Human genotoxicity: pesticide applicators and phosphine.

Fumigant applicators who, 6 weeks to 3 months earlier, were exposed to phosphine, a common grain fumigant, or to phosphine and other pesticides had significantly increased stable chromosome rearrangements, primarily translocations in G-banded lymphocytes. Less stable aberrations including chromatid deletions and gaps were significantly increased only during the application season, but not at this later time point. During fumigant application, measured exposure to phosphine exceeds accepted national standards. Because phosphine is also used as a dopant in the microchip industry and is generated in waste treatment, the possibility of more widespread exposure and long-term health sequelae must be considered.

Cytogenetic studies of long-term survivors of childhood acute lymphoblastic leukemia.

Ten long-term survivors of childhood acute lymphoblastic leukemia were studied to determine if cytogenetic abnormalities were present in lymphocytes following discontinuation of therapy. The study included patients diagnosed between 1969 and 1974 who had received radiation therapy and a minimum of 3 years systemic chemotherapy. At study, the patients had been off all therapy from 1.3 to 6.5 years (median, 4 years). Peripheral blood lymphocytes were examined for spontaneous chromosome breakage and sister chromatid exchanges. In addition, G-banded metaphase and prometaphase chromosomes were analyzed. Chromosome breakage was found to be within normal limits for all patients. Likewise, there was no significant difference between patients and controls with respect to sister chromatid exchange frequency. However, seven of the ten patients were found to have one or more cells with nonclonal karyotypic abnormalities. Our results indicate that although long-term survivors of childhood acute lymphoblastic leukemia treated with intensive radiation and combination chemotherapy do not demonstrate chromosome instability or DNA damage as measured by breakage and sister chromatid exchange, a majority of these patients have a subpopulation of lymphocytes with nonclonal chromosome abnormalities years after stopping therapy.

Chromosome rearrangements in fumigant appliers: possible relationship to non-Hodgkin's lymphoma risk.

Appliers of pesticides (n = 18) who are exposed to the fumigant phosphine or who have a mixed exposure to other pesticides and phosphine demonstrate a significant increase in chromosome rearrangements in G-banded chromosomes from peripheral blood compared to control subjects (n = 26). Appliers who had discontinued using phosphine for at least 8 months prior to specimen collection (n = 5) do not demonstrate significant increases in chromosome rearrangements compared to controls. Breakpoint analysis of 6,138 metaphases from all subjects demonstrates 196 breaks per 3605 metaphases in exposed subjects and 102 breaks per 2,533 metaphases in control subjects. Bands with significantly more breaks than expected based on band length in all study subjects were 1q32, 3p14, 7p15, and 14q11. Three of these four bands had significantly more breaks than expected in the exposed group, and all four bands had a significant excess of breaks in the control group. There are four bands with a significant excess of breaks in the exposed group and no breaks in the control group; each of these occurs in a known protooncogene region. These are 1p13 (NRAS), 2p23 (NMYC), 14q32 (ELK2), and 21q12 (ETS-2). Most breaks at bands 1p13, 14q32, and 21q22 are associated with chromosome rearrangements and occurred in appliers who have a mixed exposure to phosphine and other pesticides. Cytogenetic abnormalities, i.e., rearrangements and/or deletions involving bands 1p13, 2p23, and 14q32, are associated with non-Hodgkin's lymphoma. We speculate that these findings could relate to the risk of evolution of a neoplastic clone in these workers. Epidemiological studies of similarly exposed workers indicate an excess of non-Hodgkin's lymphoma.

Folate metabolism and chromosomal stability in the fragile X syndrome.

Folate metabolism and the effects of folic acid on chromosome stability were studied in four related patients with the fragile X syndrome. In three adults, uptake and subsequent utilization of folate compounds for conversion of deoxyuridylate to thymidylate by marrow cells and stimulated lymphocytes, and the affinity and maximal transport velocity of erythrocyte membrane carriers, were normal. Numbers of sister chromatid exchanges and double-stranded DNA breaks were comparable in cells from patients and control subjects, but both were increased after incubation in folate-deficient media. In vitro expression of the fragile site was strikingly reduced by oral folate therapy. It is concluded that the folate-sensitive chromosomal defect in this syndrome is limited to a specific site, Xq28, and there is no generalized tendency to frequent DNA breaks or recombination. Although expression was modified by folic acid treatment in the patients, no consistent abnormality of folate metabolism could be identified.