Effects of aging on the induction of angiosarcoma.

Adult, Sprague-Dawley albino rats of four different ages (6, 18, 32 and 52 weeks) were exposed to 940 ppm vinyl chloride by inhalation for 24 weeks, 5 days/week, 7 hr/day. In each age group, there were 110 to 128 males and the same number of females. The similarly housed control group, which was not exposed to vinyl chloride, consisted of the same number of males and females in each age group. All animals that died spontaneously, or were sacrificed moribund, or were killed at scheduled times (3, 6 and 9 months after initial exposure) were autopsied. All organs were examined grossly, and several tissues from each animal were examined microscopically. The older the rats were when they were first exposed, the greater the incidence of angiosarcomas. The incidences of angiosarcomas in the four age groups (from youngest to oldest) in the exposed males in the nonscheduled sacrifice groups were: 0/37 (0%); 0/44 (0%); 3/45 (6.7%); and 13/55 (24%). Similarly, for the females, these incidences were: 2/38 (5.3%); 7/47 (15%); 23/49 (47%); and 11/54 (20%). Most of the angiosarcomas were highly anaplastic, primary tumors in the livers that metastasized to the lungs. Only one angiosarcoma was seen in all the control rats; that occurred in subcutaneous tissue. This study demonstrated that older adult animals and females are more susceptible to the angiosarcoma-inducing effects of vinyl chloride than young adult animals and males, respectively.

Pneumoconiosis in animals exposed to poly(vinyl chloride) dust.

Rats, guinea pigs and monkeys were exposed by inhalation (6 hr/day, 5 days/week) for up to 22 months to a 13 mg/m3 concentration of PVC dust. Autopsies on rats and guinea pigs were performed after 12 months of exposure and on monkeys after 22 months after 22 months of exposure. Lung function tests were performed on monkeys after 9, 14 and 22 months of exposure. Aggregates of alveolar macrophages containing PVC particles were found in the lungs of all animals. These aggregates were more numerous in the monkey lungs. No fibrosis or significant cellular infiltrates were present in or near these cellular aggregates. No significant effects on pulmonary function could be demonstrated in the monkeys exposed to PVC. Under the conditions of this experiment, inhaled PVC produced a benign pneumoconiosis.

An evaluation of reports of dioxin exposure and soft tissue sarcoma pathology among chemical workers in the United States.

A review of employment records and tissue specimens of seven workers, reported previously as having occupational dioxin exposure and soft tissue sarcomas, confirms that four workers had employment of 2 to 19 years in the production of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) or trichlorophenol, products contaminated with 2,3,7,8-tetrachlorodibenzodioxin, the most toxic dioxin isomer. Of these individuals, two have confirmed soft tissue sarcomas. In addition three individuals who worked for companies which made 2,4,5-T also have confirmed soft tissue sarcomas. Their employment records do not show specific assignment to 2,4,5-T or trichlorophenol departments; however, one individual worked for 10 d in the production of pentachlorophenol, which is contaminated with different isomers of dioxin. Methodological problems are discussed which must be addressed in the epidemiologic evaluation of the outcome of soft tissue sarcoma.

Automated characterization of particles extracted from human lungs: three cases of tungsten carbide exposure.

An automated scanning electron microscope-energy dispersive x-ray analysis-image analysis system was used to characterize particles extracted from three human lung samples which had suspected occupationally-induced lung disease. The particles were isolated from the lung tissues by low temperature ashing and deposited on Nuclepore filters. Particles in randomly selected fields of view for each filter were automatically sized, analyzed for 32 elements, and classified according to their chemistry by the system. For each of the three lung specimens, large numbers of particles were found which indicated exposure to cemented tungsten carbide products. The particle analysis data was collected at a rate of 200 particles per hour which is considerably faster than the rate at which manual, in situ analyses can be performed.

An evaluation of the inhalation toxicity of one commercial proteolytic enzyme preparation.

The inhalation toxicity of a commercial proteolytic enzyme preparation containing 12% subtilisin Carlsberg was studied in experimental animals. Guinea pigs that had been pretreated by a series of intradermal injections of the enzyme preparation in saline solution died as a result of a single 6-hour exposure to the enzyme preparation at an air concentraion of 41.2 mg/m-3, while normal guinea pigs and pretreated guinea pigs that were dosed with an antihistamine immediately prior to exposure survived. The 6-hour LC50 for pretreated guinea pigs was determined as 24.7 mg/m-3. Normal rats, normal rabbits, and pretreated rabbits survived exposures to the enzyme preparation at concentrations as high as 36.8 mg/m-3. Pathologic examinations revealed changes only in the lungs of the exposed animals. These pulmonary alterations appear to be reversible. A histamine release is suggested as the primary effect of a secondary exposure to this proteolytic enzyme preparation.

Identification of stainless steel welding fume particulates in human lung and environmental samples using electron probe microanalysis.

Open lung biopsy specimens from two welders and air samples from their workplace environments were examined with the electron probe microanalyzer. X-ray analysis showed that the majority of particles found in the lung tissue from both workers and in the air samples to be composed of varying amounts of iron, chromium, manganese and nickel, the major components of some types of stainless steel. Based upon these analyses, it was concluded that the majority of the particles in both biopsy specimens were a result of the workplace environment.

Determination of the tumorigenic potential of methylene-bis-orthochloroaniline.

Methylene-bis-orthochloroaniline (MOCA) induced a wide spectrum of neoplasms in male rats fed either a protein-adequate (27 percent casein) or a protein-deficient (8 percent casein) diet. The concentrations of MOCA used were 125, 250, 500 and 1000 ppm. Increasing doses of MOCA in either diet resulted in decreased survival times. MOCA induced pulmonary adenomas, adenocarcinomas, mammary gland adenocarcinomas, Zymbal gland carcinomas, hepatocellular carcinomas, and hemangiosarcomas. In both diet groups the lungs were the most sensitive organs to the induction of neoplasms by MOCA. The incidence of primary pulmonary neoplasms in the lowest dose tested (125 ppm) was 6 percent (p less than or equal to 0.01), while in the highest dose (1000 ppm) it was 70 percent (p less than or equal to 0.01). The hepatocellular carcinoma incidence in rats fed a protein-deficient diet with 500 ppm MOCA was 18 percent, whereas in rats fed a protein-adequate diet with the same MOCA concentration this incidence was only 4 percent. The mean urinary concentration of MOCA in the group of rats fed the lowest dose (125 ppm-PD) was 0.63 ppm, a concentration comparable to that measured in the urine of workers exposed to MOCA.

Chronic inhalation of short asbestos fibers.

An animal inhalation study was initiated to study the chronic biological effects of inhalation of short chrysotile asbestos fibers. Rats and monkeys were exposed for 18 months, 7 hr/day, 5 days/week to a specially prepared, chrysotile asbestos aerosol. Based upon daily chamber measurements, the mean concentration of fibers in the chamber air was 1.0 mg/m3. By phase contrast microscopy, the number of fibers greater than 5 micron in length was determined to be 0.79 fiber per cubic centimeter. Rats were autopsied for pathological and histochemical examination at 1, 3, 6, 12, 18, and 24 months after initiating exposures. No significant differences in the histochemical data were seen between the exposed and control groups. Gross and histopathologic examination of exposed and control groups of rats indicated no compound-related lesions, including fibrosis. Open lung biopsies were performed on the chrysotile-exposed and the control monkeys 28 months after initiating exposures. Histopathologic evaluation of the lung biopsy tissue showed the presence of asbestos bodies adjacent to the terminal bronchioles of the asbestos-exposed monkeys. There was no observed fibrosis in pulmonary tissue. All monkeys are being maintained for an indefinite period and observed for signs of latent pulmonary disease.

4,4'-methylene-bis-ortho-chloro-aniline (MBOCA): absorption and excretion after skin application and gavage.

4,4'-methylene-bis-ortho-chloro-aniline ( MBOCA ) is an aromatic amine and industrial chemical that has been shown to cause cancer of several different organs in rats and mice and bladder cancer in dogs. The purpose of this study was to determine the efficacy of using urinary concentrations of MBOCA as a means for evaluating extent of exposure. Male Sprague-Dawley rats were given MBOCA and [14C] MBOCA by either gavage or skin application. Concentrations and amounts of 14C were measured in urine, feces, skin and total carcasses, and parent MBOCA in urine at several intervals after application. The percentages of administered doses excreted and retained in the animals were calculated and comparisons made. Within 72 hr after gavage 16.5% of the administered compound was excreted in urine as 14C but only 0.25% as parent MBOCA . In the same interval after skin application a maximum of 2.54% of administered MBOCA was excreted as 14C but only 0.008% as parent MBOCA . Seventy-two hours after gavage 13.7% of the administered dose was retained in the tissues, and after skin absorption 5-13% was retained. With gavage the rate of excretion of 14C in urine and feces was very high in the first 24 hr (68.3%) but fell off rapidly (2.07%) by the third day. After skin absorption the rates of excretion of 14C were fairly constant over a 3-day period. Less MBOCA was absorbed from the skin if the skin was washed within 8 hr after application, as compared to waiting 24 hr or not washing at all. The amount of parent MBOCA detected in urine is a very small amount of that applied or absorbed. The percentage detected and the rates of excretion depend upon the route of administration, and the interval between exposure and sampling. For these reasons urinary analysis for MBOCA can be used only as very imprecise indicators of extent of recent exposure.

Carcinogenic effects of antimony trioxide and antimony ore concentrate in rats.

This study was initiated because of a suspected increase in incidence of lung cancer in antimony smelter workers in England. Three groups of 8-mo-old Wistar-derived rats (90 males and 90 females per group) were exposed by inhalation to either Sb2O3 [time-weighted average (TWA) 45 mg/m3], Sb ore concentrate (TWA 36 + 40 mg/m3), or filtered air (controls) for 7 h/d, 5 d/wk, for up to 52 wk and sacrificed 20 wk after terminating exposures. Serial sacrifices (5 rats/sex/group) were performed at 6, 9, and 12 mo. Autopsies and histopathological examinations were performed on all animals. The dusts and animal tissues were analyzed for Sb, arsenic, and other inorganic elements by atomic absorption and proton-induced X-ray emission methods. The most significant findings were the presence of lung neoplasms in 27% of females exposed to Sb2O3 and 25% of females exposed to Sb ore concentrate (p less than 0.01). None of the male rats in any group or the female controls developed lung neoplasms. There were no significant differences in incidences of cancer of other organs between exposed and control rats. These results were compared with other published results, including an animal inhalation study with Sb2O3 in which lung tumors were also induced. Higher concentrations of arsenic were found in tissues from female rats than from male rats. For example, arsenic levels in blood of control males, control females, Sb2O3 males, Sb2O3 females, Sb ore males, and Sb ore females were 60, 123, 115, 230, 71, and 165 micrograms arsenic/g dry blood, respectively, 9 mo after initiating exposures.

Carcinogenic and toxicologic effects of inhaled ethylene oxide and propylene oxide in F344 rats.

The chronic inhalation toxicity and carcinogenicity of ethylene oxide (EO) and propylene oxide (PO) were evaluated in a 2-year inhalation bioassay. Five groups of male weanling Fischer 344 rats, 80 per group, were exposed at 0 ppm (shared control; filtered air), 50 ppm EO, 100 ppm EO, 100 ppm PO, or 300 ppm PO (7 hr/day, 5 days/week) for 104 weeks. Body weights from rats exposed to EO and PO at all exposure concentrations were significantly reduced compared to controls. A statistically significant increase in mortality was observed in all groups of exposed rats compared to controls. Skeletal muscle atrophy in the absence of any sciatic nerve neuropathology was found in rats exposed at 100 ppm EO and 300 ppm PO. Statistically significant associations between EO exposure and an increased incidence of the following rat neoplasms were observed: mononuclear cell leukemia, peritoneal mesothelioma, and mixed cell brain glioma. Among rats exposed to PO there was a dose-dependent increase in the incidence of complex epithelial hyperplasia in the nasal passages, and two adenomas were detected in the nasal passages of rats exposed at 300 ppm PO. The incidence of adrenal pheochromocytomas was elevated in both PO exposure groups, but not in a dose-related manner. All rat groups were affected by an outbreak of Mycoplasma pulmonis infection which occurred about 16 months into the study. This infection alone and in combination with the epoxide exposures affected the survival of rats in this study, and influenced the development of the proliferative lesions in the nasal mucosa of the PO-exposed rats. No treatment-related changes in any clinical chemistry or urinalysis indices were detected. PO exposure did not increase the incidence of the three neoplasms associated with EO exposure; however, adrenal pheochromocytomas and proliferative lesions of the nasal cavity were increased in rats exposed to PO.