaled in human breath. Thirteen-week inhalation toxicology studies of isoprene were conducted in male and female F344 rats and B6C3F1 mice at exposure concentrations of 0, 70, 220, 700, 2200, and 7000 ppm (6 h/day; 5 days/week). In addition, 26-week inhalation studies at the same exposure levels, followed by a 26-week recovery period, were conducted in male rats and mice. The 13-week exposures produced no discernible exposure-related toxic effects in rats. Interstitial cell hyperplasia of the testis was observed in all male rats in the 7000 ppm group after 26 weeks of exposure; following the 26-week recovery period the only effect in rats was a marginal increase in benign testicular interstitial cell tumors. In mice, isoprene induced toxic and carcinogenic effects at multiple organ sites. Following the 26-week exposure and 26-week recovery periods, incidences of neoplastic lesions in the liver, lung, forestomach, and harderian gland were significantly increased. Neoplastic effects were observed at 700 ppm and higher exposures. Non-neoplastic lesions in mice exposed to isoprene included spinal cord degeneration, testicular atrophy, degeneration of the olfactory epithelium, and epithelial hyperplasia of the forestomach. A partial hindlimb paralysis and a nonresponsive macrocytic anemia were also seen in mice. Most of the toxic and carcinogenic effects caused by isoprene, as well as the species' difference in response, had been observed after inhalation exposures to 1,3-butadiene.

The purpose of this study was to evaluate the toxicity and potential carcinogenicity or cocarcinogenicity of ozone exposure in rats. Fischer-344/N (F-344/N) rats were exposed 6 hr/day, 5 days/wk, to 0, 0.12, 0.5, or 1.0 ppm ozone by inhalation for 2-yr and lifetime exposures. The cocarcinogenicity study included subcutaneous administration of 0, 0.1, or 1.0 mg/kg body weight of 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and inhalation of 0 or 0.5 ppm ozone to male rats. NNK was administered by subcutaneous injections 3 times per week for the first 20 wk with ozone inhalation exposure. The ozone inhalation exposure was for 2 yr (104 wk), including the first 20 wk of NNK treatment and continuing for 84 wk after the last NNK injection. Ozone exposure caused a concentration-related increase in inflammation of the centriacinar region of the lung. There was also increased fibrosis and an extension of the bronchiolar epithelium in these centriacinar regions to involve the proximal alveoli. There was no increased incidence of neoplasms at any site, including the lung, that was associated with ozone exposure. Rats administered 1.0 mg/kg body weight NNK alone had an increased incidence of bronchiolar/alveolar neoplasms, but this effect was not enhanced by ozone exposure. Ozone exposure for 2 yr and lifetime was associated with site-specific toxic alterations in the nasal passage and lung similar to those previously described for short-term exposures. While there was significant attenuation of the pulmonary lesions as compared to short-term exposures, lesions persisted in the lifetime study and there was evidence of a mild progressive fibrosis. We conclude that under the conditions of these studies: (a) ozone exposure is not carcinogenic to either male or female F-344/N rats, (b) ozone does not enhance the incidence of pulmonary neoplasms in F-344/N rats exposed to a known pulmonary carcinogen (NNK), and (c) mild site-specific toxic lesions characteristic of ozone exposure persist in the nasal passage and lung throughout the lifetime of the rat with continued ozone exposure.

When cattle were superovulated with an FSH preparation containing no detectable LH (FSH-W), more viable embryos were recovered as compared with a standard preparation containing LH (FSH-P), with no change in the total number of ova + embryos recovered (Donaldson et al., 1986). To determine the basis for the increased embryo viability, we compared numbers of developing follicles and concentrations of estradiol in their follicular fluid at two times during the course of superovulatory treatment with FSH-P vs. FSH-W. Holstein heifers (n = 10/group) were injected with 3.5 mg of FSH-P or FSH-W twice daily beginning on Day 9 of the estrous cycle. Animals were ovariectomized either 48 h (Group 1) or 72 h (Group 2) after the initiation of treatment; heifers in Group 2 were also given a luteolytic injection of prostaglandin F2 alpha 24 h before ovariectomy. All follicles greater than S mm in diameter were dissected from the ovaries and follicular fluid was aspirated and stored frozen. Heifers injected with FSH-W had more follicles greater than 5 mm than heifers treated with FSH-P (21 + 4 vs. 11 + 3 in Group 1 and 28 + 5 vs. 20 +/- 5 in Group 2, respectively; p less than 0.05) and a significantly greater percentage of follicles from FSH-W animals were healthy (estrogen-active; 99 vs. 85% in Group 1 and 98 vs. 89% in Group 2, respectively; p less than 0.025). Estradiol concentrations in follicular fluid were more strongly correlated (p less than 0.001) with follicular size when heifers were treated with FSH-P vs. FSH-W.(ABSTRACT TRUNCATED AT 250 WORDS)

Criteria for the selection of aerosol concentrations to be used in inhalation studies assessing the toxicity and carcinogenicity of chemical substances were discussed by the authors in a meeting sponsored by the National Toxicology Program. Concepts in the design of aerosol inhalation studies emerged from that meeting and are being communicated through this publication. Inhalation studies assessing the toxicity and carcinogenicity of aerosols have often used maximum exposure levels on the basis of technological feasibility. Evidence has now accumulated that the amount of pulmonary burden of deposited particles impacts on particle clearance above some as yet not well-defined exposure concentration. The sequelae are such that lung clearance decreases with increased particulate burden to the point of approaching complete cessation. This paper focuses on the major determinants in establishing maximal aerosol concentrations for use in inhalation toxicity studies with special emphasis on experimental design features to assess lung retention. The subject matter of this paper is a rapidly developing area in terms of knowledge. Accordingly, the contents of this article are intended as guidelines and not as absolute rules for the conduct and interpretation of inhalation exposure studies.

Arachidonic acid initiates the irreveresible aggregation of human platelets on conversion to the bicyclic prostaglandin endoperoxides, PGG2 and PGH2. An enzyme in arterial walls catalyzes the conversion of PGG2 and PGH2 to PGX, which inhibits human platelet aggregation. Preincubation with monocyclic peroxides (3-(alpha-hydroxyethyl)-1,2-dioxane, 3-(alpha-hydroxypropyl)-1,2-dioxolane or 3-methyl-3-(hydroxymethyl)-1,2-dioxolane) completely inhibited arachidonic acid initiated aggregation. Similarly, two analogs of PGH2, (15S)-hydroxy-9 alpha, 11 alpha-(epoxymethano)prosta-5Z, 13E-dienoic and (15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano)prosta-5Z, 13E-dienoic acids, initiated irreversible aggregation of platelets. but were completely blocked by the monocyclic peroxides. Aggregation initiated by ADP or epinephrine was also completely inhibited by the cyclic peroxides. Aggregation of human platelets appears initiated through an endoperoxide receptor which can combine with either the natural bicyclic prostaglandin peroxides or the synthetic monocyclic peroxides. Natural inhibitors, such as PGX, may well be monocyclic endoperoxides similar to the compounds studied here.