Transplacental and transgenerational carcinogenesis

Effects of exposure to carcinogens at early stages of ontogenesis are considered. An increased cancer risk due to prenatal exposure may be related to: 1) exposure of the fetus during pregnancy to chemicals able to cross the placental barrier or to radiation; 2) exposure to a chemical or radiation of the parents or one parent prior to conception. In transplacental carcinogenesis, the effects observed after birth are a consequence of a direct interaction of the carcinogen with somatic cells of the fetus. DES and radiation were shown to increase cancer risk in humans following exposure during pregnancy, while in experimental animals a large variety of chemicals of quite different structure (including the widely used therapeutic agent cisplatin) were demonstrated to induce tumors in the progeny after administration during pregnancy. The experimental multigeneration effect of carcinogens is manifested in an increased incidence of tumors in several generations of untreated descendants of: a) females exposed to carcinogen during pregnancy; b) males exposed to carcinogen prior to mating with untreated females. The inherited change may be an initiating event revealed by the exposure during post-natal life to a promoting agent. In humans deleterious information inherited through the germ cells (occurring either following a spontaneous error in DNA replication and repair or as a consequence of a chemical or physical agent) can increase the risk of developing cancer in certain individuals by several orders of magnitude (retinoblastoma, familial polyposis of the colon and some others). The multigeneration transmission of carcinogenic risk is also demonstrated by cancer prone families that are probably more frequent than originally thought, with a risk that is one order of magnitude higher than in general population. Familial clusterings of cancer may also indicate germline mutations in one or more genes. Thus the inherited predisposition to cancer that is observed today may, at least in part, be explained by the exposure to environmental noxious agents in previous generation(s). Since humans are exposed throughout life to many environmental agents, either carcinogenic or capable to enhance the progression of cancer, an understanding of the contribution of prenatal exposure to carcinogens could improve the efficacy of prevention.     

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.     

What do animal cancer tests tell us about human cancer risk?: Overview of analyses of the carcinogenic potency database

Many important issues in carcinogenesis can be addressed using our Carcinogenic Potency Database, which analyzes and standardizes the literature of chronic carcinogenicity tests in laboratory animals. This review is an update and overview of our analyses during the past 15 years, using the current database that includes results of 5152 experiments on 1298 chemicals. We address the following: 1. More than half the 1298 chemicals tested in long-term experiments have been evaluated as carcinogens. We describe this positivity rate for several subsets of the data (including naturally occurring and synthetic chemicals), and we hypothesize and important role in the interpretation of results for increased cell division due to administration of high doses. 2. Methodological issues in the interpretation of animal cancer tests: constraints on the estimation of carcinogenic potency and validity problems associated with using the limited data from bioassays to estimate human risk, reproducibility of results in carcinogenesis bioassays, comparison of lifetable and summary methods of analysis, and summarizing carcinogenic potency when multiple experiments on a chemical are positive. 3. Positivity is compared in bioassays for two closely related species, rats and mice, tested under similar experimental conditions. We assess what information such a comparison can provide about interspecies extrapolation. 4. Rodent carcinogens induce tumors in 35 different target organs. We describe the frequency of chemicals that induce tumors in rats or mice at each target site, and we compare target sites of mutagenic and nonmutagenic rodent carcinogens. 5. A broad perspective on evaluation of possible cancer hazards from rodent carcinogens is given, by ranking 74 human exposures (natural and synthetic) on the HERP indes.     

Effect of size, shape and hardness of particles in suspension on oral texture and palatability

Trans-species, multiple site (particularly common site between species), mutagenic rodent carcinogens are less affected by the influences of polymorphic genes than are chemicals inducing more limited carcinogenic effects. Trans-species carcinogens, therefore, should represent a first priority for attention for human health risk.     

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.     

Genetic polymorphisms in xenobiotic metabolizing enzymes as a determinant of susceptibility to environmental mutagens and carcinogens in humans

Xenobiotic metabolizing enzymes are known to play a role in the metabolic activation of environmental mutagens and carcinogens to exert their carcinogenic effects as well as detoxification by increasing their hydrophilicity. These enzymes include cytochrome P450s, glutathione S-transferases (GSTs), acetyltransferases (NATs) and sulfotransferases. Genetic polymorphisms in many of these enzymes, such as CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1, GSTP1 and GSTT1, have been shown to occur, which result in the altered expression of enzymatic activities. This suggests that the genetic polymorphisms may affect the individual susceptibility to environmental carcinogens and thus play a role in human carcinogenesis. Recently, the mutations that confer those polymorphisms of xenobiotic metabolizing enzymes have been identified and genotyping methods for the genetic polymorphisms have been developed. Specific phenotypes and genotypes for CYP1A1, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1 and GSTP1 have been associated with susceptibility to malignant diseases including lung, bladder and colon cancers, although the association was not confirmed in some studies. A number of factors such as degree of exposure to environmental carcinogens and the role of xenobiotic metabolizing enzymes in human carcinogenesis should carefully be evaluated in understanding genetic susceptibility.     

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 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     

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.     

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.     

Susceptibility to esophageal cancer and genetic polymorphisms in glutathione S-transferases T1, P1, and M1 and cytochrome P450 2E1

Genetic polymorphisms in enzymes involved in carcinogen metabolism have been shown to influence susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is primarily responsible for the bioactivation of many low molecular weight carcinogens, including certain nitrosamines, whereas glutathione S-transferases (GSTs) are involved in detoxifying many other carcinogenic electrophiles. Esophageal cancer, which is prevalent in China, is hypothesized to be related to environmental nitrosamine exposure. Thus, we conducted a pilot case-control study to examine the association between CYP2E1, GSTM1, GSTT1, and GSTP1 genetic polymorphisms and esophageal cancer susceptibility. DNA samples were isolated from surgically removed esophageal tissues or scraped esophageal epithelium from cases with cancer (n = 45), cases with severe epithelial hyperplasia (n = 45), and normal controls (n = 46) from a high-risk area, Linxian County, China. RFLPs in the CYP2E1 and the GSTP1 genes were determined by PCR amplification followed by digestion with RsaI or DraI and Alw26I, respectively. Deletion of the GSTM1 and GSTT1 genes was examined by a multiplex PCR. The CYP2E1 polymorphism detected by RsaI was significantly different between controls (56%) and cases with cancer (20%) or severe epithelial hyperplasia (17%; P < 0.001). Persons without the RsaI variant alleles had more than a 4-6-fold risk of developing severe epithelial hyperplasia (adjusted odds ratio, 6.0; 95% confidence interval, 2.3-16.0) and cancer (adjusted odds ratio, 4.8; 95% confidence interval, 1.8-12.4). Polymorphisms in the GSTs were not associated with increased esophageal cancer risk. These results indicate that CYP2E1 may be a genetic susceptibility factor involved in the early events leading to the development of esophageal cancer.     

Genetic predisposition testing for cancer: effects on families' lives

Genetic testing to identify a predisposition to the development of cancer affects not only the person undergoing DNA analysis but also his or her entire family. Multiple complex issues arise in conjunction with the clinical application of this new tool for assessing cancer risk. Counseling families regarding genetic risk is multifaceted and requires genetic knowledge that may go beyond the expertise of the health care provider. The article describes the psychosocial effects of cancer predisposition testing on families, ethical and social concerns of cancer risk testing, and implications for nurses in counseling individuals and families considering predisposition testing.     

Cancer predisposition, radiosensitivity and the risk of radiation-induced cancers. III. Effects of incomplete penetrance and dose-dependent radiosensitivity on cancer risks in populations

Recent studies have identified a number of genes in the human genome at which germinal mutations predispose the individuals to one or another type of cancer. These studies also show that not all individuals carrying the mutant genes develop cancers (i.e., the mutant genes are not fully penetrant). At least some of these predisposed genotypes also have a higher sensitivity to cancers induced by ionizing radiation than those who are not so predisposed, which may be dependent on dose. This paper presents an analysis of the impact of such heterogeneity on estimates of cancer risks for an irradiated population. This is done by extending the Mendelian one-locus, two-allele model of cancer predisposition and radiosensitivity developed earlier to allow for incomplete penetrance and dose dependence of radiosensitivity differentials among genotypes. The model is applied to recently published data for breast cancer and hereditary non-polyposis colon cancer using a range of possible values for the strength of predisposition and radiosensitivity differentials. It is shown that, after radiation exposures, the ratio of cancer risks in a heterogeneous population relative to that in a homogeneous population increases with increasing dose, but that the dose dependence of the relative risk diminishes at higher doses. Likewise, the attributable risk (i.e. the proportion of the increase in risk that is due to both increased susceptibility and increased radiosensitivity) and the proportion of attributable risk due to increased radiosensitivity also increase with dose, and the dose dependence of each measurement also diminishes at higher doses. However, when the proportion of cancers due to the susceptible genotypes is small (<10%) (as is likely to be the case for breast cancer in non-Ashkenazi women), the increases in the relative risk and attributable risk are marked only when there are very large increases in cancer susceptibility (>1000-fold) and radiosensitivity (>100-fold) in the susceptible group. When the proportion of cancers due to the susceptible genotypes is appreciable (> or = 10%) (as may be the case for breast cancer in Ashkenazi Jewish women), there may be large increases in the relative risk and attributable risk for comparatively modest increases in cancer susceptibility (>10-fold) and radiosensitivity (>100-fold) in the susceptible subpopulation. For any given combination of strength of predisposition and radiosensitivity differential, incomplete penetrance dilutes the effect.     

Gene--environment interactions in the application of biomarkers of cancer susceptibility in epidemiology

Metabolic susceptibility genes are important determinants of individual susceptibility to the effects of environmental carcinogens. These genes follow the form of 'type 2' gene-environment interaction, whereby the polymorphic genetic risk factor functions only in the presence of an environmental exposure. Two different effects of carcinogen dose have been observed for these genes. Sometimes, increasing dose leads to a decreasing interaction, so that cases with the genetic risk factor have lower exposures than those cases without it. Other examples of a direct dose effect, whereby increasing exposure leads to increased interaction, have also been described. We propose a model based on multiple logistic regression to assess the nature of the dose effect in this type of gene-environment interaction. This model allows for distinction between these two dose effects, and other effects such as protective or non-interactive effects of environmental and genetic risk factors.     

Polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin induce intrachromosomal recombination in vitro and in vivo

Polychlorinated aromatic hydrocarbons such as polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are extremely stable and widely distributed environmental pollutants. These chemicals are animal carcinogens and probable human carcinogens, and TCDD is possibly one of the most potent toxins ever evaluated by the United States Environmental Protection Agency. Polychlorinated aromatic hydrocarbons score negatively in most genotoxicity assays, including the Ames (Salmonella) assay. Although their mechanism of toxicity is not well understood, they induce aryl hydrocarbon (AH) hydroxylases and bind to the AH receptor, which is believed to mediate toxicity. Here, we determine effects of polychlorinated aromatic hydrocarbons in genotoxicity assays that score for DNA deletions by intrachromosomal recombination in vivo and in vitro. In this study, TCDD, Aroclor 1221, and Aroclor 1260 induced deletions in vivo in the mouse embryo; Aroclor 1221 and Aroclor 1260 induced deletions in yeast. We also show that the induced deletion events did not correlate with induction of AH hydroxylase. None of the tested compounds induced CYP1A-associated ethoxyresorufin-O-deethylase activity in mouse embryos or in vitro. These results clearly demonstrate a genotoxic activity of polychlorinated aromatic hydrocarbons in vitro and in vivo, which is independent of induction of cytochrome P450 activity. Because genetic instability and deletions may be mechanistically involved in carcinogenesis, these results may encourage further research to determine whether such genotoxic mechanisms may be useful for cancer risk assessment of polychlorinated aromatic hydrocarbons.     

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.     

Current Perspectives on Occupational Cancer Risks

On the basis of the International Agency for Research on Cancer's evaluations of occupational exposures, 22 occupational agents are classified as human carcinogens and an additional 22 agents as probable human carcinogens. In addition, evidence of increased risk of cancer was associated with particular industries and occupations, although no specific agents could be identified as etiologic factors. The main problem in the construction and interpretation of such lists is the lack of detailed qualitative and quantitative knowledge about exposures to known or suspected carcinogens. The recent examples of recognized occupational carcinogens, such as cadmium, beryllium, and ethylene oxide, stress the importance of the refinement in the methods for exposure assessment and for statistical analysis on the one hand and the potential benefits from the application of biomarkers of exposure and early effect on the other hand. Other trends that may be identified include the increasing practice of multicentric studies and investigations of exposures relevant to white collar workers and women. Finally, there is a need for investigation of occupational cancer risks in developing countries.     

Regional anaesthesia--children are different

Is Helicobacter pylori a true carcinogen? Most carcinogens are physical, chemical or viral agents which give rise to the development of neoplasia by inducing alterations in cellular DNA. Evidence for the carcinogenic potency of such agents is usually based on dose-response curves and animal models and there is often a direct association with (epi-) genetic events. Despite the absence of such data, H. pylori has been designated as a definite cause of human cancer. This designation is largely based on epidemiological evidence. H. pylori is a carcinogen in the sense that infection with this organism induces a persistently inflamed gastric mucosa which is associated with an increased proliferative state and an increased gastric cancer risk. As such, 1-2% of the infected subjects are estimated to develop cancer, with an incidence probably close to nine times higher than that among non-infected subjects. There is a need for additional mechanistic knowledge on this association between chronic epithelial inflammation and carcinogenesis. An additional important question is whether H. pylori eradication may contribute to gastric cancer prevention. As progressive mucosal abnormalities such as atrophy and metaplasia do not regress after such intervention, the major benefit in terms of cancer prevention is likely to be to infected subjects who have not yet developed permanent gastric mucosal damage. This is in agreement with data suggesting that the role of H. pylori may be confined to the initial stages of carcinogenesis.     

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.     

Aromatic amine DNA adduct formation in chronically-exposed mice: considerations for human comparison

Lifetime chronic exposure of mice to the aromatic amines 4-aminobiphenyl (ABP) and 2-acetylaminofluorene (AAF) produces liver and urinary bladder tumors. In parallel experiments, DNA adduct levels in target tissues reach a steady-state (a balance between adduct formation and removal) after about four weeks of either AAF or ABP ingestion. For these and other carcinogens, steady-state DNA adduct levels most frequently increase linearly with dose, but the formation of tumors also depends upon a variety of factors, including the proliferative capacity of the target tissue, the sex of the animal, genotoxic properties of the specific adducts formed, and other unknown events. Chronic dosing experiments in animal models are of interest for human risk assessment because human exposure is typically intermittent, involving repeated exposures. However, it is to be expected that in a genetically-diverse human population, where the lifetime averages > 70 years, the relationship between tumorigenesis and DNA adduct formation will be relatively more complex than that observed in mice. From our studies of chronic ABP exposure in male mice, we have obtained the daily dose of ABP and the steady-state level of N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP) adduct associated with a 50% mouse bladder tumor incidence. Our attempt at a human extrapolation for adducts and urinary bladder cancer in smoking males (20-40 cigarettes/day) is based on the ABP dose per cigarette, values for the dG-C8-ABP adduct in bladder biopsies of lifetime heavy smokers at age approximately 70, and the smoking-related bladder tumor incidence (absolute lifetime risk) for Caucasian males in the United States aged 65-84 years. The extrapolation has produced two major predictions, one related to adduct formation and the other related to tumorigenesis. First, the observed level of smoking-related dG-C8-ABP in DNA of human bladder epithelium, expressed as a function of daily ABP intake, is about 3500-times higher than similar data for mice, which suggests that humans may perform the biotransformation of ABP more efficiently than mice. Second, at a similar bladder tumor incidence, mouse bladder contained adduct concentrations that were much higher than those observed in human bladder; for example, at a 2.6% tumor incidence, mouse bladder contained an average of 55.5 fmol dG-C8-ABP/microgram DNA (1850 adducts/10(8) nucleotides), while bladders from Caucasian male smokers contained an average of 0.036 fmol dG-C8-ABP/microgram DNA (1.2 adducts/10(8) nucleotides). This suggests that factors other than ABP-DNA adducts, such as adducts of other carcinogens, the influence of promoters, and synergistic effects of all of these factors contribute substantially to smoking-related bladder cancer in humans.