Marvin Kuschner

Squamous ceil carcinomas of the lung and esthesioneuroepitheliomas of the olfactory epithelium were produced in high incidence in rats following inhalation of 0.1 ppm of bis(chloromethyl)ether. These findings imply a significant potential occupational hazard.

Inhalation exposure experiments with the direct-acting alkylating agent epichlorohydrin (ECH) were done on noninbred male Sprague-Dawley rats. Single 6-hour exposure to ECH and follow-up for 14 days showed the median lethal concentration to be about 360 ppm. Further inhalation experiments were done with 6-hour exposure 5 days/week. A short-term 30-exposure regimen with 100 ppm ECH produced malignant squamous cell carcinomas of the nasal cavity in 15 of 140 rats and respiratory tract papillomas in 3 rats. Among 100 rats, lifetime exposure to 30 ppm yielded 1 malignant squamous carcinoma of the nasal cavity plus 1 nasal papilloma. No nasal or respiratory tract tumors were produced by lifetime exposure of 100 rats to 10 ppm. As controls, 100 air-treated and 50 untreated rats were used. A dose-rate effect was observed for ECH inasmuch as 30-day exposure to 100 ppm (3,000 ppm-days) produced 15 cancers in comparison to the 1 cancer from the lifetime exposure to 30 ppm (8,700 ppm-days) and no cancers from lifetime exposure to 10 ppm (2,500 ppm-days).

A panel of pathologists classified 121 cases of lung cancer from American uranium miners by cell type, and 138 cases of cancer in non-miners. Undifferentiated carcinomas showed a higher incidence with increasing radiation exposure and age and cigarette matched controls. At high radiation exposures, the WHO 2B cell type accounted for more than half the total. An average of 15.9 years elapsed from the beginning of mining to development of cancer. It was longest among the highly exposed men and was shortest among men with small cell, undifferentiated carcinoma who had less than 700 Work Level Months exposure. In all age and cigarette groups, radiation exposure increased the small cell, undifferentiated, but decreased the epidermoid tumors. Age showed an increase in epidermoid carcinoma. Undifferentiated small cell types were slightly increased among the lowest exposure groups. These increases and an excess of these cell types among South African gold miners seem to establish a trend.

Concentrations of 0.25 and 0.5 mug/ml calcium chromate (CaCrO4-2H2O)dissolved in Dulbecco's medium were found to alter the growth behavior of BHK21 cells in culture. Treated cells grew as shortened fibroblasts and in random orientation. The changes detected during the first two weeks of culture in the presence of the metal became more pronounced as the number of growth passages increased. In addition to the alterations noted above, chromate-treated cells grew into large clusters in Methocel (an alternative technique to the agar suspension system), while untreated cells underwent, at most, only one or two divisions in Methocel. These alterations in growth properties were irreversible and persisted after removal of the treated cells from chromate-containing medium, suggesting that a heritable change had occurred as opposed to a transient, chromate-dependent alteration of cell growth. This experimental observation suggests that chromate salts and perhaps salts of other metals can transform BHK21 cells in vitro or can select for spontaneously transformed cells.

Rats and hamsters were exposed to 0.1 ppm bis(chloromethyl)ether (BCME) six hours per day, five days per week throughout their lifetime. Additional groups of rats were given 10, 20, 40, 60, 80, and 100 exposures to 0.1 ppm BCME and then held until death. Forty cancers originating in the respiratory tract were found in the 200 rats involved in these studies. These included 14 cancers of the lung and 26 cancers of the nasal cavity. They occurred in dose-related fashion. A single undifferentiated carcinoma of the lung was seen in a hamster.