Detection of genetically hazardous exposures using short-term tests for genetic damage can be an important tool for the prevention of cancer and reproductive disorders. An assay for 6- thioguanine resistant (6-TG(r)) human peripheral lymphocytes has been developed by R. J. Albertini and his colleagues. They have recently used cloning methods to demonstrate by traditional criteria that the drug resistant variants are mutants. This assay could be very useful for in vivo human monitoring of environmental, therapeutic, and occupational exposure to mutagenic substances. However, before it can be used for human monitoring, several aspects of the formation of TG(r) variants in response to mutagen exposure need to be characterized. The characteristics to be evaluated are: (1) the latency between the onset of mutagen exposure and the appearance of TG(r) variants; (2) the persistence of variants in the peripheral blood; (3) the range of variability among individuals in response to a consistent treatment; (4) the response of the assay to two major types of mutagenic agents; and (5) the sensitivity of the assay relative to a more established genetic endpoint (structural chromosome damage). We propose to evaluate these characteristics by examining three human populations and also by conducting experiments with mice. The human populations to be studied will be groups of about 10 multiple sclerosis patients and 6 rheumatoid arthritis patients being treated with a single mutagenic agent, cyclophosphamide, and about 24 cancer patients being treated with x-irradiation. In the animal experiments, lymphocytes will be isolated from mouse spleens and assayed for TG(r) variant frequency using both the autoradiographic and the clonal methods. The animal model will also be used to investigate dose-response relationships. These studies will determine whether the TG(r) lymphocyte assay is sufficiently sensitive for use in human genetic monitoring, and whether the effects are persistent enough to detect cumulative damage from chronic exposure.
| Ammenheuser, M M; Au, W W; Whorton Jr, E B et al. (1991) Comparison of hprt variant frequencies and chromosome aberration frequencies in lymphocytes from radiotherapy and chemotherapy patients: a prospective study. Environ Mol Mutagen 18:126-35 |
