International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 15/1. Genetic effects of ethanol

Alcoholics have a higher frequency of chromosomal aberrations and sister-chromatid exchanges (SCEs) in their peripheral lymphocytes. In human and mammalian cells in vitro, ethanol generally does not induce genetic damage, but it induces SCEs in the presence of an exogenous metabolic system. In human lymphocytes in vitro, ethanol induces SCEs in the presence of alcohol dehydrogenase. In animals in vivo, ethanol induces a variety of genetic effects, including SCEs, micronuclei, dominant lethal mutations and aneuploidy in mouse eggs. There is some indication that ethanol may lead to genetic damage in sperm. In bacteria, ethanol is at best marginally active. Ethanol leads to anomalous chromosome segregation in Aspergillus, to mutations in yeast, to chromosomal aberrations and SCEs in plant root tips and to disturbances of meiosis and micronuclei in tetrads in Zea and Tradescantia respectively. The first metabolite of ethanol, acetaldehyde is mutagenic in a variety of test systems. The mutagenic activity of acetaldehyde in bacteria is questionable, but there is no doubt of its mutagenic activity in a variety of eukaryotic test systems in vitro as well as in vivo.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 15/3. Human acetaldehyde levels: aspects of current interest

The determination of acetaldehyde levels in blood and other tissues is a difficult task, and depends on the method used. Different methods and their pros and cons are discussed in detail. Quantitative results are shown for endogenous acetaldehyde levels and for acetaldehyde levels during alcohol intoxication. One article pertains to acetaldehyde bound to blood and tissue proteins.     

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 2. Diet, mutation and cancer

Experimental research designed to determine the effects of variations in diet on the carcinogenic and mutagenic processes is difficult to conduct and even more difficult to interpret in terms of the likely response that such variations will have on the expression of human cancer and mutation. Although some of these difficulties may be due to a failure to persuade adequate numbers of highly trained nutritionists to enter into this type of research, a more germaine reason may be that the high level of complexity of both diet and the disease processes is such as to confound present efforts at interpretation. It is suggested that a stepwise analysis of the effects of dietary factors on each critical stage in carcinogenesis or mutagenesis may ultimately lead to results that are more easily interpreted in terms of human response. To this end it is proposed that studies of DNA-carcinogen or DNA-mutagen adduct formation, or other DNA damage, DNA replication and relevant DNA repair at the target site may be a useful guide to the effect of nutritional changes on mutation and/or cancer initiation. DNA replication at various stages of carcinogenesis, modification of hormonal levels, modification of immune response, or other factors as influenced by diet may provide markers for cancer development. The integration of this data to give an overall perception of the effects of nutrition is briefly discussed.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 15/7. Reproductive consequences of alcohol abuse: males and females compared and contrasted

The adverse effects of ethyl alcohol on the hypothalamic pituitary gonadal axes of men and women are discussed with particular attention being given to effects of alcohol upon reproduction. Data obtained from acute and chronic alcohol exposure studies are presented. The putative pathophysiologic mechanisms responsible for disturbed reproductive performances in alcohol abusing individuals are discussed where sufficient data are available.     

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 3. The concept of negativity in experimental carcinogenesis

The problems that arise in the interpretation of experimental data on chemical carcinogenesis are addressed. In particular, the difficulties in demonstrating negative results are shown to present problems in delineating carcinogens from noncarcinogens. The use of the virtually safe dose estimated under the assumption of low dose linearity is shown to lead to potentially anomalous results if used indiscriminately in bioassays in which no statistically significant increase in tumor occurrence is induced. It is suggested that there is a need to establish an operational definition of negativity in carcinogenesis, with the realization that this definition may be revised in light of new information. The establishment of negativity in aligning data from positive and negative experiments and in considering possible thresholds is also discussed.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 15/2. Metabolism and metabolic effects of ethanol, including interaction with drugs, carcinogens and nutrition

Different pathways of alcohol metabolism, the alcohol dehydrogenase pathway, the microsomal ethanol-oxidizing system and the catalase pathway are discussed. Alcohol consumption leads to accelerated ethanol metabolism by different mechanisms including an increased microsomal function. Microsomal induction leads to interactions of ethanol with drugs, hepatotoxic agents, steroids, vitamins and to an increased activation of mutagens/carcinogens. A number of ethanol-related complications may be explained by the production of its first metabolite, acetaldehyde, such as alterations of mitochondria, increased lipid peroxidation and microtubular alterations with its adverse effects on various cellular activities, including disturbances of cell division. Nutritional factors in alcoholics such as malnutrition are discussed especially with respect to its possible relation to cancer.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper 5/6. Perspectives in mutation epidemiology, 6. A 1983 view of sentinel phenotypes

A sentinel phenotype is a clinical disorder or syndrome that (1) occurs sporadically as a consequence of a single, highly penetrant mutant gene, (2) is a dominant or X-linked trait of considerable frequency and low fitness, and (3) is uniformly expressed and accurately diagnosable with minimal effort at or near birth. Although 1828 autosomal dominant traits are known in human beings, 36 can be considered as candidate sentinel phenotypes, along with 5 X-linked disorders. Based on surveys of malformations in infants and children, 16 additional traits are proposed beyond previous lists. In Hungary, the 24 syndromes or defects with reliable manifestations in newborn infants occur with a frequency of 2.5-3.3 per 10 000 live births. As markers of human mutations, sentinel phenotypes have the advantage of representing germinal mutations that result in significant health problems. There are severe disadvantages that have, to date, prevented the launching of a field demonstration of the value of these phenotypes in mutation epidemiology. Agreement on a list of phenotypes has been delayed by continued recognition of two or more distinct genetic diseases within what was once thought to be a single disorder. For the same reason, most of the candidate sentinel phenotypes have not been assigned unique codes in the International Classification of Diseases. Each of the disorders is so rare and has features that overlap with so many other syndromes that highly trained clinical dysmorphologist and pediatric ophthalmologists would have to be engaged in any study. The sentinel phenotype approach, like other strategies in mutation epidemiology, would encounter problems with linkage among files of data, privacy, and access to sufficiently large populations. In contrast with the approach using multiple protein variants (as in the study of blood from offspring of survivors of the atomic bombs in Hiroshima and Nagasaki), the sentinel phenotype approach would likely be much less expensive and would encounter far fewer false attributions of paternity, but also would require a much larger study population. The best option for the present, in our opinion, is to broaden and sustain critical discussion of the approach. Perhaps the goal should be to plan a field demonstration by involving appropriate clinicians, epidemiologists, and public health officials. A pilot effort underway in Hungary may well give insight to applying the approach in a significantly larger population.     

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Working Paper 7/1/1. Mutational events in the etiology of arteriosclerotic plaques

The arteriosclerotic plaque is the lesion most often associated with cardiovascular disease, which is the leading cause of death in North America and Western Europe. Plaques are composed of cells (mostly smooth muscle cells but also macrophages and some lymphocytes) and formed elements (cellular debris, collagen, elastin, glycosaminoglycans, lipid droplets, cholesterol crystals and sometimes calcium deposits). Proliferation of smooth muscle cells is essential to plaque formation and development. Most theories of plaque development have viewed this proliferation as a secondary event following an initiating stimulus (e.g., endothelial injury). According to this view, the proliferating smooth muscle cells are otherwise identical to the large number of non-proliferating smooth muscle cells in the artery wall. The 'monoclonal' hypothesis of plaque formation presents a fundamentally different view; namely, that the cell proliferation critical to plaque development follows the stable transformation of smooth muscle cells and that the plaques can therefore be viewed as benign smooth muscle cell tumors of the artery wall. Environmental agents, including viruses and chemicals that have been previously associated with cell transformation and tumorigenesis may therefore also contribute directly to plaque development. Data are provided from in vivo and in vitro studies in support of this proposition. Evidence is also presented that in standardized assays human and animal plaque DNAs elicit responses similar to those elicited by tumor DNAs. Thus, both plaque formation and tumorigenesis may share common mechanisms.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC working paper No. 5. Genotoxicity tests as predictors of carcinogens: an analysis

Differences between the results of numerical validation studies comparing in vitro and in vivo genotoxicity tests with the rodent cancer bioassay are leading to the perception that short-term tests predict carcinogenicity only with uncertainty. Consideration of factors such as the pharmacokinetic distribution of chemicals, the systems available for metabolic activation and detoxification, the ability of the active metabolite to move from the site of production to the target DNA, and the potential for expression of the induced lesions, strongly suggests that the disparate sensitivity of the different test systems is a major reason why numerical validation is not more successful. Furthermore, genotoxicity tests should be expected to detect only a subset of carcinogens, namely genotoxic carcinogens, rather than those carcinogens that appear to act by non-genetic mechanisms. Instead of relying primarily on short-term in vitro genotoxicity tests to predict carcinogenic activity, these tests should be used in a manner that emphasizes the accurate determination of mutagenicity or clastogenicity. It must then be determined whether the mutagenic activity is further expressed as carcinogenicity in the appropriate studies using test animals. The prospects for quantitative extrapolation of in vitro or in vivo genotoxicity test results to carcinogenicity requires a much more precise understanding of the critical molecular events in both processes.     

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Working Paper 7/1/3. Animal studies suggesting involvement of mutagen/carcinogen exposure in atherosclerosis

It is very important to elucidate the causative agents of atherosclerosis because coronary heart disease and cerebrovascular disease are the main causes of death in the developed countries. The evidence for a monoclonal origin of atherosclerotic plaques in humans prompted the study of the involvement of mutagens/carcinogens in the development of atherosclerosis. Polycyclic hydrocarbons, including 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene, were shown to act as initiators and/or accelerators in atherosclerotic plaque formation in the chicken, pigeon and mouse. Radiation and oxygen radicals were also demonstrated to be involved in the development of atherosclerosis in animals.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC publication No. 13. The need for biological risk assessment in reaching decisions about carcinogens

The prudent assumption that carcinogen bioassays in rodents predict for human carcinogenicity is examined. It is suggested that in certain cases, as for example the induction of tumors against a high incidence in controls, or in situations in which high dose toxicity may be a critical factor in the induction of cancer, the probability that animal bioassays predict for humans may be low. The term 'biological risk assessment' is introduced to describe that part of risk assessment concerned with the relevance of specific animal results to the induction of human cancer. Biological risk assessment, which is almost entirely dependent on an understanding of carcinogenesis mechanisms, is an important addition to present mathematical modeling used to predict the effects of animal carcinogens that have been demonstrated after high dose exposure, to the effects of the much smaller doses to which humans are perceived to be exposed. Evidence for the conclusions reached by biological risk assessment may sometimes be supported by a careful review of human epidemiological data.     

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Working Paper 7/1/2. Shared risk factors for cancer and atherosclerosis--a review of the epidemiological evidence

This paper reviews the epidemiological literature of relevance for the hypothesis that somatic mutation is involved in the formation of the atherosclerotic plaque. Assuming that somatic mutations are involved in atherogenesis, one would expect at least some of the risk factors for cancer and for atherosclerosis to be identical. Therefore, the review covers the correlated occurrence of cancer and atherosclerotic disease. Special interest is given to populations at high risk of cancer, including subpopulations with certain genetic diseases, and populations exposed to certain carcinogenic environmental agents including ionizing radiation, vinyl chloride monomer (VCM), arsenic, tobacco, and various industrial combustion effluents containing polycyclic aromatic hydrocarbons (PAHs). Exposure to combustion effluents from burning of tobacco or fuel is associated with an increased risk of cancer and atherosclerotic disease. Combustion effluents constitute a complex mixture of potentially hazardous agents, however, and the observed correlation of cancer and atherosclerosis among exposed persons cannot be unambiguously interpreted as evidence of a common etiology of the two groups of diseases. For ionizing radiation, arsenic, and VCM there is suggestive evidence that these agents possess an atherogenic effect beside their well-known carcinogenic properties. Both arsenic and VCM seem to have a specific affinity to the vascular bed causing various lesions including angiosarcomas and atherosclerotic plaques. Regarding ionizing radiation, the atherogenic effects seem to be localized to heavily irradiated fields. Beside the carcinogenic and atherogenic effects, exposure to arsenic, VCM, and ionizing radiation brings about an increase in the incidence of mutations and chromosomal aberrations. A theory involving somatic mutation in the pathogenesis of the atherosclerotic plaque could be consistent with the observed biological effects of ionizing radiation, arsenic, and VCM. The scant data from families with certain inherited diseases may also be consistent with an involvement of the genome in the pathogenesis of atherosclerosis. In conclusion, there is strong epidemiological evidence that several factors associated with an increased risk of cancer are also associated with an increased risk of atherosclerosis.