Chronic dermal studies of petroleum streams in mice.

During petroleum refining, a large number of products are generated which have varying chemical and physical properties. These are known in the industry as petroleum streams. In order to characterize their carcinogenic activity, a number of these commercially produced streams were administered to C3H/HeJ mice in chronic dermal bioassays. The bioassays were conducted using one of two study designs: the first set of test materials was applied for a lifetime and the second set for 24 months. In the lifetime study, the last mice in the test groups survived for periods of 31 to 32 months. Middle distillates, boiling in the range 115-390 degrees C, were found to decrease the lifespan of exposed mice compared to controls or streams of higher and lower boiling ranges. These middle distillate streams included straight run kerosine, hydrodesulfurized middle distillate, straight run middle distillate, light catalytic cracked distillate, and 90/10% and 70/30% mixtures of the last two. The middle distillate streams also proved to be active as carcinogens, with tumor incidence ranging from 16 to 67%. Light alkylate naphtha, heavy catalytic reformed naphtha, vacuum residuum, and unleaded gasoline did not demonstrate significant carcinogenic potency. Heavy thermal cracked naphtha, heavy catalytic cracked naphtha, and hydrotreated light naphthenic distillate were dermal carcinogens of low potency in this study. Administration of light catalytic cracked naphtha led to a low incidence of very late developing tumors with a mean latency of 118 weeks. Application of the 0.1% solution of catalytic cracked clarified oil in toluene did not result in a significant incidence of tumors, but the 10% solution caused almost 100% mortality and 100% tumor incidence in 12 months. There was no correlation between carcinogenic potency and the indices of irritation, alopecia, erythema, and scabbing. Only two of the streams tested, hydrotreated light naphthenic distillate and 10% catalytic cracked clarified oil, contain polynuclear aromatic hydrocarbons (PNAs) and may be presumed to be complete carcinogens. The middle distillates and heavy naphthas are nonmutagenic and essentially free of PNAs. Their activity may result from promotion of already-initiated skin sites. Where comparisons could be made, reducing the exposure period from a lifetime (29-32 months) to 24 months did not change the evaluations of stream carcinogenicity except in the case of light catalytic cracked naphtha where six of the seven mice that developed tumors did so after 24 months.

Oncogenic potential of inhaled hydrazine in the nose of rats and hamsters after 1 or 10 1-hr exposures.

Hydrazine (N2H4) is used as a fuel for missiles and standby power systems of operational military aircraft. Maintenance of missiles and aircraft may result in accidental human exposure to high concentrations for brief periods of time. The purposes of this study were to assess the oncogenic potential of N2H4 in rats and male hamsters exposed to a high concentration of N2H4 for repeated short exposures and to investigate the relationships of acute and subchronic effects of N2H4 to nasal tumorigenesis. In phase 1 (acute and subchronic) and Phase 2 (lifetime experiments, groups of male and female Fischer 344 rats and male Syrian golden hamsters were exposed by inhalation to 0, 75 (Phase 2 only), or 750 ppm N2H4 for 1 (acute) or 10 (subchronic) 1-hr weekly exposures. Rodents were euthanized 24 hr after exposures 1 and 10 and 24 to 30 months poststudy initiation. Significant reductions in body weight were observed in N2H4-treated rodents compared to controls during the exposure interval. No hydrazine-induced mortality was detected. Histopathologic examination after the acute and subchronic exposures revealed degeneration and necrosis of transitional, respiratory, and olfactory epithelia in the anterior nose and, in rats exposed subchronically, squamous metaplasia of the transitional epithelium. Minimal to mild rhinitis resulted from N2H4 exposures. Apoptosis was observed in olfactory and squamous metaplastic transitional epithelium. Lesions occurred at sites reportedly having high air-flow and generally appeared to be more severe in the anterior portion of the nose. By 24 months, the squamous metaplastic transitional epithelium reverted back to normal-appearing transitional epithelium. By 24+ months, low incidences (sexes combined) of hyperplasia (5/194, 2.6%) and neoplasia (11/194, 5.7%) were detected, principally in the transitional epithelium of the 750 ppm N2H4-treated rats. A similar incidence of hyperplasia (2/94, 2%) and neoplasia (5/94, 5.3%) was detected in the high-exposure group of hamsters. The location and type of N2H4-induced proliferative lesions were similar to those reported in a chronic N2H4-exposure study (5.0 ppm x 6 hr/day x 5 days/week for 1 year) conducted in our laboratory, but the chronic study had much higher incidences (rats, sexes combined: hyperplasia 15.5% vs 2.6% and polypoid adenoma 44.6% vs 5.2%). The product (CD) of concentration + time was the same (750 ppm hours) for the high-dose groups for both studies, but the duration of exposure was 150 x longer and the concentration was 150 x lower in the chronic study.(ABSTRACT TRUNCATED AT 400 WORDS)

Chronic and initiation/promotion skin bioassays of petroleum refinery streams.

Nine refinery streams were tested in both chronic and initiation/promotion (I/P) skin bioassays. In the chronic bioassay, groups of 50 C3H/HeJ mice received twice weekly applications of 50 microl of test article for at least 2 years. In the initiation phase of the I/P bioassay, groups of CD-1 mice received an initiating dose of 50 microl of test article for 5 consecutive days, followed by promotion with 50 microl of phorbol-12-myristate-13-acetate (0.01% w/v in acetone) for 25 weeks. In the promotion phase of the I/P bioassay, CD-1 mice were initiated with 50 microl of 7,12-dimethylbenzanthracene (0.1% w/v in acetone) or acetone, followed by promotion with 50 microl of test article twice weekly for 25 weeks. The most volatile of the streams, sweetened naphtha, and the least volatile, vacuum residuum, were noncarcinogenic in both assays. Middle distillates, with a boiling range of 150 degrees-370 degrees C, demonstrated carcinogenic activity in the chronic bioassay and acted as promoters but not initiators in the I/P bioassay. Untreated mineral oil streams displayed initiating activity and were carcinogenic in the chronic bioassay, presumably due to the presence of polycyclic aromatic hydrocarbons of requisite size and structure. A highly solvent-refined mineral oil stream lacked initiating activity. These results indicate that the I/P bioassay, which takes 6 months to complete, may be a good qualitative predictor of the results of a chronic bioassay, at least for petroleum streams. Furthermore, the I/P bioassay can provide insight into possible mechanisms of tumor development.

Long-term inhalation toxicity of hydrazine.

Year-long intermittent exposures of rats, mice, hamsters, and dogs to hydrazine were conducted using concentrations of 0.05, 0.25, 1.0, and 5.0 ppm. Rats were held 18 months postexposure; hamsters, 1 year postexposure; mice, 15 months postexposure; and dogs, 38 months postexposure. Male and female rats exhibited dose-dependent incidences of benign nasal adenomatous polyps and smaller numbers of malignant nasal epithelial tumors after 1 year of exposure to hydrazine and 18 months postexposure holding. Nasal tumors were often associated with chronic irritation and were most frequent in male rats, with an incidence of greater than 50% in the highest exposure group. Hamsters exposed to 0.25-ppm and higher concentrations showed pathologic changes characteristic of degenerative disease, including amyloidosis. After exposure to 0.5 ppm hydrazine, hamsters developed a 10% incidence of benign nasal polyps compared to 0.5% in controls. Small numbers of colon neoplasms and thyroid parafollicular cell adenomas were found in hamsters, but only in the highest concentrations tested. Lung adenomas appeared to be marginally increased in mice exposed to 1.0 ppm hydrazine, the highest concentration tested in this species. No consistent clinical or pathological effects were seen in dogs during or after exposure to hydrazine at any concentration. Using amyloidosis as a criterion, a no-effect level was not achieved in hamsters. In rats, there appeared to be a marginal production of nasal tumors at 0.05 ppm, while mice showed no effects at 0.25 ppm. This study has demonstrated that the nasal respiratory epithelia of rats and hamsters are the most sensitive tissues to the tumorigenic action of hydrazine following inhalation exposures. This is similar to the reaction of rats to formaldehyde, another highly reactive water-soluble compound.

A 90-day vapor inhalation toxicity study of decalin.

A subchronic 90-day inhalation study was conducted to determine the toxic effects of decalin, a commonly used industrial solvent. Experimental groups consisting of male and female beagle dogs, male and female Fischer-344 rats, and female C57BL/6 mice were continuously exposed to decalin concentrations of 5 or 50 ppm. An unexposed control group was also maintained. All dogs and a portion of each rodent group were sacrificed and examined at exposure termination, while the remaining rodents were held for observation up to 21 months postexposure. No distinct exposure-related lesions were noted in dogs. Dog body weights, organ weights, and blood clinical pathology were also normal. At exposure termination hepatocellular cytoplasmic vacuolization was noted in female mice exposed to both concentrations. This liver tissue change was reversible and was not a significant finding in female mice examined during the 21-month postexposure observation period. In male rats, decalin exposure produced nephropathy characterized by hyaline droplets, necrosis, and intratubular casts. Accentuated tubular degeneration and medullary mineralization were noted in exposed rats held for long-term postexposure observation. There was no associated abnormal increase in mortality nor alterations in serum, blood urea nitrogen, or creatinine levels. Female rats were free of decalin-induced renal damage. There was a slightly greater incidence of commonly occurring pituitary tumors in both mice and rats; however, the tumor incidence was not dose related. The results of this study suggest that the toxic effects of decalin are similar to those previously described for other hydrocarbon solvents and fuels.

Six month inhalation toxicity of fluomine dust.

Fluomine is a cobalt chelate of interest in life support systems of high altitude aircraft. Rats, mice, guinea pigs and dogs were exposed to fluomine particles for a six month period on an industrial-type schedule. Chronic exposure of the dust caused a statistically significant decrease in the mean body weights of the test rats when compared to their respective control group. The dust had irritative effects on the respiratory systems of rats and dogs at the highest exposure level. A concentration of 0.1 mg/m3 is a suggested threshold limit at or below which no serious effects should occur.

The mammalian toxicity of fluomine dust.

Fluomine is a cobalt chelate compound which complexes molecular oxygen and releases it on heating. This property has led to its use a a regenerable oxygen source in high-altitude aircraft. Investigations into the acute effects of exposure to fluomine by various routes were undertaken as first steps in the toxicological characterization of the material. Single-dose rat and mouse oral administration led to LD50 values of 123 mg/kg for male CF1 mice and 187 mg/kg for male Sprague-Dawley rats. The LC50 values for single four-hour inhalation periods varied from 112 mg/m3 for male rats to 416 mg/m3 for male mice. Fluomine proved to be highly irritating when instilled in the eyes of rabbits and to the lungs of rats on inhalation. Exposure of rabbit skin to the compound demonstrated moderate irritancy particularly in areas of abrasion. Positive reactions to intradermal challenge were demonstrated after both intradermal and inhalation sensitization of guinea pigs.