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F H Sobels

Publications and source records attributed to F H Sobels.

At least 19 recordsLinked to original sources
PubMed1993

Approaches to assessing genetic risks from exposure to chemicals.

An effort to assess and quantify genetic risks from human exposure to mutagenic chemicals is urgently needed; otherwise genetic toxicology may well lose its credibility. Genetic biomonitoring provides us with an indication of mutagenic effectiveness in human somatic cells. The populations and chemicals selected for such studies form a useful database for genetic risk-assessment studies. Extrapolation to what can be expected in germ cells of exposed individuals should be possible by using good dosimetry (adducts) and a parallelogram approach. The principle is that genetic damage in the inaccessible human germ cells can be estimated by determining the effects on lymphocytes (or other somatic cells) from humans and mice and in germ cells of mice. Worldwide, opportunities for the costly mouse germ cell studies are limited. Knowledge of type of DNA adducts, their persistence and/or removal and dominant lethal studies, will be helpful in predicting stage sensitivity. Extrapolation from a lowest effective dose level is proposed. The available data for ethylene oxide and benzene are reviewed. The risk of heritable translocations in progeny of populations exposed to ethylene oxide is so high that more precise estimates seem desirable. In discussing the expression of the induced mutations, the importance of dominant mutations and of heterozygous effects of deletions and other recessives is pointed out. The molecular changes underlying dominant mutations in man are more limited than is the case for recessive mutations. This raises the question whether mutagenic agents can produce the specific changes leading to recoverable, dominant mutations. Extrapolation from increased mutation rates to predictable increases of human disease, whether by doubling dose or direct methods, have been criticized.

Animals↗
PubMed1990

International symposium on strategies for the control of mutagenic and carcinogenic risk: current status and perspectives, Friday, May 5, 1989, Bologna.

The 18 posters, grouped under mutagenicity testing, metabolic activation, mechanisms of mutation and chromosome damage, human monitoring and safety are critically discussed. It is pointed out that rather than applying a single test, a battery of well-validated in vitro and in vivo tests is required. As a testing strategy, the one developed by Ashby is briefly mentioned. The value of the Salmonella assay and of in vitro cytogenetics as short term tests for detecting carcinogens, and of the bone marrow micronucleus test as one for assessing germ cell mutagenesis is pointed out. Various assays now available for measuring gene mutations in human lymphocytes and erythrocytes are briefly described. Since we have a considerable data-base for germ cell mutations in the mouse and data are now being collected for mutations in human somatic cells, the importance of studies on mutation induction in somatic cells of the mouse is emphasized. Such data on mouse somatic cells will help to define with greater precision mutation induction to be expected in human germ cells; that is genetic risks in humans on the basis of a "parallelogram-like" extrapolation using somatic mutations in man and germ cell mutations in the mouse can now be calculated.

Animals↗
PubMed1990

The effect of multi-locus deletions in heterozygotes; a model study using Drosophila.

In a model study using Drosophila, we examined the heterozygous effects of a number of well-defined X-chromosomal deletions (i.e., those differing in location, but of about the same length, and those differing in length but located in the same general region), using relative viability and/or fertility as indicators. Most of the deletions were originally isolated in radiation or chemical mutagenesis experiments and maintained since then in stocks using appropriate balancer chromosomes. The results show that (i) most of the deletions have pronounced deleterious effects in heterozygotes; (ii) the size of the deletion per se is not a critical factor in determining relative heterozygous viability, but its location is and (iii) it is possible to tentatively identify, with respect to the deletions, putative genes that affect viability in Drosophila.

Animals↗
PubMed1989

Models and assumptions underlying genetic risk assessment.

Various methods employed for estimating the genetic risks of radiation are reviewed. With the doubling-dose method, genetic damage is expressed as an increase in cases of known genetic disease. The actual doubling dose is based on figures obtained with the mouse. There have been no recent data on induced mutation frequencies. Recent results suggest that the prevalence figure for multifactorial disease may be at least one order of magnitude higher than before. Various assumptions underlying the doubling-dose concept are discussed in the light of recent findings on: (1) spontaneous mutations resulting from insertion elements, and (2) the comparability between spontaneous and induced mutations. The so-called direct method makes use of figures for induction of dominant mutations affecting the skeleton and the lens of the eye in the mouse, and of translocation induction in monkeys. Induction rates are converted to overall rates of induced dominant effects in man by applying certain assumptions. The proportionality between dose and effect is the basis for all genetic risk assessments. The possible significance of data on human lymphocytes indicating a threshold below 4 rad and the induction of repair enzymes by low radiation doses is discussed. The parallelogram approach is based on the principle that estimates can be obtained on the amount of genetic damage that cannot always be assessed directly. Thus mutations in mouse germ cells can be predicted by using mutation frequencies in cultured mammalian cells and O6-ethylguanine adducts. Measurement of haemoglobin mutations in human and mouse erythrocytes, and of HPRT-deficient mutations in lymphocytes of man and mouse should make more precise estimates of mutation frequencies in human germ cells possible. The development of a database on mutations in somatic cells of the mouse, their induction frequencies and molecular nature are considered an important priority. Used in combination with mouse germ-cell mutation frequencies, they should enable more precise risk estimates on the basis of mutations in somatic cells of man.

Abnormalities, Radiation-Induced↗
PubMed1989

The nature of X-ray and chemically induced mutations in Drosophila in relation with DNA repair.

This paper describes the spectrum of mutations induced by alkylating agents and ionizing radiation in Drosophila. Specifically, the genotoxic profile of the alkylating agents is set against their carcinogenic potency. Alkylating agents that react preferentially with N-atoms in the DNA are relatively poor mutagens, especially so in repair-competent (early) germ cells, and likewise weak carcinogens when compared to those that are more efficient in O-alkylation. Genetic techniques combined with molecular analysis of X-ray and neutron induced mutations show that ionizing radiation induces primarily break-type mutations in a repair proficient background. Both multi-locus deletions as well as small intragenic deletions of only a few base-pairs are observed. The small deletions occur between direct repeats of 2-3 nucleotides, one copy of which is retained in the mutant allele. Possibly, these deletions are the result of repair processes. The effect of changes in DNA-repair (excision repair deficient) is reflected by a "hypermutability" for alkylating agents specifically for N-alkylators, indicating that the normal efficient error-free repair of N-alkylation damage can explain the high exposure doses required for tumor induction in mammals. The frequency of X-ray induced whole-body white mutations, recovered in excision repair deficient Drosophila, is only slightly enhanced, when compared to the repair proficient situation. In contrast, mosaic mutations occur 3-4 times more frequent, indicating that part of the X-ray damage, normally removed by the excision repair process, is not a major impedement during replication.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylating Agents↗
PubMed1985

Studies in comparative chemical mutagenesis.

This paper presents a review of various collaborative studies in comparative mutagenesis. The following studies are briefly described: (1) the chemical mutagenesis programme of the European Community, (2) Drosophila studies with various alkylating agents of different s (Swain-Scott) factors, (3) the evaluation by the International Commission for Protection against Environmental Mutagens and Carcinogens (ICPEMC) Committee 1, (4) the Environmental Protection Agency's Gene-Tox Programme, (5) the first and second United Kingdom Environmental Mutagen Society (UKEMS) collaborative studies, and (6) the International Programme on Chemical Safety (IPCS) collaborative study on in vitro tests. The need for chemical dosimetry is emphasized. One of the main conclusions is that, of the mammalian point mutation assays, the L5178Y (TFTR, trifluorothymidine resistant) system showed greatest detection capability in the second UKEMS study. The consensus conclusion of the IPCS in vitro study was that chromosomal aberrations are considered to be the optimal assay for complementing the Salmonella assay and offer the additional advantage that aneuploidy, polyploidy, and sister chromatid exchanges can also be easily assessed.

Alkylating Agents↗
PubMed1985

Studies on mutagen-sensitive strains of Drosophila melanogaster. VI. The effect of DNA-repair deficiencies in spermatids, spermatocytes and spermatogonia irradiated in N2 or O2.

This study was aimed at ascertaining the extent to which paternal repair processes possibly deficient in mei-9a, mei-41D5 and mus-101D1 genotypes would affect the recovery of radiation-induced recessive lethals in early spermatids, spermatocytes and spermatogonia. These germ cell stages were sampled in two 2-day broods from freshly hatched males, that were irradiated as 24-h old pupae in O2, or N2 followed by N2 or O2 post-treatment. Spontaneous mutation frequencies were higher in mei-9 and mei-41 males, and thus appropriate corrections were applied to the radiation data. Only with mei-9 males a clear and consistent increase of the radiation-induced mutation frequency was observed. The effect is somewhat more pronounced in brood B, presumably representing spermatogonia, than in brood A and is observed after radiation in either O2 or N2. The paternal repair process thus differs from the maternal one in that it also responds to radiation damage induced in O2. The finding that, following irradiation under anoxia, post-treatment with O2 (versus that with N2), also lowers the mutation frequency in mei-9 males, indicates that the repair defect in mei-9 does not interfere with oxygen-dependent post-radiation repair. Thus there are two different paternal repair processes in these early stages of spermatogenesis: that is, one controlled by mei-9 and one depending on oxygen. Mei-41 and mus-101 do not appear to interfere with the paternal repair process. The frequency of translocations recovered from these stages was likewise not affected by mus-101.

Animals↗
PubMed1983

The influence of deficiencies in DNA-repair on MR-mediated reversion of an insertion-sequence mutation in Drosophila melanogaster.

MR is a frequently occurring mutator in Drosophila melanogaster inducing mutation by the incorporation of insertion sequences. In the presence of MR a mutation at the singed (sn) locus induced by MR, reverts to wild-type at a high frequency of 1.7%. This reversion system which presumably involves the removal of an insertion element, was used to study the effects of defective DNA repair. Thus, reversion frequencies were compared in progeny of flies with mei-9, deficient for excision repair, mei-41, deficient for post-replication repair, or with both mei-9 and mei-41. The data show that under conditions of defective DNA repair, the frequency of MR-mediated reversion, is consistently decreased in comparison to repair-proficient conditions. This effect is explained by assuming that defective repair interferes with some steps in the process of reverse mutation involving the removal of insertion sequences. The observed reduction in reversion frequency may well result from selective elimination of cells in which the reversion process has not been completed.

Animals↗