International Commission for Protection Against Environmental Mutagens and Carcinogens. Power frequency electric and magnetic fields: a review of genetic toxicology.

Epidemiologic studies have reported a modestly increased risk of childhood leukemia associated with certain electric power wire configurations. Since cancer likely involves DNA damage, this review discusses the evidence of direct and indirect genetic toxicity effects for both electric and magnetic fields at 50- and 60-Hz and miscellaneous pulsed exposures. Exposure conditions vary greatly among different end points measured, making comparisons and conclusions among experiments difficult. Although most of the available evidence does not suggest that electric and/or magnetic fields cause DNA damage, the existence of some positive findings and limitations in the set of studies carried out suggest a need for additional work.

High frequency of large spontaneous deletions of DNA in tumor-derived CHEF cells.

Spontaneous mutations arising at the HPRT locus were examined in 126 mutants recovered from a series of six CHEF-derived cell lines. Altered restriction fragment patterns were characterized by Southern blot hybridization, and gene expression by RNA blot hybridization. Point mutants and gene-expression mutants predominated in the control (nontumorigenic) 18-1D-3 cell line and in two tumor-derived lines, one of which (16-2 Tuk 4) displayed a mutator phenotype. In the other three lines, the majority of mutants had large partial or whole gene deletions. These results suggest that mutant enzymes in DNA replication or repair play an important role in neoplastic progression by causing extensive deletions in DNA, including excision of genes that encode tumor-suppressor functions, and deletion of regulatory sequences in protooncogenes.

Killing and mutation of human lymphoblast cells by aflatoxin B1: evidence for an inducible repair response.

Diploid human lymphoblast cells exhibit apparent saturation of mutation induced by exposure to aflatoxin B1, despite a linear increase in the amount and proportion of the aflatoxin-DNA adducts formed. The saturation is neither a cell cycle phenomenon nor a result of a genetically heterozygous population. Examination of the biphasic nature of aflatoxin-DNA adduct loss in vivo shows initial, rapid removal of all adduct species, followed by a slow loss of the aflatoxin-N7-guanine adduct alone. We hypothesize that these data reveal two modes of adduct loss in these cells. The first is an inducible, error-free system that is short-lived, turning off as adduct levels fall below the induction threshold of some 1000 total adducts/cell. The second loss is slower and results from spontaneous depurination of remaining aflatoxin-N7-guanines. Our data are in agreement with the possibility that apurinic sites thus generated are responsible for the mutation observed. A major paradox arises from the fact that aflatoxin-related premutagenic depurinations are estimated to be only 10% of the number of spontaneous depurinations estimated by others to occur in human cells in a 1-h period.

Mutation of xeroderma pigmentosum lymphoblasts by far-ultraviolet light.

Survival and mutation were measured after UV irradiation in a human diploid B-lymphoblastoid line, XPA3, derived from a xeroderma pigmentosum patient of complementation group C. Relative to a normal human lymphoblastoid line, the XPA3 cells were more sensitive to killing as evidenced by a diminished shoulder in the survival curve and a steeper slope in the log-linear portion of the survival curve. While XPA3 cells were also more sensitive to mutation than normal cells, the data are complex. We interpret them to show a diminished threshold and a greater slope in the mutation curve at fluences which are not appreciably toxic. Examination of the 3H-TdR labeling index and rate of DNA synthesis after irradiation indicated that, at low equitoxic UV fluences (S greater than or equal to 0.85), XPA3 cells in S phase failed to slow their rate of DNA synthesis to the same extent as normal cells. Thus, fewer XPA3 than normal cells accumulated in S phase at relatively non-toxic fluences. However, at fluences which were toxic to XPA3 but not to normal cells, the early effects on DNA synthesis for both cell types were virtually indistinguishable. Our observations suggest that XPA3 cells have a reduced repair capacity for UV damage both because of a reduced rate of DNA repair and because uninterrupted passage through S phase reduced the time available for repair before fixation of both lethal and mutational damage. Furthermore, we interpret the relatively greater slopes in survival and mutation curves as an indication that, in XPA3 cells, there is a greater probability that an unrepaired lesion will result in cell death or mutation.

Methylmethacrylate is a mutagen for Salmonella typhimurium.

The long-term effects of exposure to monomeric methylmethacrylate have yet to be established. We have measured the toxicity and mutagenicity of methylmethacrylate for Salmonella typhimurium. At levels of thirty-four millimolar, methylmethacrylate exhibited 28 per cent of the mutagenic activity of an equimolar dose of dimethylnitrosamine. Methylmethacrylate alone exhibited toxicity to the bacteria, but when the methylmethacrylate was incubated with a rat-liver enzyme metabolizing system, mutagenesis was induced. These findings suggest that an intermediate metabolite of methylmethacrylate is mutagenic to Salmonella typhimurium.

Mutation of human cells by kerosene soot.

The polycyclic aromatic hydrocarbon fraction of a kerosene soot induced forward mutation in human diploid lymphoblasts when coincubated with Sprague-Dawley rat liver postmitochondrial supernatant. Two components of the kerosene soot extract, benzo[a]pyrene (BP) and cyclopenta[cd]pyrene (CP), were also tested. TP was not mutagenic at the concentration found in the soot extract, although it was active at higher concentrations. The amount of CP present could account for approximately 8% of the total mutation observed with the soot. The results were compared to data obtained previously in a similar mutation assay in Salmonella typhimurium. The protocol described permits the facile assay of mutation at the hgprt locus in human lymphoblasts; such mutation is induced by compounds of complex mixtures requiring mixed-function oxygenase activity for metabolism to genetically active derivatives.

Relative sensitivities of forward and reverse mutation assays in Salmonella typhimurium.

Forward mutation to 8-azaguanine resistance and reverse mutation to histidine prototrophy were measured in Salmonella typhimurium after treatment with 16 mutagens of both base-substitution and frameshift classes. The two approaches were found to be equisensitive for all 16 mutagens--i.e., induction of significant mutation occurred at similar concentrations in the forward mutation assay and in the most sensitive of the five Ames tester strains.

Comparative mutagenicity of ICR-191 to S. typhimurium and diploid human lymphoblasts.

Concentration-dependent mutagenicity of ICR-191 has been measured in Salmonella typhimurium strain TA98 and in a diploid human cell line. In both cell systems, approximately equigenerational exposure produced mutation linearly related to concentration in the lower range of ICR-191 concentrations tested. Saturation behavior was observed in the human cell assay but not in the bacterial assay. However, a 25-fold greater concentration of ICR-191 was required to induce a significant rise in the mutant fraction in the S. typhimurium assay than in the human cell assay. These differences may be linked to the differences in the biochemical events required for mutation or in the time of exposure to ICR-191.