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U H Ehling

Publications and source records attributed to U H Ehling.

8 recordsLinked to original sources
PubMed1979

Induction of dominant lethal mutations in male mice by fosfestrol.

Using the dominant lethal assay, the ability of fosfestrol, a diethylstilboestrol derivate, to induce mutations in male mice was tested and confirmed. Up to 300 mg/kg of fosfestrol the induction of mutations occurs exclusively in spermatozoa. A dose of 600 mg/kg of fosfestrol induces dominant lethal mutations up to 10 days posttreatment. The majority of induced dominant lethal mutations in all dose groups are expressed as loss after implantation.

Animals↗
PubMed1979

Procarbazine-induced specific-locus mutations in male mice.

Procarbazine is used in drug-combination treatment of Hodgkin's disease. The specific locus method was used to test and confirm the ability of procarbazine to induce gene mutations in pre- and post-meiotic germ cells of male mice. The lowest dose of procarbazine that significantly increased the mutation frequency in As spermatogonia over the control frequency was 400 mg/kg (P = 0.003). The corresponding dose for the post-spermatogonial germ-cell stages was 600 mg/kg (P = 0.009). The dose--response was linear for the point estimates of the mutation frequencies after treatment of As spermatogonia with 0, 200, 400 and 600 mg/kg. The point estimate of the mutation frequency at the 800 mg/kg level was one-third of that expected from a linear extrapolation. Variation in mutation rates among the 7 loci between the lowest (a locus) and the highest (p locus) was 12-fold. Only 24% of procarbazine-induced specific locus mutations in As spermatogonia were lethal in the homozygous condition. From the mutation spectra and the viability tests, it is concluded that procarbazine-induced mutations may be mainly due to base-pair changes. Procarbazine-induced specific-locus mutations fulfilled the criteria for the estimation of the doubling dose, the dose necessary to induce as many mutations as occur spontaneously. The doubling dose of procarbazine in As spermatogonia of mice was 114 mg/kg. The therapeutic dose for procarbazine is about 215 mg/kg. If man and mouse were equally sensitive, this dose would induce 1.9 times as many mutations as arise spontaneously. From the incidence of patients with Hodgkin's disease (1 : 42 000) the calculated population dose of procarbazine is 5.12 micrograms/kg. Assuming equal sensitivity between the sexes we can calculate, for an estimated number of 30 000 genes, the induction of about 22 mutations per million children due to procarbazine treatment. The same number of induced mutations can be calculated if the risk of patients is used for the estimation of the genetic hazard.

Animals↗
PubMed1977

Dominant lethal mutations in male mice.

Dominant lethal mutations are due to chromosome aberrations as demonstrated by analysis of first cleavage. With a sample size of 40-45 mice per dose the induction of dominant lethal mutations by 10 mg/kg of methyl methanesulfonat (MMS) can be detected in spermatids in the mating interval 9-12 days posttreatment (6-11%). In the same mating interval a dose of 150 mg/kg of MMS induces 100% dominant lethal mutations. MMS and other chemical mutagens can be characterized by their different spermatogenic response. The germ cell stage specific induction of dominant lethal mutations by chemical agents is very likely due to their different pathways and therefore, to different effects on the structural and macromolecular changes during spermatogenesis. The feasibility of standardizing test protocol for the dominant lethal assay in mice, based on collaborative studies, is discussed. The reproducibility of results and the sensitivity of the induction of dominant lethal mutations in the collaborative studies demonstrate the usefullness of the method for mutagenicity screening.

Animals↗
PubMed1976

Mutagenicity testing and risk estimation with mammals.

Mammalian test systems are currently used for mutagenicity screening. The necessity and the limitations of standardizing these methods are discussed for dominant-lethal assay. In addition to the refinement of standard methods, the development of new systems in mammals is emphasized. One promising approach is the detection of presumed somatic mutations. Another new development takes advantage of electrophoretic methods for detecting induced structural alterations of gene products. Mammalian experiments will be essential for the assessment of risks from chemical mutagens. The development of standards for the controlled use of chemical mutagens should be guided by the experience accumulated in radiation genetics. Two methods, the measurement of specific-locus mutation rates in mice and the direct determination of the phenotypic damage of dominant genes affecting the skeleton of mice, are recommended for the assessment of the hazard of chemical mutagens.

Animals↗
PubMed1976

[Genetic hazards in a technological age (author's transl)].

The maximal tolerable risk for mankind due to radiation and chemically induced mutations has been accepted as an increased mutation rate of 25%. A linear dose-effect relationship has been assumed and from the experimentally obtained mutation rate due to irradiation of mouse spermatogonia, the following risk factors were obtained: 1. The doubling dose for specific locus in the mouse is representative of recessive conditions. 2. The mutation rate depends on dose rate and fractionation of the irradiation. 3. The extrapolation factor for using these mammalial results in man is about 1.2. 4. The results of specific locus investigations are representative of all the mutation-types in a mouse that have been investigated. 5. Both sexes are similarly affected. On the above premises, a radiation dose of approximately 75 mrem per annum would increase the spontaneous mutation rate in man by about 9% per generation. The risk due to chemical mutagens should not exceed that due to radiation. Methods similar to those used for radiation risks are able to estimate the chemical risk to the population. The tolerable risk to the population from chemical mutagens depends partly on the radiation burden, but the extent of the chemical burden is unknown. This can only be estimated if the law provides for measurements of mutagenicity for drugs, food additives, biocydal agents and industrial chemicals. A risk analysis should be carried out for those chemo-mutagens which are essential. The chemical burden of all permitted mutagens should not exceed the spontaneous mutation rate by 10% per generation at the most. The human hereditory stock can be protected from irreparable damage only if one succeeds in establishing norms for the controlled use of chemical mutagens similar to the regulations which already exist for radiation protection.

Animals↗