Biomedical subjects
Publications and source records attributed to T Schramm.
A glossary of terms related to chemical carcinogenesis is presented. The definitions proposed are based on the current state of understanding mechanisms of the action of chemical carcinogens.
Proceeding from a goal proclaimed by the WHO to reduce the cancer mortality in the European region in persons not older than 65 years up to the year 2000 at least by 15%, necessary activities, concerning chemical carcinogens are discussed. Determinants of cancer risk including the main categories of chemical carcinogens are described. Special attention is called to the inhibitors of initiating processes and of promotors and antipromotors. To reduce the cancer risk substantially by elimination or reduction of individual carcinogens or risk factors only it is not to be expected. Consequently more complex activities in cancer prevention seem to be necessary concerning carcinogens, anticarcinogens, promotors and antipromotors.
The influence of sulphamic acid, sulfanilamide, p-aminosalicylic acid and ascorbic acid on the nitrosation behaviour of Analgin (active agent: noramidopyrinmethane sulfonate) was investigated in the pH range between 1.2 and 6.0 under simulated conditions of the human stomach. Using a colorimetric measuring method, the three last-mentioned compounds proved suitable as nitrosation inhibitors; preference should be given to ascorbic acid because of its better inhibitory capacity in the very weakly acidic pH range. Sulphamic acid is inadequate because it stimulates nitrosation in this pH range. The distinct inhibitory action of ascorbic acid was verified under simulated conditions of the human stomach in further 9 drugs undergoing nitrosation at different rates, which contain the active agents: aminophenazone, clomipramine, imipramine, desipramine, ampicilline, oxacilline, phenoxymethylpenicilline, ethambutole or piperazine. Despite the use of high doses of ascorbic acid, no complete inhibition of nitrosation could be achieved in the majority of drugs investigated.
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To test "fermosinR'-yeast grown on petroleum hydrocarbons for carcinogenic potency the product was fed chronically at a dietary level of 15% to male and female rats (Wistar). Animals of the control group received the Institute's stock diet, similar to the yeast diet but without "fermosinR'. Feeding of "fermosinR'-diet did not affect the incidence nor the latency period nor the type of tumors compared with the control rats. Studies in mice (XVII) included two separate experiments. In the first one the dorsal skin of the animals was painted by extracts from yeast twice weekly and treated with the co-carcinogenic agent croton oil once a week. In the second experiment the mice were painted by extracts from pork of animals feed with "fermosinR'. The results obtained in rats and in mice did not reveal any evidence for carcinogenic potency of "fermosinR'-yeast.
This evaluation of experimental, clinical, and epidemiological current publications tries to assess the potential relevance of retinoids for oncology. Beginning with a discussion of the significance of retinoids in physiology in general, the following chapters deal with the role of retinoids in differentiation processes and in carcinogenesis induced by chemical, physical and viral factors, with the interference of retinoids during the promotion phase of carcinogenesis, as well as with their action on transplanted tumors and on cell and organ cultures. Finally possible side effects of retinoids are discussed. In spite of intensive international research in this field the results are to some extent inconsistent or even contradictory. Therefore it seems premature at the present time to recommend the routine use of retinoids for prevention or therapy of malignant tumours.
Aberrations in the regulation of cell divisions and in cell differentiation, mainly by alterations of DNA, e.g. by mutations of regulator genes or DNA sequences control expression of specific genes, are involved in the development of malignancies. Also recombination processes may take part. Besides alteration of cellular DNA, incorporation of viral DNA can also give rise to neoplastic cells in which the viral oncogenes correspond to certain cellular genes. But there is also evidence that malignant transformation can be caused solely on the basis of epigenetic processes, e.g. by alterations of gene expression. Most chemicals are activated by metabolizing enzymes to their ultimate forms which can react both with DNA and RNA, or with proteins. Correlations to carcinogenic activity have been proved so far to exist only after binding to DNA. The mode of metabolization, DNA-repair, and immunological processes may decisively modify the action of carcinogenic factors, with species-, individual-, organ-, and tissue-specific factors possibly being involved.
Screening and testing of chemicals for carcinogenic potency are parts of toxicological test programs and of efforts in primary cancer prevention. At present evidence of carcinogenicity of a chemical can be obtained from epidemiological studies or from long-term bioassays in mammals. Suggestive evidence may derive from results obtained in short-term tests. This is an additional but important information, in some cases it may be the only one we have up to now. Short-term tests do not have in vivo induction of tumors in animals as an endpoint. Their basis are interactions of the chemicals tested (metabolites) with cellular macromolecules. The main types of short-term tests used at present include: Mutagenesis assays with bacteria, mammalian cells, yeasts and moulds, with Drosophila and with whole mammals, transformation assays of cells in vitro, assays of DNA-damage and repair and of cytogenetic damage. Using test-batteries is recommended in order to minimize "false"-negative and/or "false"-positive results. Sensitivity, specificity and prediction value are important criteria of short-term tests. The results obtained may be influenced by metabolic activation/deactivation. Qualitative correlations in the order of 90% or more are being reported between results of at least some short-term tests and results from long-term bioassays. The existence also of quantitative correlations is still under discussion. Short-term tests are applied in different fields of risk assessment and prevention of health hazards. However up to now the conclusive demonstration that a chemical is a carcinogen still requires a significant induction of tumors in vivo.
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Screening tests (short-term tests) can be utilized as methods to select suspicious chemicals which should or must be further tested in long-term animal experiments. Up to now long-term animal bioassays rank prominent in predicting possible carcinogenicity of a compound in man even when taking into account all limitations of evaluation and extrapolation of results obtained to man. Any substance which is shown to cause tumors in animals should be considered carcinogenic and therefore to be a potential hazard for man, Distinction between "animal" carcinogens and "human" carcinogens is not justified and should be avoided. Screening of chemicals and testing for carcinogenicity are parts of protective measurements related to primary cancer prevention. In special cases it can be necessary to weigh risk against benefit from a chemical to enable realistic political decisions in the field of health protection.
Testing of chemicals for carcinogenic activities is an important part of a comprehensive toxicological test program. Screening tests (short-term tests) can be utilized as methods to select suspicious chemicals which should or must be further tested in long-term animal experiments. Up to now long-term animal bioassays, even when taking into account all limitations of evaluation and extrapolation of results to man, rank prominent in predicting carcinogenicity of a compound in man. Any substance which is shown to cause tumors in animals should be considered carcinogenic and therefore a potential hazard for man.
Environmental factors are considered to be the main causes creating human cancer risks. Some of the topical problems involved, resulting from the existence of defined or discrete carcinogens and so called carcinogenic risk factors, are discussed. Up to now it has been rather difficult to analyse them exactly. Qualitative and quantitative aspects of the assessment of carcinogens and the relevance of short-term tests, long-term bioassays and epidemiological studies are discussed. It is estimated that the possibilities to assess cancer risks have improved during the last few years.
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A clarification is made of the meanings of the terms 'human carcinogen' and 'animal carcinogen' in cancer research, cancer prevention and legislative actions. A chemical proven to have carcinogenic activity in animals should be considered to represent a risk to humans. However, non-experts tend to consider that 'animal carcinogens' produce cancer only in animals and can be neglected with regard to the human situation. The use of these terms should thus be avoided or they should be used as standard terms based on generally accepted and available definitions.
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The actual possibilities to test chemical substances for carcinogenic activities are critically assessed. Short-term-tests are especially discussed. By these tests--now utilized for screening of chemicals--specific biological activities can be determined, which correlate with carcinogenic effects in vivo. The phase of checking and improving the vitro-tests is not yet finished with regard to the rate of correlation of the results from those tests and the results from long-term experiments in animals as well as from clinical and epidemiological human data. Parallel to this investigations, results from long-term-tests should be critically evaluated, because the experimental induction of tumors in animals is up to now the only way to prove carcinogenic activity of a chemical. Short-term-tests should be utilized as screening methods for the selection of suspicious substances, which should or must be further tested in long-term animal experiments. At present results from short-term-tests are not sufficient to classify a substance as a carcinogen or a non-carcinogen. Certain short-term-tests can and will get significance for the evaluation of the carcinogenic risk of chemicals to man when comparing the metabolism of carcinogens in vitro using enzymatic systems of a series of mammalians including man.
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