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At least 649 records · Page 36Linked to original sources
PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. The importance of the hydrophobic interaction in the mutagenicity of organic compounds.

The derivation of new QSAR and the review of published QSAR for the mutagenicity of a variety of chemicals acting on a variety of bacterial systems uncovers two classes of equations. 12 examples include a term for hydrophobicity and of these 12, 11 require activation either by S9 or cytosolic enzymes for the reduction of nitro compounds. There are 4 examples of direct-acting mutagens which do not require activation. Of these 4, 3 do not contain a term for hydrophobicity. The odd example is that of the sulfonate esters which do not require activation, but contain a term in log P. The hydrophobicity factor is not correlated with the type of bacteria used for the test.

Amines↗
PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. Application of SAR methods to non-congeneric data bases associated with carcinogenicity and mutagenicity: issues and approaches.

In both industry and government, structure-activity relationships (SAR) are capable of playing an important decision-support role in estimating the potential mutagenicity or carcinogenicity of chemicals for which bioassay test results are unavailable. Traditional SAR modeling approaches, however, are usually restricted to the consideration of structurally similar chemical congeners. The highly structurally diverse nature of current carcinogenicity and mutagenicity data bases has motivated development of more general SAR approaches, potentially applicable to the treatment of diverse, non-congeneric mutagenicity and carcinogenicity data bases. Three specific approaches are considered in some detail--Ashby's structural alerts model, classified as a "rule-based" SAR approach, and the computerized CASE fragment-based method and TOPKAT linear discriminant equation method, both classified as "correlative" SAR approaches. Relative strengths and limitations, and a number of common features and important distinctions between these 3 methods are discussed. Rule-base methods are highly flexible and able to incorporate many different types of relevant information, yet are biased towards current knowledge, viewpoints, and mechanistic assumptions, that may or may not hold true. Correlative SAR methods are less biased and offer the promise of "discovering" potentially new SAR associations that could lend fresh insight into the basis for a structure-activity association. However, problems associated with their application to non-congeneric data bases relate to: modeling multiple or overlapping mechanisms of action with a single relationship; defining the range of applicability of models in complex multi-dimensional structure-activity space; assigning confidence levels to predictions in the absence of knowledge concerning mechanisms of activity; and determining the potential mechanistic significance of diverse model parameters. It is argued that many of these concerns can be partially alleviated by careful application of statistical procedures, scrutiny of model results, and establishment of reasoned limits to the range of model applicability. The most significant confidence-building measure, however, will be a rationalization of the correlative SAR model and model parameters in terms of principles of chemical reactivity and postulated molecular mechanism(s) for the biological activity. Hence, it is recommended that models and model descriptors be designed to facilitate mechanistic interpretation and hypothesis generation. Finally, problems in comparing the relative predictive capabilities of different SAR approaches are discussed, and strategies for SAR investigation involving integration of existing techniques are suggested.

Animals↗
PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. Working paper no. 2. Spontaneous mutations in mammalian cells.

Spontaneous or background mutation in mammals plays an important role in both medical and evolutionary contexts. However, establishing mutation frequencies or rates has not always been easy. When the field of mammalian mutagenesis was in its infancy, the word "variant" rather than "mutant" was often used because the genetic nature of the observed phenotypic alterations could not be adequately proven. Nowadays numerous target genes have been identified in which mutant frequencies can be measured, and occasionally even rates can be estimated. Indeed, the genetic basis for 'variants' now often comes from direct DNA sequencing. This review describes the most often used and best understood genetic markers for mutation research and examines their usefulness. In addition, mutational specificity is compared for several loci and the use of DNA-sequence data in determining the origins of spontaneous mutation is also discussed. An important observation is that spontaneous mutation frequencies of similarly sized genes can vary by more than an order of magnitude. Chromosomal location, the nature of the gene product and mutational specificity may offer a partial explanation.

Animals↗
PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. Working paper no. 5. Impact of the molecular spectrum of mutational lesions on estimates of germinal gene-mutation rates.

Review of the molecular characteristics of the variants identified at a series of disease loci suggests significant differences among loci in the relative frequency of nucleotide substitutions versus more complex events such as deletions. Some common features are repeatedly observed in each class of variant. For example, a high proportion of the nucleotide substitutions involve transitions of deoxycytidine and are suggested to result from deamination of cytosine at 5-methyl-CpG sites. Similarly, deletions of three or fewer nucleotides are relatively common in the non-nucleotide substitution class and these deletions are often associated with a seven-nucleotide core sequence. A significant fraction of the larger deletions and rearrangements may be associated with repetitive elements. Many of the deletion events do not appear to involve a chromosomal recombination mechanism. Mechanisms involving transcription slippage and chromatid exchange have been suggested as possible alternative mechanisms for generating deletion events. The spectrum of mutational events identified, e.g. nucleotide substitutions versus deletions, differs between loci and is probably a reflection of both the gene structure and the selective pressure to generate a disease phenotype. This locus specificity (at both the biological and molecular level) would appear to have significant potential to compromise estimates of increases in the gene germinal mutation rate following exposure to mutagenic agents.

Deoxyribonucleotides↗
PubMed1981

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC working paper 2/5: mutagenesis in mammalian cells.

Chemical mutagenesis in animal cells is a complex process. Whereas some chemicals are mutagenic in their original form, others such as the nitrosamines and polycyclic hydrocarbon carcinogens are mutagenic only when enzymatically activated. The active form, or ultimate carcinogen, can interact with proteins and nucleic acids, altering amino acids and producing modified bases in DNA. The modified bases do not usually constitute mutations as produced. Instead they are acted on by the DNA enzymes of the cell, which repair most damaged bases but occasionally insert incorrect base sequences at or near the sites of damage. The frequency at which mutant animal cells are recovered depends upon the selection conditions in culture, upon whether the mutation selected is in a gene present in single or multiple active copies, and upon whether expression is dominant or recessive. Many studies depend on selecting for 8-azaguanine- or 6-thioguanine-resistant mutants, which are due to mutations in the HGPRT locus present in a single active copy on the X-chromosome. Other widely used systems depend on selecting for ouabain resistance, which is dominant and results from a change in the sodium/potassium ATPase activity, or on selecting for thymidine kinase mutants in heterozygous Tk+/Tk- mouse cells. Many other types of mutation including nutritional markers are recessive and express only in cells carrying a single active gene copy, as is sometimes the case in established cell lines. The types of base damage causing mutations have been identified in very few cases only, and little is known about the enzymatic mechanisms of mutagenesis. However, chemical mutagenesis in cultured animal cells provide a practical way of testing chemicals and radiations for mutagenicity directly in animal cells, and much has been learned about the mutagenicity of various carcinogenic substances. To date, there is reasonable qualitative agreement between these results and those obtained in the widely used liver microsome-activated bacterial mutagenesis test systems.

Animals↗
PubMed1981

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC working paper 2/3: carcinogens and carcinogenesis enhancers.

The concept that chemical agents may lead to enhancement of carcinogenesis, rather than to its complete induction, is explored to explain the inexact correlation between carcinogen prescreening tests and the results of whole animal bioassays. It is suggested that carcinogenesis-enhancing agents are non-genotoxic chemicals which are positive in animal carcinogenesis bioassays. The importance of understanding the mechanisms of action of carcinogenesis-enhancing agents is emphasized.

Animals↗
PubMed1982

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC working paper 2/6. An appraisal of predictive tests for carcinogenicity.

The history of the development of the DNA damage-induced somatic mutation theory of cancer induction, and of the development of predictive tests for carcinogenicity, is reviewed briefly. On the basis of present information, it is concluded that all predictive tests for carcinogenicity of chemicals should be based primarily on validation using established carcinogens and non-carcinogens. The validation studies reported frequently suffer from limitations in design. Predictive tests pass through three stages during validation. First, the developing tests have been subjected to limited validation but show sufficient promise to warrant further development. 10 such tests are identified from the 100 tests reported in the literature. The second stage test can be considered as developed, when adequate validation studies have been completed to enable the selection of a test for its particular performance criteria. Only 9 such tests were identified of which only 1 still requiring further development can be considered as a useful primary screening test. 2 further tests can be considered as confirmatory tests to be used as a back-up to bacterial mutation assays. Finally, the established tests have been validated on a large scale in several laboratories. At present there is only one established test, namely the Salmonella/microsome test (Ames test). A second assay, based on E. coli, may be considered in this category because of its similarity to the Salmonella test. In conclusion, some guidelines for using predictive tests for regulatory and other purposes are given.

Animals↗
PubMed1982

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC working paper 5/1: Perspectives in mutation epidemiology. 1. Incidence and prevalence of genetic disease (excluding chromosomal aberrations) in human populations.

Detailed knowledge of the birth frequency or the cumulative incidence over all ages of genetic diseases in human populations is a prerequisite for assessing the magnitude of possible genetic hazards caused by environmental mutagens. However, both theoretical and practical difficulties are involved in precisely measuring the total frequency of these diseases. Two sets of data from large-scale population studies, one from Northern Ireland and the other from British Columbia, are compared with each other and with the results from ad hoc surveys for individual monogenic disorders. With due allowance for differences in approach, examination indicates that the data from the large-scale population studies are inadequate. However, it could provide a crude estimate of the total frequency of genetic diseases and a fairly reliable estimate of the individual frequency of certain genetic disorders with early onset that are familiar and readily diagnosed. In addition to environmental mutagens, there are a number of factors associated with current human activity that may change the incidence of genetic diseases. In order to monitor the human population for environmental mutagens, the change in frequency of sporadic cases of those genetic diseases that arose from fresh mutation and that can be easily detected as early as possible should be followed closely. The mechanism of data collection currently being employed in some countries for childhood cancers, certain congenital malformations, and inborn errors of metabolism could be extended to include the so-called sentinel phenotypes. The rationale and feasibility of using retinoblastoma and Wilms' tumor (nephroblastoma) as examples of such population monitoring are described.

British Columbia↗
PubMed1983

International Commission for Protection Against Environmental Mutagens and Carcinogens. Dosimetry of genotoxic agents and dose-response relationships of their effects.

Dose-response relationships and determination of dose of mutagens and carcinogens are summarized and discussed on the basis of conceptual and kinetic aspects. Different dose definitions may be referred to steps in the chain of events from exposure (or emission) to observed effects. A system is applied to show the influence of various processes on the kinetics of the transfers between consecutive steps. The same system illustrates processes influenced by protraction and fractionation of dose, synergists, comutagens/cocarcinogens, heritable factors, etc. The response at a given dose is expected to depend on the product of consecutive transfer functions. An application of general rules of chemical kinetics shows that when a chemical is introduced at a sufficiently low level, all processes affecting the transfers and therefore the transfer functions themselves become first-order, provided the induction status of enzymes and the cell-division rate remain constant. Under the same conditions, dose-response relationships are expected to be linear, i.e. without "safe" thresholds. However, present knowledge of the kinetics of repair at low levels of DNA damage and of the kinetics of induction of repair functions is not enough complete to be decisive. These considerations and the fact that observed dose-response data in some cases indicate the existence of thresholds but in others appear able to reject the threshold hypothesis lead to the conclusion that, generally, dose-response curves are most probably linear down to dose zero. However, certain mutagens/carcinogens give rise to lesions repaired so effectively that quasi-thresholds appear in certain subpopulations or organs.

Animals↗