Dietary carcinogens, environmental pollution, and cancer: some misconceptions

Various misconceptions about dietary carcinogens, pesticide residues, and cancer causation are discussed. The pesticides in our diet are 99.99% natural, since plants make an enormous variety of toxins against fungi, insects, and animal predators. Although only 50 of these natural pesticides have been tested in animal cancer tests, about half of them are carcinogens. About half of all chemicals tested in animal cancer tests are positive. The proportion of natural pesticides positive in animal tests of clastogenicity is also the same as for synthetic chemicals. It is argued that testing chemicals in animals at the maximum tolerated dose primarily measures chronic cell proliferation, a threshold process. Cell proliferation is mutagenic in several ways, including inducing mitotic recombination, and therefore chronic induction of cell proliferation is a risk factor for cancer.     

Priorities for cancer prevention: lifestyle choices versus unavoidable exposures

Although cancer prevention in the USA and other developed countries focuses on disease attributable to lifestyle factors such as smoking, alcohol intake, sun exposure, and obesity, cancer caused by involuntary exposures is a concern. The term environmental is ambiguously used to distinguish between lifestyle and unavoidable exposures. The general community is said to be vulnerable to carcinogens encountered in pollution, contaminated food, and consumer products. In view of these concerns, assessments of the carcinogenicity of particular chemicals are of little assistance in prevention of cancer. Appraisal of cancer attributable to widespread and localised pollution, pesticides, endocrine disrupting chemicals, and consumer products yields diverse outcomes, from established causation to absence of harm. The precautionary principle is not a practicable approach for unknown carcinogenic risks. Procedures for individuals to reduce exposure to recognised or suspect carcinogens in consumer products are not effective measures for cancer prevention. Anxiety concerning insidious cancer causation could divert attention from proven means of cancer prevention.     

Natural pesticides present in edible plants are predicted to be carcinogenic

Based upon the US National Toxicology Program (NTP) rodent carcinogenicity data base, CASE, an artificial intelligence structure-activity evaluation method, predicts that a large proportion of natural pesticides present in edible plants are rodent carcinogens.     

Evaluation of the carcinogenic risk of environmental chemicals

Many carcinogens have been detected in our environment, and chemicals which have been shown to induce cancers in experimental animals have been largely eliminated. However, there are still many chemicals which have not been studied in rodent carcinogenicity tests. In this paper, we review the evaluation of carcinogenic risk of environmental chemicals to humans. Carcinogenic risk to humans is evaluated primarily in three different phases: carcinogenicity studies in animal experiments, in vitro short-term screening studies, and finally human epidemiological studies. There are 30 chemicals, processes or industries which have been subject to these three phases and determined to be carcinogenic to humans by the International Agency for Research on Cancer (IARC). Carcinogenic risk of chemicals should be evaluated quantitatively by their threshold doses, TD50 and virtually safe dose (VSD). Furthermore, the target organ of the carcinogen should also be taken into account, which has been emphasized by the demonstration of carcinogenicity of BHA in the forestomach of rats. Summational, synergistic, antagonistic and inhibitory effects of chemicals should also be discussed. It is important to establish a guideline for detecting and eliminating environmental carcinogens in order to prevent cancer in humans.     

Endocrine disrupting pesticides: a leading cause of cancer among rural people in Pakistan

Evidence on the relationship between cancer and occupational exposure to pesticides and endocrine disrupting chemicals is reviewed. In animal studies it has been proved that majority of endocrine disrupting pesticides are carcinogenic. In humans, pesticides have been classified as carcinogens by the International Agency for Research on Cancer. Farmers may therefore be at higher risk for acute and chronic health effects associated with pesticides. Human data, however, are limited by the small number of studies that evaluate individual endocrine disrupting pesticide. Cancer of the breast, ovary, prostate, testis, and thyroid are hormone-dependent, which fostered research on the potential risk associated with occupational and environmental exposure to the so-called endocrine-disrupting pesticides. Professional as well as public exposure to pesticides raises cancer risk. Interaction with adjuvant and with other toxicants increases the actual risk. On the other hand, organochlorine pesticides and triazine herbicides require further investigation for a possible etiologic role in some hormone-dependent cancers.     

1. HUMAN POPULATION MONITORING FOR CANCER PREVENTION

Most of the chemicals classified by the International Agency for Research on Cancer (IARC) as human carcinogens are mutagenic across test systems, cf. [www.epa.gov/gapdb ] and induce tumors at multiple sites in rodent species. They are therefore readity detected in short term tests for gene-tic and related effects (GRE), in animal carcinogenesis bioassays and in human monitoring studies. Carcinogens that are not genotoxic may be studied using new toxicogenomic approaches as will be discussed. A Chemical Effects in Biological Systems (CEBS) database is planned by the National Center for Toxicogenomics to contain information on such compounds. The 1992 Preamble to the IARC Monographs     

Impacts of chemicals on liver cancer risk

Primary liver cancer (PLC) is of multifactorial etiology. Chronic infections by hepatitis B (HBV) and hepatitis C (HCV) viruses are major risk factors for most PLC cases worldwide, although mechanisms through which the infections cause PLC are still unknown. Epidemiologic and experimental evidence indicates that exposure to certain chemicals can also contribute significantly to PLC development, some of which have been designated as human liver carcinogens (Group 1) by the International Agency for Research on Cancer. These include aflatoxins and chronic consumption of alcoholic beverages. Many naturally occurring and synthetic chemicals have been shown to induce liver cancer in experimental animals. Humans are exposed to these carcinogens via accidental contamination of food or water; usually at levels far lower than those that are carcinogenic to experimental animals. Consequently, assessment of possible human PLC risk associated with such exposures is complex and uncertain. Evidence regarding aflatoxin as a human carcinogen has been extensively documented and is reviewed as an example of the usefulness of parallel experimental and epidemiological investigations in cancer risk assessment. Aflatoxins are toxic metabolites of certain spoilage molds that are potent liver carcinogens in experimental animals and frequently contaminate human diets. Collectively, epidemiologic data together with evidence from many types of experimental models defines the role of aflatoxin exposure in PLC causation. Molecular epidemiology involving the use of biomarkers of exposure has been particularly effective in linking aflatoxin exposure to PLC. Biomarkers of aflatoxin exposure have been validated with particular thoroughness. Dose-response relationships between biomarker levels and liver tumor incidence were first established in experimental animals. The biomarkers were then employed in pilot studies of limited scale in humans to define sensitivity, specificity, accuracy, and reliability parameters. Further validation in transitional epidemiological studies assessed intra- and interindividual variability, background levels, external dose-marker relationship, and feasibility for use in larger population-based studies. Finally, prospective epidemiological studies were conducted to evaluate biomarker effectiveness in identifying PLC risk.     

Response of the ke test to NCI/NTP-screened chemicals. II. Genotoxic carcinogens and non-genotoxic non-carcinogens.

A physico-chemical carcinogen-screening test was used to measure the rate constants of electron attachment, kes, of 105 chemicals that had been screened in long-term rodent bioassays and short-term in vitro tests by the NCI/NTP. In the ke test, a pulse-conductivity technique is used to generate and monitor the decay of excess electrons that serve as nucleophilic surrogates for the target tissue of rodents. Of the 61 chemicals that had been found to be rodent carcinogens as well as Salmonella mutagens, 36 yield kes that are equal to or greater than the diffusion-controlled ke of carbon tetrachloride and are considered to be positive ke test responses. In contrast, 29 of the remaining 44 chemicals that are putative non-carcinogens and non-mutagens yield kes that are negative ke test responses. These results are combined with the ke responses of 46 non-mutagenic carcinogens and 20 mutagenic non-carcinogens that were reported earlier and are evaluated to determine the degree to which the measure of electron-accepting capacity that ke provides complements or overlaps the electrophilicity or DNA reactivity of chemicals that is indicated by positive mutagenicity responses in the Ames Salmonella tester strains or by positive structural alerts, S/As, of the chemicals. The combined ke test results indicate that the overall predictivity of the ke test is comparable to and complements the Ames Salmonella test and S/As in identifying rodent carcinogens. Moreover, the electrons serve as non-discriminate nucleophilic targets for both genotoxic and non-genotoxic electron-accepting molecules and appear to attach with equal efficiency to carcinogens that are active in various tissues of rodents. This property of excess electrons suggests that the predictivity of the ke test could be enhanced by combining the measured ke with an appropriate lipophilicity or pharmacokinetic parameter. A pre-chemical electron-transfer step that had been proposed to precede chemical interactions between the carcinogen and target tissue is discussed in light of recent developments in electron-donor/-acceptor chemistry and in the application of structure--activity relationships to identify carcinogens.     

Aetiology of oesophageal cancer: some operative factors.

Of the thousands of chemicals tested, the only compounds found to be potent carcinogens for the oesophagus are the N-nitrosamines. Many of these compounds are readily formed from common precursors in the environment (eg example in food during its storage or preparation) and also in vivo in the human stomach. Exposure is therefore likely to be ubiquitous. Although man may be exposed to other oesophageal carcinogens these have yet to be chemically identified, and at present nitrosamines are the sole contenders for the role of initiators of oesophageal cancer in man. Evidence suggests strongly that oesophageal cancer is initiated world-wide by nitrosamines, and promoted by secondary factors, the nature of which varies with the population concerned, notably alcohol in Europe and the USA, dietary deficiencies in China and Iran, mycotoxins in South Africa. When several risk factors coincide in one locality, the result can be a very high incidence of oesophageal cancer, with no one major cause.     

Organochlorines and breast cancer risk

Organochlorines are a diverse group of synthetic chemicals that include polychlorinated biphenyls (PCBs), dioxins, and organochlorine pesticides such as dichlorodiphenyl-trichloroethane (DDT), lindane, and hexachlorobenzene. Although use of DDT and PCBs has been banned in the United States since the 1970s, some organochlorine compounds have accumulated and persisted within the environment. As a result, measurable amounts can still be found in human tissue. Because some organochlorine compounds act as estrogen agonists or antagonists within in vitro and experimental animal systems, a possible association of breast cancer risk with organochlorine exposure has been hypothesized and investigated. Although a few studies support this hypothesis, the vast majority of epidemiological studies do not. While some of these compounds may have other adverse environmental or health effects, organochlorine exposure is not believed to be causally related to breast cancer. Women concerned about possible organochlorine exposure can be reassured that available evidence does not suggest an association between these chemicals and breast cancer.     

Response of the ke test to NCI/NTP-screened chemicals. I. Non-genotoxic carcinogens and genotoxic non-carcinogens

The response of a physico-chemical carcinogen-screening test, the k(e) test, to 46 rodent carcinogens and 20 putative non-carcinogens that had been screened in long-term two-species bioassays by the National Cancer Institute/National Toxicology Program are reported. All of the chemicals screened are those that yield mutagenicity responses in the Ames Salmonella/microsome test that are either equivocal or contrary to the rodent carcinogenicity responses. The electron attachment rate constants, k(e)S, of the test chemicals in cyclohexane at 21 degrees C were measured using a pulse-conductivity technique. The k(e)S of 27 of the 46 rodent carcinogens (59%) are equal or greater than the diffusion-controlled k(e) of carbon tetrachloride, which is regarded as the boundary between a positive and negative response; the k(e)S of 8 of the 20 mutagenic non-carcinogens (40%) are less than diffusion-controlled. If the boundary between positive and negative k(e) responses is decreased to half the diffusion-controlled k(e), six additional carcinogens yield a positive ke response which increases the k(e) test sensitivity to 72% while the specificity to non-carcinogens remains at 40%. Comparison of these k(e)S with measures of the chemicals' electrophilicity that had been inferred from chemical structure indicates that k(e) provides a markedly different measure of electrophilicity and one that complements the Ames Salmonella assay. The use of the k(e) test as an analytical tool to indicate the presence of electron-attaching impurities in solvents such as benzene is discussed, as is the sensitivity of the k(e) test to rodent-liver carcinogens.     

Occupational cancer in Britain. Exposure assessment methodology

To estimate the current occupational cancer burden due to past exposures in Britain, estimates of the number of exposed workers at different levels are required, as well as risk estimates of cancer due to the exposures. This paper describes the methods and results for estimating the historical exposures. All occupational carcinogens or exposure circumstances classified by the International Agency for Research on Cancer as definite or probable human carcinogens and potentially to be found in British workplaces over the past 20-40 years were included in this study. Estimates of the number of people exposed by industrial sector were based predominantly on two sources of data, the CARcinogen EXposure (CAREX) database and the UK Labour Force Survey. Where possible, multiple and overlapping exposures were taken into account. Dose-response risk estimates were generally not available in the epidemiological literature for the cancer-exposure pairs in this study, and none of the sources available for obtaining the numbers exposed provided data by different levels of exposure. Industrial sectors were therefore assigned using expert judgement to 'higher'- and 'lower'-exposure groups based on the similarity of exposure to the population in the key epidemiological studies from which risk estimates had been selected. Estimates of historical exposure prevalence were obtained for 41 carcinogens or occupational circumstances. These include exposures to chemicals and metals, combustion products, other mixtures or groups of chemicals, mineral and biological dusts, physical agents and work patterns, as well as occupations and industries that have been associated with increased risk of cancer, but for which the causative agents are unknown. There were more than half a million workers exposed to each of six carcinogens (radon, solar radiation, crystalline silica, mineral oils, non-arsenical insecticides and 2,3,7,8-tetrachlorodibenzo-p-dioxin); other agents to which a large number of workers are exposed included benzene, diesel engine exhaust and environmental tobacco smoke. The study has highlighted several industrial sectors with large proportions of workers potentially exposed to multiple carcinogens. The relevant available data have been used to generate estimates of the prevalence of past exposure to occupational carcinogens to enable the occupational cancer burden in Britain to be estimated. These data are considered adequate for the present purpose, but new data on the prevalence and intensity of current occupational exposure to carcinogens should be collected to ensure that future policy decisions be based on reliable evidence.     

Cell-mediated cytotoxicity against human bladder cancer

Chemically non-reactive carcinogens, such as polycyclic hydrocarbons, have to be metabolized by cellular enzymes in order to exert their biological effects including mutagenicity. Chinese hamster V79 cells can be efficiently mutated from 8-azaguanine susceptibility to resistance by N-methyl-N-nitro-N-nitrosoguanidine. But these cells do not metabolize polycyclic hydrocarbons and were therefore not mutated by these compounds. A system of cell-mediated mutagenesis with carcinogenic hydrocarbons has been developed, by co-cultivating V79 cells with lethally irradiated rodent cells that can metabolize the carcinogens. The number of mutations was dependent on the number of metabolizing cells and the carcinogens were not mutagenic when V79 cells were co-cultivated with non-metabolizing cells. Inhibition of the hydrocarbon metabolizing enzymes by 7,8-benzoflavone, inhibited mutagenicity. Cell-mediated mutagenicity was obtained with the carcinogenic hydrocarbons 7,12-dimethylbenz (a)anthracene, benzo(a)pyrene and 3-methylcholanthrene and there was no mutagenicity with the non-carcinogenic hydrocarbon benz(a)anthracene. The degree of mutagenicity was related to the degree of carcinogenicity and the method detected mutagenicity with 0.1μg/ml. It is suggested that cell-mediated mutagenesis with human cells should provide a useful system to test for environmental chemicals hazardous to humans that have to be metabolically activated.     

Application of the results of carcinogen bioassays to man.

Animal experiments to test for the possible carcinogenic activity of chemicals provide the best and only deeply researched method for the detection or environmental carcinogens for man. The fact that most known human carcinogens give tumors in animals encourages the belief that these tests have validity. However, there are significant differences in the numbers of the exposed populations of men and animals, in the part of the lifespan during which each is exposed, in the metabolic activation of the carcinogens, and in the longevity of men and experimental rodents. For regulatory purposes, we must assume that the results of bioassay in rodents will closely parallel tumor induction in man, although we cannot be sure of this. In some cases, such as rodent bladder tumors associated with bladder stone, or subcutaneous sarcomas arising locally to massive injection of food dyes, there may be reason to reject an association. It is only by continued research into the way in which both man and laboratory animals react to carcinogens that we may hope to refine our methodologies and obtain an accurate, well-defined net to trap potential environmental carcinogens without depriving the community of chemicals, through false associations or false positive results that may be of great value, sociiologically or economically.     

Pesticides and cancer

Epidemiologic evidence on the relationship between chemical pesticides and cancer is reviewed. In animal studies, many pesticides are carcinogenic, (e.g., organochlorines, creosote, and sulfallate) while others (notably, the organochlorines DDT, chlordane, and lindane) are tumor promoters. Some contaminants in commercial pesticide formulations also may pose a carcinogenic risk. In humans, arsenic compounds and insecticides used occupationally have been classified as carcinogens by the International Agency for Research on Cancer. Human data, however, are limited by the small number of studies that evaluate individual pesticides. Epidemiologic studies, although some-times contradictory, have linked phenoxy acid herbicides or contaminants in them with soft tissue sarcoma (STS) and malignant lymphoma; organochlorine insecticides are linked with STS, non-Hodgkin's lymphoma (NHL), leukemia, and, less consistently, with cancers of the lung and breast; organophosphorous compounds are linked with NHL and leukemia; and triazine herbicides with ovarian cancer. Few, if any, of these associations can be considered established and causal. Hence, further epidemiologic studies are needed with detailed exposure assessment for individual pesticides, taking into consideration work practices, use of protective equipment, and other measures to reduce risk.     

Rodent Carcinogenicity of Peroxisome Proliferators and Issues on Human Relevance

Abstract

A variety of substances such as hypolipidemic drugs, phthalate ester plasticizers, pesticides, and industrial solvents have been shown to increase the size and number of peroxisomes in rats and mice. They are grouped under the generic term peroxisome proliferators (PP) because of their unique property of inducing peroxisome proliferation. There are marked species differences in response to PP. Rats and mice are most sensitive, and hamsters show an intermediate response while guinea pigs, monkeys, and humans appear to be relatively insensitive or non-responsive at dose levels that produce a marked response in rodents. Out of over 100 PP identified to date, about 30 have been adequately tested and shown to be carcinogenic, inducing tumors (primarily in the liver) upon chronic administration to rats and/or mice; hence, chemicals which induce the proliferation of peroxisomes have formed a unique class of chemical carcinogens. It is now well documented that activation of the “peroxisome proliferator-activated receptor α” (PPARα) is involved in PP-induced liver growth and carcinogenesis in rodents. PPAR,is also present in human cells; however, the levels reported are about 10% of those found in the liver of rodents. The human relevance of rodent tumors induced by PP has been the subject of debate over the last decade. Review of the existing evidence on PPAR-,agonists by a recent International Life Science Institute (ILSI) workgroup following a human relevance mode of action (MOA) framework has concluded that despite the presence of similar pathways in humans, it is unlikely that the proposed MOA for rodent tumors is plausible in humans, taking into account kinetic and dynamic factors. The data, however, did not permit a definitive conclusion that the animal MOA is not plausible in humans. While these agents appear unlikely to be hepatocarcinogens in humans at expected levels of human exposure, it remains uncertain to some experts in the field whether there is no possibility of carcinogenic potential under any circumstance of PP exposure, and if the potential human carcinogenicity of these chemicals can be summarily ignored. A number of remaining issues on human relevance of rodent tumors induced by PP are discussed.     

Prenatal and childhood exposure to carcinogenic factors

Transplacental carcinogenic effects have been demonstrated for about 60 chemicals in eight animal species and even in the human. Many carcinogens are much more active in the fetus than in the adult animal. The stage specificity of transplacental carcinogenesis is characterized by the possibility of inducing tumors only at certain stages of embryogenesis (at the end of organogenesis and during the whole period of histogenesis). Risk of transplacental carcinogenesis is owing to the passage of carcinogens or their active metabolites into embryonic tissue and the possibility of metabolic activation of substances within the fetus. In this connection, four main pathways can be hypothesized for the carcinogenic effect of a substance on the fetus. Organotropism with transplacental carcinogenesis is determined by genetic predisposition, differentiation, and proliferative activity in the target tissues. For indirect carcinogens the level of metabolizing enzymes is also important. Teratogenesis and carcinogenesis can be either independent processes or pathogenetically related to each other (eg, DES action). Experimental data can readily be applied to the discussion of prophylaxis of prenatal tumors in the human.     

Carcinogenicity of mutagens: predictive capability of the Salmonella mutagenesis assay for rodent carcinogenicity

A total of 224 chemicals that have been tested in long-term studies for carcinogenicity in rats and mice by the National Cancer Institute and the National Toxicology Program were tested for mutagenicity in Salmonella typhimurium. Correlations between mutagenicity and carcinogenicity were examined. The influences of chemical structure, rodent species and organ responses, and bacterial strain responses on the carcinogenesis/mutagenesis correlations were also examined. Not all carcinogens induced tumors in both rats and mice. A clear mutagenic or equivocal mutagenic response in Salmonella was predictive for 77% of the carcinogens or equivocal carcinogens, although only 54% of the 149 carcinogens or equivocal carcinogens were mutagens, and 58% of the nonmutagens were carcinogens or equivocal carcinogens. The proportion of mutagens and equivocal mutagens that were not carcinogenic or equivocal was 23%. There was no apparent way to distinguish the mutagenic carcinogens from the mutagenic noncarcinogens by the responses of the specific Salmonella strains. The proportions of different chemical classes in the data base strongly affected the correlations; 40% of the chlorinated carcinogens were mutagens, whereas 75% of the amines and 100% of the nitro-containing carcinogens were mutagens. Because 29% of the chemicals (30% of the carcinogens) were chlorinated, the poor correlation of this class was reflected in the overall correlation. It is concluded that the use of the Salmonella mutagenicity assay is warranted for the identification of carcinogens, but not for noncarcinogens. The proportion of carcinogens detected as mutagens is dependent on the specific classes of chemicals tested and on the rodent species used to define the carcinogens.     

Endocrine Disruptors and Breast Cancer Risk – Time to Consider the Environment

The term endocrine disruptors is used to describe a variety of natural and manmade substances that have thecapacity to potentially interfere with and modify the normal physiology of endocrine system either by mimicking,blocking or modulating the actions of natural endogenous hormones. The rising incidence of breast cancer overthe last 50 years and the documented higher incidence in urban as compared to rural areas suggest a relationshipto the introduction and increased use of xenoestrogens in our environment. The literature has developed overthe last decades where initial experiments on endocrine disruptors did not support an involvement in breastcancer, and then evidence mounted implicating various environmental factors including hormones, endocrinedisrupting chemicals and non-endocrine disrupting environmental carcinogens in the pathogenesis of breastcancer. Available data support the hypothesis that exposure to endocrine disruptors in utero leaves a signatureon mammary gland morphogenesis so that the resulting dysgenic gland becomes more predisposed to developtumors upon exposures to additional insults later on during life. Exceptionally, exposure to phytoestrogens couldbe beneficial to human health. Most of the available data are from well developed countries while the developingcountries are still understudied regarding these issues. Here, we raise a note of caution about potential role ofenvironmental toxins including endocrine disruptors in breast cancer development and call for serious measuresto be taken by all involved parties in the developing world.     

In-vivo carcinogenicity of 2-nitro-oxaphenalenes

2-Nitro-oxaphenalenes are synthetic chemicals which were synthesized in the authors' laboratory. They are the most efficient mutagenic compounds on mammalian cells in culture. They are chemically related to the nitro-naphthofuran family by the displacement of the heterocycle on the naphthalene ring. Since nitro-naphthofurans have a strong mutagenic activity in bacterial tests without metabolic activation and are active in-vivo carcinogens, the purpose of this study was to demonstrate the carcinogenic activity of two 2-nitro-oxaphenalenes. The two compounds were injected s.c. into Wistar rats initially 6-weeks-old. They were dissolved in dimethylsulfoxide (DMSO) at a concentration of 1 mg/ml. A s.c. injection of 0.5 ml containing 0.5 mg of carcinogen was given once a week in the neck of each animal tested. Five control animals were not injected and five animals received 0.5-ml injection of DMSO every week to serve as a control. The animals developed tumors only at the site of injection. The tumors were classified as high grade fibrosarcomas. This experiment demonstrates that: (i) 2-nitro-oxaphenalenes are very active in-vivo carcinogens in rats; (ii) there is a good correlation between the high mutagenic activity especially in mammalian tests and the strong carcinogenicity of the compounds; and (iii) the presence of a 6-methoxy group increases by two-fold the carcinogenic potential.