Frej Stenbäck

Carcinogenicity of Benzo(a)Pyrene and Dusts in the Hamster Lung (Instilled Intratracheally with Titanium Oxide, Aluminum Oxide, Carbon and Ferric Oxide)

The possible carcinogenic or fibrogenic effects of intratracheal instillation of a polycyclic hydrocarbon, benzo(a) pyrene (B(a)P), alone or in combination with several dusts - titanium dioxide (TiO2), aluminum oxide (Al2O3), carbon (C), and ferric oxide (Fe3O3) - were investigated in hamsters. When administered alone, the dusts induced interstitial cell proliferation, bronchial epithelial alterations and a few granulomatous changes in the pulmonary system, but no tumors. B(a)P alone induced only two tracheal papillomas. However, combined treatment with B(a)P and the dusts caused a number of tumors, dependent upon the dust used. B(a)P plus TiO2 in a small particle size (below 0.5mu) induced papillomas, squamous cell carcinomas and a few adenomas and adenocarcinomas of the larynx, trachea and lungs. These were morpholoigcally similar to neoplasms found after B(a)P and Fe2O3 treatment. B(a)P, combined with C or Al2O3, induced mainly laryngeal and tracheal papillomas. B(a)P- and C-treated hamsters also showed a few lung adenocarcinomas.

Lack of toxicity and carcinogenicity of some commonly used cutaneous agents

The potential carcinogenicity and toxicity of several commonly used cutaneous agents (benzophenone, propylene glycol, isopropyl myristate, resorcinol, 2-ethyl-1,3-hexanediol, p-aminobenzoic acid and pyrogallol) were studied in female Swiss mice by administering repeated applications of the chemicals on the skin for the life-span of the animals. Tumors seen in both control and treated animals were mainly lymphomas, hemangiomas of the liver and lung adenomas, as well as tumors of other organs. A statistically significant increase in tumor incidence caused by the chemical treatment was not seen. Skin lesions, slight inflammation and ulceration were seen, but no persistent cutaneous abnormalities occurred. A few skin tumors were seen in treated areas as well as in untreated areas and in control animals. Thus a carcinogenic or toxic potential which would affect the use of these agents in man was not detected.

Tumur induction by 7H‐dibenzo[c,g] carbazole in the respiratory tract of Syrian hamsters

The respiratory tract of male and female Syrian golden hamsters was treated intratracheally with 7H-dibenzo[c,g]carbazole (DBC), a tobacco smoke component. The carcinogen was given by multiple instillations at two dose levels. At the lower dose (9 mg), 35 of 46 hamsters (72%) developed respiratory tract tumors. The group receiving treatment at the higher dose level (30 mg) died earlier because of the toxicity of the compound. In this group, 15 of 45 animals (33%) had respiratory tract tumors. These occurred in the larynx, trachea, bronchi, and lungs, but predominated in the trachea and bronchi. Morphologically, most tumors were papillomas and squamous cell carcinomas. This study indicates the highly potent carcinogenic effect of DBC and that respiratory tumors can be induced in this model system without any carrier dust.

Experimental Respiratory Carcinogenesis in Hamsters: Environmental, Physicochemical and Biological Aspects

The respiratory tract of Syrian golden hamsters was exposed to polycyclic hydrocarbons alone and in combination with dusts. These included benzo(a)pyrene (B(a)P), silicon dioxide (SiO2), ma

Antibody stimulation of benzo(a)pyrene carcinogenesis.

Benzo(a)pyrene (BP) was conjugated to horse serum albumin (HSA) and then attached to aldehyde fixed human erythrocytes. These cells were used in a passive hemagglutination test to measure BP antibody. BP antibodies were found to be induced in Swiss mice injected with tumorigenic doses of BP. Of the mice treated with BP, those which developed tumors soonest had the highest levels of BP antibody. This observation suggested that the antibody to BP may stimulate tumor development. When rabbit antibody to BP was injected with BP a significantly increased tumor formation occurred. Active immunization using BP conjugated to a foreign protein also significantly increased tumor formation when the mice were treated with BP. Our findings suggest that the immune response to carcinogens is an important component of the carcinogenic process.

Morphogenesis of Experimental Lung Tumors in Hamsters: The Effects of Carrier Dust

In this paper, the biological and morphological characteristics of lung tumors induced in hamsters by subcutaneous injections of diethylnitrosamine (DEN) and intratracheal instillations of benzo(a)pyrene (BaP) and the effect of carrier dusts, such as ferric oxide (Fe2O3), are discussed. These results are compared with alterations induced with other polycyclic hydrocarbons such as 7H-dibenz(c,g)carbazole, dibenz(a,i)pyrene, and various other carrier dusts in previous studies, as well as environmental agents, cigarette smoke condensate, and gasoline exhaust. In the present study, DEN induced tumors (mostly papillary) of the upper respiratory tract. The distribution and types of tumor induced by intratracheal instillations of polycyclic hydrocarbons and dusts in the larynx, trachea, and lungs (i.e., papillomas, squamous cell carcinomas, adenomas, and adenocarcinomas), depended on both the carrier agent and carcinogen to a varying degree, and bore no relation to particle size or retention time. The intratracheal instillation method offers a reliable means of inducing respiratory tumors similar to those in man, using chemicals found in our environment.

Synergistic effect of ferric oxide on dimethylnitrosamine carcinogenesis in the Syrian golden hamster.

The carcinogenic effect of dimethylnitrosamine (DMN) injected subcutaneously in Syrian golden hamsters as well as the synergistic effect of intratracheal instillations of ferric oxide were studied. DMN alone induced cavernous hemangiomas, hemangioendotheliomas, hemangioendotheliosarcomas, as well as one hepatoma of the liver and one papilloma of the forestomach, but no tumors of the respiratory system. When ferric oxide was given in addition to DMN, liver tumors of vascular and biliary origin were seen, in addition to tumors of the nasal cavity, neuroepithelial tumors and one adenoma. It was concluded that subcutaneously injected DMN is a powerful hepatic carcinogen for the Syrian golden hamster, producing liver tumors of vascular, bile duct as well as liver cell origin. The lack of tumorigenic effect in the respiratory system was considered to be due to the lack of metabolism of DMN in the lung. Die carcinogene Wirkung von subkutan injiziertem Dimethyl-Nitrosamin (DMN) beim syrischen Goldhamster sowie der synergistische Effekt von intratrachealer Instillation von Eisenoxyd wurde untersucht. DMN allein verursachte cavernöse Haemangiome, Haemangioendotheliome, Haemangioendotheliosarkome sowie ein Hepatom in der Leber und ein Papillom des Magens, aber keine Tumoren des Atmungstraktes. Wenn Eisenoxyd zusätzlich zu DMN gegeben wurde, konnten Lebertumoren vaskulären und biliären Ursprungs gefunden werden, aber auch noch Tumoren der Nasenhöhle, neuroepitheliale Tumoren und ein Adenom. Daraus wird geschlossen, daß subkutan injiziertes DMN ein sehr wirksames Carcinogen für den syrischen Goldhamster darstellt, das Lebertumoren vaskulären, biliären und hepatozellulären Baues erzeugt. Das Fehlen der cancerogenen Wirkung im Atmungstrakt wird auf das Fehlen eines Metabolismus des DMN in der Lunge zurückgeführt.

Role of particle size in the formation of respiratory tract tumors induced by benzo(a)pyrene.

Abstract The role of particle size in experimental respiratory tumor formation was studied by intratracheal instillation of two different particle sizes of benzo(a)pyrene into Syrian golden hamsters. One group of hamsters received large particles (64% above 10 μm), the second group was treated with smaller-sized particles (98% less than 10 μm). Otherwise, treatment was similar. Only 5 respiratory tumor-bearing animals of 48 were found in the group receiving small particles, whereas 31 respiratory tumor-bearing animals of 48 were found in the group which received the larger particles. Analysis of the retention rate of instilled B(a)P showed that small particles cleared much more rapidly from the lungs than did the larger particles.

Ultraviolet light irradiation as initiating agent in skin tumor formation by the two-stage method

Abstract The biological and morphological characteristics of neoplastic progression in mouse skin induced by the two-stage method, using ultraviolet light as an initiator and croton oil as a promoter, were studied by biological and histological methods. Ultraviolet light proved to be an effective initiator in skin tumor formation, when followed by repeated applications of croton oil. In comparison with experiments using 7,12 -dimethylbenz(a)anthracene (DMBA) as an initiator, the average latent period was longer and the number of tumor-bearing animals and of tumors was lower. Morphologically, an orderly epidermal hyperplasia, progressing through papillomatous hyperplasia and ending in extroverted squamous cell papillomas, occurred in only a few animals. The proliferation of epithelial cells induced by multiple u.v. irradiation was disorderly with distinct cytological and histological abnormalities. A few squamous cell carcinomas developed from the borders of ulcers induced by repeated u.v. light applications. Efforts to increase the neoplastic response, by giving either u.v. light 10 times prior to promotion or croton oil immediately after each of 16 u.v. irradiations, did not increase the total number of tumors but did induce some malignant ones. These studies emphasize the specificity of initiation and promotion in skin tumor formation and the different actions of physical and chemical carcinogens on animal skin, depending upon the combination of progression and persistence of destructive and proliferative actions specific to each agent.

Effects of different dusts on respiratory carcinogenesis in hamsters induced by benzo(a)pyrene and diethylnitrosamine

Abstract The modes of interaction between (a) subcutaneously injected diethylnitrosamine (DEN) and intratracheally instilled ferric oxide (Fe 2 O 3 ); and (b) benzo(a)pyrene (B(a)P) and dusts; namely, Fe 2 O 3 , aluminium oxide (Al 2 O 3 ) or carbon (C) intratracheally instilled, were studied in Syrian golden hamsters. The objective was to determine whether or not an initiation-promotion type relationship existed. DEN alone induced laryngeal and tracheal papillomas and, when followed by Fe 2 O 3 , elicited lung tumors. These tumors may be auto-tranplanted tumors. Fe 2 O 3 followed by DEN treatment, and simultaneous DEN/Fe 2 O 3 treatment produced tumors of the larynx and trachea in the same way as DEN alone. Single applications of DEN and of Fe 2 O 3 induced 1 tracheal papilloma. A number of forestomach papillomas, as well as other tumors, such as adrenal cortex adenomas, were seen in treated groups and in similar numbers in the untreated controls. Repeated applications of B(a)P alone and Fe 2 O 3 given before or after B(a)P failed to induce more than a few laryngeal and tracheal tumors. A significant number of tumors occurred only when both agents, B(a)P and dust, were administered simultaneously. Thus, no significant initiating-promoting action by dusts on DEN or B(a)P-induced lung tumorigenesis in the respiratory tract of Syrian golden hamsters was observed. It is concluded that Fe 2 O 3 acts as a carrier agent, enhancing the effects of B(a)P.