Strategies for evaluating carcinogenic substances

Cancer from exposure to chemicals is known for more than two centuries. Today, approximately 40 compounds have been identified as unequivocally carcinogenic in humans, more than 300 have been shown to be carcinogenic in animal experimentation. Accordingly, an old system subdivides carcinogens as human carcinogens (A1), animal carcinogens (A2, and compounds being suspective of exerting carcinogenic activity. There exist no threshoulds of effect for notorious carcinogens. In order to improve the protection of those exposed to carcinogens in the working area, a special type of tolerance values has been introduced (technical guidance values, TRK). Contrary to MAK-values, these TRKs take into account a certain residual cancer risk which in most cases can not be quantified. The amount of acceptable residual risks is a matter of political consensus which has to be organized between the societal groups involved. For the purpose of quantitative comparisons, "unit risks" have been introduced; the problematics of this category is discussed to some extend.     

Experimental study of the effect of formaldehyde during embryogenesis on the activity of rat liver enzyme systems in ontogenesis]

Leaf tobacco contains minute amounts of lead 210 (210Pb) and polonium 210 (210Po), both of which are radioactive carcinogens and both of which can be found in smoke from burning tobacco. Tobacco smoke also contains carcinogens that are nonradioactive. People who inhale tobacco smoke are exposed to higher concentrations of radioactivity than nonsmokers. Deposits of 210Pb and alpha particle-emitting 210Po form in the lungs of smokers, generating localized radiation doses far greater than the radiation exposures humans experience from natural sources. This radiation exposure, delivered to sensitive tissues for long periods of time, may induce cancer both alone and synergistically with nonradioactive carcinogens. This article explores the relationship between the radioactive and nonradioactive carcinogens in leaf tobacco and tobacco smoke and the risk of cancer in those who inhale tobacco smoke.     

Carcinogens in food: priorities for regulatory action

A pragmatic possible approach to the prioritization of chemical carcinogens occurring as food contaminants is described, based on the carcinogenic risk to the population. This should be of value in ensuring that resources for assessment and management of carcinogens in food are directed to the most important areas with regard to carcinogenic risk to the population. Key components of this approach are an assessment of the carcinogenic hazard to humans combined with estimations of intakes per person and of the proportion of the population exposed. These are used to derive an index referred to as the Population Carcinogenic Index. Concerning the hazard assessment expert judgement is used to place the chemical in one of five categories. The highest category is for chemical carcinogens that are believed to act by a genotoxic mechanism. It is recognised that such compounds may vary enormously with respect to their potency and various approaches to ranking carcinogens on the basis of potency are reviewed. The approach adopted is to subdivide the genotoxic carcinogens category into high, medium and low potency based on the TD50 value. Methods of estimating intakes and exposed populations are considered and an approach which groups these into broad categories is developed. The hazard and exposure assessments are then combined to derive the Population Carcinogenicity Index.     

The carcinogenicity of metals in humans

Epidemiologic evidence on the relation between exposure to metals and cancer is reviewed. Human exposure to metals is common, with wide use in industry and long-term environmental persistence. Historically, the heaviest metal exposures occurred in the workplace or in environmental settings in close proximity to industrial sources. Among the general population, exposure to a number of metals is widespread but generally at substantially lower levels than have been found in industry. The carcinogenicity of arsenic, chromium, and nickel has been established. Occupational and environmental arsenic exposure is linked to increased lung cancer risk in humans, although experimental studies remain inconclusive. Experimental studies clearly demonstrate the malignant potential of hexavalent(VI) chromium compounds, with solubility being an important determining factor. Epidemiologic studies of workers in chromium chemical production and use link exposure to lung and nasal cancer. Experimental and epidemiologic data show that sparingly-soluble nickel compounds and possibly also the soluble compounds are carcinogens linked to lung and nasal cancer in humans. Some experimental and epidemiologic studies suggest that lead may be a human carcinogen, but the evidence is inconclusive. Although epidemiologic data are less extensive for beryllium and cadmium, the findings in humans of excess cancer risk are supported by the clear demonstration of carcinogenicity in experimental studies. Other metals, including antimony and cobalt, may be human carcinogens, but the experimental and epidemiologic data are limited.     

Janus carcinogens and mutagens

Janus carcinogens are carcinogenic agents that, under differing conditions of cell type or dose, can instead act as anticarcinogens. Studies by Haseman and Johnson [J.K. Haseman, F.M. Johnson, Analysis of rodent NTP bioassay data for anticarcinogenic effects, Mutat. Res. , 350 (1996) 131-142], have demonstrated that many chemicals that are carcinogenic for one tissue type can have anticarcinogenic action on another tissue type. As Magni et al. [G.E. Magni, R.C. von Borstel, S. Sora, Mutagenic action during meiosis and antimutagenic action during mitosis by 5-aminoacridine in yeast, Mutat. Res., 1 (1964) 227-230] have shown in 1964, this principle holds true for chemical mutagens as well, that is 9-aminoacridine is an antimutagen in the vegetative cell and a mutagen in the sporulating cell. The conclusion can be drawn that two established carcinogens, tobacco and ionizing radiation, are indeed Janus carcinogens. In their review of 'ambiguous carcinogens' (their name), Weinberg and Storer [A.M. Weinberg, J.B. Storer, Ambiguous carcinogens and their regulation, Risk Anal., 5 (1985) 151-156], pointed out that tobacco can be classified as an ambiguous carcinogen. The strong carcinogenicity and anticarcinogenicity of tobacco smoke and/or tobacco itself (i.e., chewing tobacco) may be due to components in the mixture, not that of a single carcinogenic chemical that also may be anticarcinogenic. Kondo [S. Kondo, Health Effects of Low-Level Radiation, Kinki Univ. Press, Osaka, Japan and Medical Physics Publishing, Madison, WI, 1995, 213 pp.] has compiled data that demonstrate that human populations who survive exposures to ionizing radiation generally live longer and have less cancer than unirradiated human populations, and this Janus phenomenon goes beyond the more trivial concept of increased sensitivity to radiation of rapidly dividing tumor cells. Thiabendazole is an interesting compound in that it is both aneugenic and antimutagenic, and yet it does not appear to be a carcinogen or a mutagen. It is discussed here because aneugenesis and antimutagenesis are at extremes of the mutagenic spectrum. In general, mutagenic or carcinogenic actions usually are at least partially understood at a molecular level, whereas antimutagenic and anticarcinogenic actions usually are not. It is possible there may be numerous specific mechanisms underlying the Janus activity of different chemicals.     

Estrogen use and cancer risk: a review

The role of estrogens as carcinogens, cocarcinogens or tumor promoters, as well as their mechanism(s) of action on cancer cells, are thoroughly reviewed. Although there is ample evidence that estrogens (natural and synthetic) can induce multiple benign and malignant tumors in animals, and most of these tumors are histologically similar to that in humans, there is no direct evidence that natural estrogens (estradiol-17 beta, estrone) are carcinogenic in humans. Recent evidence in cellular and molecular oncology revealed that estrogens act by genetic and epigenetic mechanisms on cancer cells, and a close relationship between estrogens, growth factors, and oncogenes is important for human cancer. Long-term exposure to estrogens should always be regarded as increased cancer risk. Estrogen replacement therapy (ERT) by unopposed estrogens in postmenopausal women with high familial cancer risk or existent premalignant lesions should be avoided, since estrogens may act as tumor promoters. Combination of estrogens with progesterone (or other progestins) cyclically or sequentially, significantly reduce and prevent the cancer risk.     

The use of toxicologic data in mechanistic risk assessment: 1,3-butadiene as a case study

The National Research Council (NRC) recently published a report. Science and Judgment in Risk Assessment, that critiqued the current approaches to characterizing human cancer risks from exposure to chemicals. One issue raised in the report relates to the use of default options for quantitation of cancer risks. Default options are general guidelines that can be used for risk assessment when specific information about a chemical is absent. Research on 1,3-butadiene represents an interesting case study in which existing knowledge on this chemical indicates that two default options may no longer be tenable: (1) humans are as sensitive as the most sensitive animal species, and (2) the rate of metabolism is a function of body surface area rather than inherent species differences in metabolic capacity. Butadiene, a major commodity chemical used in the production of synthetic rubber, is listed as one of 189 hazardous air pollutants under the 1990 Clean Air Act Amendments. Butadiene is a carcinogen in rats and mice, with mice being substantially more sensitive than rats. The extent to which butadiene poses a cancer risk to humans exposed to this chemical is uncertain. Butadiene requires metabolic activation to DNA-reactive epoxides to exert its mutagenic and carcinogenic effects. Research is directed toward obtaining a better understanding of the cancer risks of butadiene in humans by evaluating species-dependent differences in the formation of the toxic butadiene epoxide metabolites, epoxybutene and diepoxybutane. The data include in-vitro studies on butadiene metabolism using tissues from humans, rats, and mice as well as experimental data and physiological model predictions for butadiene in blood and butadiene epoxides in blood, lung, and liver after exposure of rats and mice to inhaled butadiene. The findings suggest that humans are more like rats and less like mice regarding the formation of butadiene epoxides. The research approach employed can be a useful strategy for developing mechanistic and toxicokinetic data to supplant default options used in carcinogen risk assessments for butadiene.     

The genotype of the human cancer cell: implications for risk analysis

An extremely large database describes genotypes associated with the human cancer phenotype and genotypes of human populations with genetic predisposition to cancer. Aspects of this database are examined from the perspective of risk analysis, and the following conclusions and hypotheses are proposed: (1) The genotypes of human cancer cells are characterized by multiple mutated genes. Each type of cancer is characterized by a set of mutated genes, a subset from a total of more than 80 genes, that varies between tissue types and between different tumors from the same tissue. No single cancer-associated gene nor carcinogenic pathway appears suitable as an overall indicator whose induction serves as a quantitative marker for risk analysis. (2) Genetic defects that predispose human populations to cancer are numerous and diverse, and provide a model for associating cancer rates with induced genetic changes. As these syndromes contribute significantly to the overall cancer rate, risk analysis should include an estimation of the effect of putative carcinogens on individuals with genetic predisposition. (3) Gene activation and inactivation events are observed in the cancer genotype at different frequencies, and the potency of carcinogens to induce these events varies significantly. There is a paradox between the observed frequency for induction of single mutational events in test systems and the frequency of multiple events in a single cancer cell, suggesting events are not independent. Quantitative prediction of cancer risk will depend on identifying rate-limiting events in carcinogenesis. Hyperproliferation and hypermutation may be such events. (4) Four sets of data suggest that hypermutation may be an important carcinogenic process. Current mechanisms of risk analysis do not properly evaluate the potency of putative carcinogens to induce the hypermutable state or to increase mutation in hypermutable cells. (5) High-dose exposure to carcinogens in model systems changes patterns of gene expression and may induce protective effects through delay in cell progression and other processes that affect mutagenesis and toxicity. Paradigms in risk analysis that require extrapolation over wide ranges of exposure levels may be flawed mechanistically and may underestimate carcinogenic effects of test agents at environmental levels. Characteristics of the human cancer genotype suggest that approaches to risk analysis must be broadened to consider the multiplicity of carcinogenic pathways and the relative roles of hyperproliferation and hypermutation. Further, estimation of risk to general human populations must consider effects on hypersusceptible individuals. The extrapolation of effects over wide exposure levels is an imprecise process.     

Mechanism of action of the nongenotoxic peroxisome proliferators: role of the peroxisome proliferator-activator receptor alpha

Peroxisome proliferators are a diverse group of chemicals that include several therapeutically used drugs (e.g., hypolipidemic agents), plasticizers and organic solvents used in the chemical industry, herbicides, and naturally occurring hormones. As the name implies, peroxisome proliferators cause an increase in the number and size of peroxisomes in the liver, kidney, and heart tissue of susceptible species, such as rats and mice. Long-term administration of peroxisome proliferators can cause liver cancer in these animals, a response that has been the central issue of research on peroxisome proliferators for many years. Peroxisome proliferators are representative of the class of nongenotoxic carcinogens that cause cancer through mechanisms that do not involve direct DNA damage. The fact that humans are frequently exposed to these agents makes them of particular concern to government regulatory agencies responsible for assuring human safety. Whether frequent exposure to peroxisome proliferators represents a hazard to humans is unknown; however, increased cancer risk has not been shown to be associated with long-term therapeutic administration of the hypolipidemic drugs gemfibrozil, fenofibrate, and clofibrate. To make sound judgments regarding the safety of peroxisome proliferators, the validity of extrapolating results from rodent bioassays to humans must be based on the agents' mechanism of action and species differences in biologic activity and carcinogenicity. The peroxisome proliferator-activated receptor alpha (PPARalpha), a member of the nuclear receptor superfamily, has been found to mediate the activity of peroxisome proliferators in mice. Gene-knockout mice lacking PPARalpha are refractory to peroxisome proliferation and peroxisome proliferator-induced changes in gene expression. Furthermore, PPARalpha-null mice are resistant to hepatocarcinogenesis when fed a diet containing a potent nongenotoxic carcinogen WY-14,643. Recent studies have revealed that humans have considerably lower levels of PPARalpha in liver than rodents, and this difference may, in part, explain the species differences in the carcinogenic response to peroxisome proliferators.     

Alternatives to the 2-species bioassay for the identification of potential human carcinogens

It is proposed that the standard 2-species rodent cancer bioassay protocol, as perfected by the US National Toxicology Program (NTP), has already fulfilled its most useful role by providing an unequalled carcinogenicity database by which to re-assess the type of carcinogen worthy of definition. Continued use of this resource and time consuming protocol can no longer be justified, except in rare circumstances of high and protracted human exposure to a chemical of unknown carcinogenicity. In those rare instances an enlarged bioassay of three or four test species should perhaps be considered, there being nothing fundamental about the rat/mouse combination. In the large majority of cases, however, a practical estimation of the carcinogenic potential of a chemical can be formed in the absence of lifetime carcinogenicity bioassay data. This can be achieved by its sequential study, starting with an appreciation of its chemical structure and anticipated reactivity and mammalian metabolism. After the shortterm evaluation of a range of additional properties of the agent, including its genetic toxicity, rodent toxicity and tissue-specific toxicity, confident predictions of the genotoxic and/or non-genotoxic carcinogenic potential of the agent can be made. In most situations these predictions will be suitable for framing hazard reduction measures among exposed humans. In some situations it may be necessary to evaluate these predicted activities using limited bioassays, a range of which are considered. Extensions of these limited carcinogenicity bioassays to a standard 2-year/2-species bioassay can only be supported in cases where the non-carcinogenicity of the agent becomes the important thing to define. The US NTP have evaluated the carcinogenicity of approximately 400 chemicals over the past 20 years, at a cost of hundreds of millions of US dollars. The experience gained by that and related initiatives, worldwide, can now be harnessed to classify thousands of priority chemicals as being either probable carcinogens or probable noncarcinogens. That can now be achieved using a fraction of the earlier resources and in a fraction of the time that would be required for the conduct of 2-species bioassays. The comfort factor for one group of people of the order of the present system, coupled to the comfort factor for another group of the delay in carcinogenicity assessment enforced by the present council of perfection, are the two main factors delaying transfer to a streamlined system for assessing the carcinogenic potential of chemicals to humans. A third delaying factor in the need for new and focused test data. Coordinated acquisition of such data could rapidly remove the first two obstacles.     

Outcome of orthotopic liver transplantation in patients with haemophilia

As part of environmental toxicology, it is important to assess both the carcinogenic potential of xenobiotics and their mode of action on target cells. Since dysregulation of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, is considered as an early and essential component in the process of multistage carcinogenesis, we have studied the mode of ODC induction in Syrian-hamster-embryo(SHE) cells stage-exposed to carcinogens and to non-carcinogens. One-stage (5 hr) treatment of SHE cells with 50 microM clofibrate (CLF), a non-genotoxic carcinogen, or with 0.4 microM benzo(a)pyrene (BaP), a genotoxic carcinogen, slightly decreased basal ODC activity. Using the 2-stage exposure, 1 hr to carcinogen, then replacement by TPA for 5 hr, the ODC activity was higher than that obtained with TPA alone. This ODC superinduction was not observed when SHE cells were similarly pre-treated with non-carcinogenic compounds. Several environmental chemicals, pesticides, solvents, oxidizers and drugs were investigated with this SHE cell model. With one-stage exposure, some xenobiotics decreased basal ODC activity, while for others ODC changes were not noticeable. With 2-stage exposure (chemical followed by TPA), all carcinogens amplified the TPA-inducing effect, resulting in ODC superinduction. Comparative studies of the action of carcinogens and of non-carcinogens, using 2-stage exposure protocols, clearly show a close relationship between ODC induction rate and morphological transformation frequency.     

The causes and prevention of cancer: the role of environment

The idea that synthetic chemicals such as DDT are major contributors to human cancer has been inspired, in part, by Rachel Carson's passionate book, Silent Spring. This chapter discusses evidence showing why this is not true. We also review research on the causes of cancer, and show why much cancer is preventable. Epidemiological evidence indicates several factors likely to have a major effect on reducing rates of cancer: reduction of smoking, increased consumption of fruits and vegetables, and control of infections. Other factors are avoidance of intense sun exposure, increases in physical activity, and reduction of alcohol consumption and possibly red meat. Already, risks of many forms of cancer can be reduced and the potential for further reductions is great. If lung cancer (which is primarily due to smoking) is excluded, cancer death rates are decreasing in the United States for all other cancers combined. Pollution appears to account for less than 1% of human cancer; yet public concern and resource allocation for chemical pollution are very high, in good part because of the use of animal cancer tests in cancer risk assessment. Animal cancer tests, which are done at the maximum tolerated dose (MTD), are being misinterpreted to mean that low doses of synthetic chemicals and industrial pollutants are relevant to human cancer. About half of the chemicals tested, whether synthetic or natural, are carcinogenic to rodents at these high doses. A plausible explanation for the high frequency of positive results is that testing at the MTD frequently can cause chronic cell killing and consequent cell replacement, a risk factor for cancer that can be limited to high doses. Ignoring this greatly exaggerates risks. Scientists must determine mechanisms of carcinogenesis for each substance and revise acceptable dose levels as understanding advances. The vast bulk of chemicals ingested by humans is natural. For example, 99.99% of the pesticides we eat are naturally present in plants to ward off insects and other predators. Half of these natural pesticides tested at the MTD are rodent carcinogens. Reducing exposure to the 0.01% that are synthetic will not reduce cancer rates. On the contrary, although fruits and vegetables contain a wide variety of naturally-occurring chemicals that are rodent carcinogens, inadequate consumption of fruits and vegetables doubles the human cancer risk for most types of cancer. Making them more expensive by reducing synthetic pesticide use will increase cancer. Humans also ingest large numbers of natural chemicals from cooking food. Over a thousand chemicals have been reported in roasted coffee: more than half of those tested (19/28) are rodent carcinogens. There are more rodent carcinogens in a single cup of coffee than potentially carcinogenic pesticide residues in the average American diet in a year, and there are still a thousand chemicals left to test in roasted coffee. This does not mean that coffee is dangerous but rather that animal cancer tests and worst-case risk assessment, build in enormous safety factors and should not be considered true risks. The reason humans can eat the tremendous variety of natural chemical "rodent carcinogens" is that humans, like other animals, are extremely well protected by many general defense enzymes, most of which are inducible (i.e., whenever a defense enzyme is in use, more of it is made). Since the defense enzymes are equally effective against natural and synthetic chemicals one does not expect, nor does one find, a general difference between synthetic and natural chemicals in ability to cause cancer in high-dose rodent tests. The idea that there is an epidemic of human cancer caused by synthetic industrial chemicals is false. In addition, there is a steady rise in life expectancy in the developed countries. Linear extrapolation from the maximum tolerated dose in rodents to low level exposure in humans has led to grossly exaggerated mortality forecasts. Such extrapo     

Causes of cancer in Scandinavia and possible preventive measures

The purpose of this work is to address future possibilities for avoiding cancer. We elucidate the most important known causes of cancer in the Nordic countries during the second half of this century and provide estimates of the numbers of cancer cases that might be avoided by the year 2000 if those causes were effectively eliminated. Information on the pattern of carcinogenic exposures in each of the five Nordic countries and the associated relative risk estimates from the scientific literature were obtained. The numbers of avoidable cancers were assessed on the basis of this information together with the associated population attributable risk percent, PAR%, i.e. the proportion of a given cancer that can be avoided upon elimination of the causative factor. The main causes of cancer include smoking, alcohol consumption, exposure to occupational carcinogens, radiation, obesity and infection with human papillomavirus (HPV) and Helicobacter pylori. Annually, more than 18,000 cancers in men and 11,000 in women in the Nordic populations could be avoided by eliminating exposure to known carcinogens which is equivalent to 33 percent and 20 percent of all cancers arising in men and women, respectively, around the year 2000. Smoking habits account for a little more than half of these avoidable cases. Exposure to solar radiation, HPV and Helicobacter pylori, diagnostic and therapeutic radiation and consumption of alcohol play important roles in the causation of cancer, as each of these factors is linked with 1-5 percent of all cancers in men and women. Occupational exposures are also substantial causes in men (3 percent), and obesity is important in women (1 percent). In contrast, current knowledge is insufficient to give reliable estimates of the numbers of cancers that could be avoided by well-described modifications of dietary habits. These figures indicate that the most efficient way of reducing cancer morbidity would be to reduce the prevalence of exposure of the population to cancer-causing agents.     

Invasive tumors derived from xenotransplanted, immortalized human cells after in vivo exposure to chemical carcinogens

Several chemicals that are found in cigarette smoke or diesel oil engine exhausts, such as benzo[a]pyrene (B[a]P) and 1,6-dinitropyrene (DNP) are carcinogenic in experimental animal models. In the present study, we have exposed in vivo the xenotransplanted immortalized human bronchial epithelial cell line BEAS-2B to the ultimate carcinogen of B[a]P, benzo[a]pyrene diolepoxide (BPDE), to DNP or to the benzo[e]pyrene, a less active compound that has tumor-promoting abilities in mouse skin carcinogenesis bioassays. All three compounds were administered using slow-release beeswax pellets. After a 6 month exposure, BPDE produced two tumors in seven transplants, four tumors were seen in 10 transplants treated with DNP and one tumor was observed in five tracheal grafts exposed to B[a]P. All the neoplasms were well-differentiated invasive adenocarcinomas. Tracheal transplants exposed to beeswax without carcinogen did not show any evidence of neoplastic growth, and their luminal surfaces were lined by a single or double layer of cuboidal cells. All lines derived from the adenocarcinomas showed increased in vitro resistance to serum-induced terminal differentiation, gelatinolytic activity, s.c. tumorigenicity and invasive growth in an in vivo assay. When these cell lines were compared with previously described tumor cell lines derived from xenotransplants exposed to cigarette smoke condensate, it became clear that the latter exhibited a more aggressive invasive behavior. Nevertheless treatment with the three chemicals gave rise to tumor cell lines that exhibited a similar invasive behavior in vivo, and were able to penetrate early into the wall of the tracheal transplants in which they were seeded. These data indicate that this system based on xenotransplanted bronchial epithelial cells is a very relevant model to identify human carcinogens and to study mechanisms of bronchogenic cancer pathogenesis.     

Risk assessment of butadiene in ambient air; the approach used in the UK

The UK Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment (COC) and the related Committee on Mutagenicity provided advice on 1,3-butadiene in 1992. This followed detailed consideration of the available mutagenicity, animal carcinogenicity and epidemiology data plus information on toxicokinetics. They concluded that 1,3-butadiene was an in vivo mutagen, a potent genotoxic animal carcinogen and should be regarded as a probable human carcinogen. The Department of Health is not aware of more recent data warranting reconsideration of these conclusions. General advice on setting air quality standards for carcinogenic air pollutants was given by the COC. Although the prudent assumption of the absence of any safe level for genotoxic carcinogens was preferred, a pragmatic approach based essentially on assessment of the exposure at which no increased risk would be detected, plus a safety factor, was considered reasonable for compounds like butadiene where exposure cannot be totally avoided. This approach, plus recognition that it is unadvisable to allow ambient levels of genotoxic carcinogens to rise, is used in the UK. The procedure by which the Department of Environment's Expert Panel on Air Quality Standards recommended a value of 1 ppb for butadiene based on these principles is described.     

Cancer prevention: past, present, future

There are many examples of different types of cancers that have been prevented by appropriate measures in the past. Most of them were related to occupational, iatrogenic or accidental factors, often as the outcome of heavy exposure of humans to specific carcinogenic agents. Cancer is a disease of DNA, and is generally associated with multiple genetic alterations, these being produced in the typical case by exposure to various carcinogens, each of which exists at minute concentrations. Thus, the impact of carcinogenic factors, xenobiotics and autobiotics, is due to their actions in concert. However, a single mutation yielding genomic instability exerts a disproportionately large influence by resulting in a large number of secondary mutational events. Epigenetic changes can also not be disregarded especially from the view point of prevention of neoplasia. The occurrence of multiple primary cancers among survivors of initial primaries, and the presence of hereditary groups with a high risk of cancer development provide a strong stimulus for establishment of effective approach for cancer prevention, which should be, in principle, multi-faceted. Therefore, a holistic approach is essential with improvement in life style including choosing a balanced diet and avoidance of cigarette smoking and other sources of carcinogens, as integral elements.     

Inherited factors and environmental exposures in cancer risk

Carcinogenesis is a multistage process that results from the interaction of carcinogenic exposures, cellular macromolecules (eg, DNA), and endogenous mutational mechanisms. Involved in these processes are metabolic activation and detoxification of chemical carcinogens, genetic sequences of protooncogenes and tumor suppressor genes, and DNA repair, among others. Each of these vary widely among individuals and can be associated with increased cancer risk. Cytochrome P4501A1, P4502E1 and N-acetyl transferase 2 are examples of enzymes involved in the metabolic activation of potential environmental carcinogens such as polycyclic aromatic hydrocarbons, benzene, and aromatic amines, respectively. Germ-line mutations in these genes are common and associated with abnormal enzymatic function that are mechanistically related to quantitative changes in binding of carcinogens to DNA. Allelic frequencies for these mutations vary among different racial and ethnic populations and may explain, in part, differences in cancer rates. Risk assessments attempt to predict cancer rates in humans using mathematical models that are often based upon limited experimental data. They do not generally incorporate the numerous stages of carcinogenesis or interindividual variation. Thus, sensitive and resistant populations are not sufficiently considered. This limits the accuracy of currently applied risk assessment models.     

Clinical evaluation of hepatic bruit audible in patients with alcoholic hepatitis]

Human exposure to methylating agents appears to be widespread, as indicated by the frequent occurrence of methylated DNA adducts in human DNA. The high incidence of methylated DNA adducts even in humans thought not to have suffered extensive exposure to environmental methylating agents implies that chemicals of endogenous origin, probably N-nitroso compounds such as the strongly carcinogenic N-nitrosodimethylamine (NDMA), may be primarily responsible for their formation and raises the question of the carcinogenic risks associated with such exposure. In addition to accumulation of DNA damage, other factors (such as induced cell proliferation) appear to be important in determining the probability of induction of mutation or cancer by NDMA, implying that high to low dose risk extrapolations should not be based on the assumption of dose- or even adduct-linearity. Comparative studies of the accumulation and repair of methylated adducts in humans and animals treated with methylating cytostatic drugs do not reveal significant species differences. Based on this and the dosimetry of adduct accumulation in rats chronically exposed to very low doses of NDMA, it is suggested that the exposure needed to account for the levels of adducts found in human DNA may be of the order of hundreds of micrograms NDMA (or equivalent) per day, a level of exposure which may well represent a significant carcinogenic hazard for man.     

The Antley-Bixler syndrome. A new case without radiohumeral synostosis

Myelodysplastic syndrome (MDS) is a hematological disorder that occurs primarily in the elderly as an acquired, sporadic disease. Familial cases of MDS are rare. We have identified a kindred with three affected individuals, with early age of onset, suggesting a possible inherited predisposition to this disease. Using a molecular genetic approach, we examined whether bands 5q31 or 7q22 or both, the chromosomal regions most frequently associated with sporadic MDS, are involved in familial expression of MDS in this pedigree. Linkage analysis using polymorphic microsatellite DNA markers demonstrated that neither 5q31 nor 7q22 cosegregated with MDS in this family. There was no history of common environmental or occupational exposure among family members with MDS. In addition, analysis of polymorphisms at two loci [glutathione S-transferase T1 and M1 (GSTT1 and GSTM1)] involved in carcinogen detoxification and associated with cancer susceptibility, including increased risk for MDS, showed no evidence for enhanced sensitivity to environmental carcinogens in affected family members. Taken together, our findings suggest that (1) there is an inherited predisposition to MDS in this kindred; and (2) genes at 5q31 and 7q22, the regions most commonly associated with sporadic MDS, are excluded from a causal role in this family's disease.     

Dose-response studies and 'no-effect-levels' of N-nitroso compounds: some general aspects

One major problem in the evaluation of potential carcinogenic food additives and contaminants is that of thresholds or, better, of 'no-adverse-effect-levels'. Arguments in favor of the postulated 'irreversibility' of carcinogenic effects are based on dose-response studies, single dose and multigeneration experiments as well as on the concept of somatic mutation as the first step in carcinogenesis with subsequent transmittance of induced defects during cell replication. The problem of extrapolation of results of animal experiments using high doses to low exposure and low incidences in man is not yet solved satisfactorily. Possible practical consequences include zero tolerance, acceptable thresholds at low risk and safety factors. Acceptable intakes should never be considered constants but should be changeable as soon as new facts in regard to the safety evaluation are available.