A. Human StudiesInhalation is the major route of occupational exposure to carbon disulfide. Investigations in volunteers and occupationally exposed workers suggest that equilibrium between inhaled and exhaled CS2 is generally attained during the first 2 hr of Initially, the fraction of inhaled CS2 absorbed was relatively constant over a wide range of exposure concentrations, with approximately 70 to 80% of the inhaled carbon disulfide a b s~r b e d .~' .~~~~~~~ At equilibrium, retention of inhaled CS2 declined to approximately 15 to 45% of the inhaled vapor.61,2239289 It is interesting to note a report that described retention of inhaled CS2 in individuals not previously exposed to this agent that was greater than in those who were chronically exposed to CS2.289 Although the mechanism of the decreased retention with chronic exposure is not known, this observation does suggest caution in extrapolation of acute human exposure data to the chronic exposure situation.Percutaneous absorption is a second potential source of occupational exposure to CS2. Dutkiewicz and Baranowska" evaluated skin absorption by immersion of the hand in aqueous CS2 solutions (0.33 to 1.67 g/Q) for 1 hr. Absorption of CS2 was quantitated by two methods: indirectly by determining CS;? elimination by the lung; and by measurement of the CS2 concentration in the aqueous solutions before and after immersion of the hand. Absorption rates determined by solution analysis were found to range from 0.232 to 0.789 mg/cm2/ hr and were approximately 10 times higher than rates calculated from lung excretion of CS2. Further calculations indicated that only 3% of cutaneously absorbed CS2 was eliminated by the lung. Using the solution data, these investigators also calculated that immersion of a hand for 1 hr in a viscose rayon washing bath containing 0.1 mg/g CS2 would result in a total dose of 17.5 mg. One potential difficulty with this study, however, was that no precautions were described to prevent loss of CS2 from the solutions due to volatilization. Failure to adequately control for this variable would result in an overestimate of percutaneous absorption.Following inhalation exposure the primary route of excretion for unmetabolized CS2 is exhalation from the lung. In 1943, McKee et a1.'56 estimated that 6 to 10% of exposure. 148,156,250,254,296 Volume 11, Issue 3 CRC Critical Reviews in Toxicologyidentification of metabolite(s) responsible for the hepatotoxic effects of high-dose exposure to CS2, particularly in phenobarbital pretreated rats. The formation of the toxic metabolite(s) is thought to involve activation of CS2 by the microsomal mixed function oxidase system. Formation of Water-Soluble MetabolitesAn early study by Strittmatter et a1.226 characterized the overall disposition of the radiolabel in guinea pigs after inhalation of 35S-carbon disulfide. A small fraction (8 to 17%) of the total radioactivity recovered during the 48 hr after various inhalation exposures (13.6 ppm for 8 hr; 20.6 ppm for 16 hr, 25.7 ppm for 40 hr) was exhaled as CS2. ...

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To map tumor suppressor genes for lung adenocarcinomas, we introduced normal human chromosomes 3, 7, and 11 into the A549 tumor cell line by microcell-mediated chromosome transfer to test which chromosomes had the ability to suppress tumorigenicity. These human chromosomes, which contain the neomycin gene as a selectable marker, were transferred into A549 lung adenocarcinoma cells at frequencies of 0.3-1.8 x 10(-6). Two microcell hybrid clones with an introduced chromosome 3, two with an introduced chromosome 7, and six with an introduced chromosome 11 were isolated and examined for their growth properties and tumorigenicity in nude mice. Whereas parental A549 cells formed tumors with an average latency of 68 d, both microcell hybrids with an introduced chromosome 3 failed to form tumors for over 360 d. Similar tumorigenicity results were obtained when the clones were implanted into denuded tracheas, a more orthotopic transplantation site. The two clones with an introduced chromosome 7 were still tumorigenic; they formed tumors within 100-123 d after injection and grew progressively, although the tumors grew slightly slower than the parental cells did. Among the six clones with an introduced chromosome 11, one clone was still highly tumorigenic but did not contain an extra copy of an intact introduced chromosome 11. Three clones with a single intact copy of introduced chromosome 11 formed tumors with latency periods significantly longer than those of the parental cells. Two clones had two copies of the introduced chromosome 11, and both failed to form tumors within 1 yr of injection. These results indicate that chromosomes 3 and 11 can suppress the tumorigenicity of A549 lung adenocarcinoma cells.

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Asbestos and other mineral fibers elicit responses in several rodent cell transformation systems. The mechanism of this transformation has been hypothesized to involve specific chromosome alterations, especially changes in chromosome number. However, the cytogenetic effects of asbestos fibers in cultured human respiratory epithelium have not been well characterized. The present study examined the effects of chrysotile and crocidolite asbestos fibers on cultures of human bronchial epithelial (HBE) cells growing in serum-free medium. HBE cells were continuously treated with chrysotile (0-4 micrograms/cm2) or crocidolite (0-300 micrograms/cm2) asbestos and examined after 24, 48, 72 or 96 h for cytotoxic and cytogenetic effects. Both asbestos fiber types induced a concentration-dependent inhibition of cell proliferation and colony-forming efficiency; however, in these assays chrysotile was 100-300 times more toxic than crocidolite. Concentrations of asbestos that inhibited growth had little effect upon trypan blue exclusion or intracellular esterase activity, suggesting that the majority of asbestos-exposed cells were still viable. A 2.7-fold increase in binuclei and a 1.6-fold increase in micronuclei were observed 72 h after treatment with 4 micrograms/cm2 chrysotile. A 1.9-fold increase in binuclei was observed 72 h after treatment with 300 micrograms/cm2 crocidolite, but crocidolite did not increase the incidence of micronuclei. Chrysotile asbestos failed to induce significant numerical chromosome changes in HBE cells and increased structural aberrations only at the 24 h time point. These findings contrast with the relatively high incidences of asbestos-induced chromosome changes previously observed in some rodent cell cultures and suggest the existence of species-specific or cell-type-specific differences in either chromosome stability or mechanism(s) of asbestos-induced toxicity.