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Toxicity manifests itself as vesication in human skin exposed topically to bis(2-chloroethyl)sulfide (BCES). The destruction of the proliferating population of epidermal cells is a major component of the pathogenic process. Available data strongly suggest that damage to cellular DNA is a critical factor in the loss of these cells. However, the influence of DNA repair on this toxic response has not been adequately studied. Therefore, a study was undertaken to ascertain the influence of DNA repair on the survival of primary monolayer cultures of rat cutaneous keratinocytes exposed to BCES. The sensitive nucleoid sedimentation assay was employed for the determination of DNA damage in cultures exposed to very low levels of BCES. Initial experiments demonstrated that within 1 hr of exposure to as little as 0.1 microM BCES the structural integrity of cellular DNA was compromised, presumably resulting from the appearance of single-strand breaks in the nucleic acid. This same effect was demonstrated in basal cells derived from a stratified, cornified culture grown at the air-liquid interface and exposed topically to the vesicant. Further studies with the monolayer culture demonstrated that the gross structural integrity of the DNA in cells exposed to as much as 5 microM BCES was completely restored within the first 22 hr following the exposure. However, this repair process appeared to be inefficient since a depression of thymidine incorporation into DNA and a significant loss of DNA were exhibited in exposed cultures as long as 72 hr after the initial exposure.

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The extent of DNA single strand breaks resulting from the beta radiodecay of incorporated [3H]thymidine in DNA of mouse lymphoma cells appears to be related to the degree of growth inhibition. The extents of damage to DNA and inhibition of growth seem to be functions of the concentration of radioactivity as well as the specific activity of the radiolabeled precursor in the medium. The differences in both concentration (muCi/ml) and in the specific activity of radiolabeled precursors, may help to explain the different responses encountered when using [3H] and [14C]thymidine. When cells exposed to [3H] TdR are transferred to fresh medium, the DNA damage can be repaired. The repair is followed by an increase in the cell number with the rate of growth being similar to that of unexposed cells. Cells exposed continuously to [3H] TdR in the medium can accommodate to the radioactive stressor by repairing the DNA damage and maintaining this repair capability throughout the exposure.