Complete Carcinogen Research Articles

Health effects of coal mining and combustion: carcinogens and cofactors.

Some polynuclear aromatics (PNA) have been found to be potent carcinogens for all tissues and organs of experimental animals that have been exposed to them, but different dose levels are needed for these effects. They have been known for decades to cause cancer at the site of application but also at certain sites distant from the area of contact. Although some hydrocarbons are potent and complete carcinogens, the majority of related hydrocarbons was originally found to be inactive. Since they generally appear together, it was important to know more about their interaction, particularly whether they would synergize, or antagonize. The polycyclic hydrocarbons have been studied by subcutaneous injection, where they prove very potent carcinogens. They are also very active on the skin of mice where they produce cancer on prolonged application. Inhalation studies, require larger doses yielded negative results until particulate matter was introduced which facilitated the development of lung tumors. Although iron oxide dust was used initially, other dusts were also capable of enhancing the response of the tissue to benzo(a)pyrene carcinogenesis. This point is of importance, particularly since the inhalation of PNA in situations of air pollution or coal mining involves particulates, although of a different type. Soot is not a homogenous substance and several factors determine its properties. Soots will lose some of the absorbed chemicals during their residence in air, but they retain their PNAs for long periods of time when they reach the soil. The carcinogenicity of PNAs in the adsorbed state may be completely absent, depending on particle size of the soot and availability of eluting capability of the tissues or cells in contact with the soot. Whenever the carcinogenic polynuclear aromatics can be eluted they will be active in producing cancer if their residence is adequate. There seems to be no reason to assume that a large increase in coal combustion in the future will by necessity lead to greater risks of cancer to the coal miners or the general urban dweller, because activities to be started now can take into consideration the requirements necessary for control of air pollution in mines as well as in cities. If new uses of coal will be developed, it will be a completely different situation, and statements about the carcinogenic risk from coal utilization do not apply there. Although some of the same carcinogenic PNAs are involved in the health hazards from those processes, other carcinogens and also cocarcinogens will be present, and the exposed workers will not have the apparent benefits of adsorption of PNAs on soot.

The carcinogenic effect of TPA (12-0-tetradecanoylphorbol-13-acetate) when applied to the skin of hairless mice.

Groups of hairless mice received one, two, five and fifty applications of 20 nmoles TPA (12-0-tetradecanoylphorbol-13-acetate) on the skin of the back, and were observed for 20 months. The animals developed some papillomas, some squamous cell carcinomas, some fibrosarcomas of the dermis, and some malignant and benign tumours in internal organs. There was a small, not significantly different, incidence of benign and malignant tumours after 1, 2 and 5 paintings, and a significantly higher tumour incidence after 50 applications. Apart from reticuloses, which are commonly seen in these animals, the occurrence of other tumours is believed to be related to the TPA treatment. The results are interpreted as showing that TPA, like croton oil, should be regarded as a complete carcinogen.

The effects of weak or non-carcinogenic polycyclic hydrocarbons on 7, 12-dimethylbenz[ a]anthracene and benzo[ a]pyrene skin tumor-initiation

Benzo[e]pyrene (B[e]P) inhibited 7,12-dimethylbenz[a]anthracene (DMBA) skin tumor-initiation in mice by 84%, whereas pyrene and fluoranthene inhibited DMBA initiation by 50 and 34%, respectively. However, B[e]P, pyrene and fluoranthene had either no significant effect or a slight enhancing effect on benzo[a]pyrene (B[a]P) skin tumor-initiation. In addition, B[e]P had essentially no effect on the initiating ability of (+/-)B[a]P-7 beta,8 alpha-diol-9 alpha,10 alpha-epoxide. As a tumor-initiator, B[e]P was found to have very weak activity at a 252 microgram/level (0.4 papillomas/mouse at 40 weeks) and no activity at 100 microgram. When given at a dose of 100 microgram twice weekly, B[e]P induced 2.1 papillomas/mouse at 30 weeks, and 25% of the mice had carcinomas at 40 weeks. However, B[e]P carcinogenic activity is weak when compared to B[a]P, which can induce a comparable tumor response at a dose of 5 microgram twice weekly. When B[e]P was tested as a tumor promoter at a dose of 100 microgram twice weekly after DMBA initiation, it induced 4.5 papillomas/mouse at 30 weeks and a 45% carcinoma incidence at 40 weeks, which was approximately twice as effective as B[e]P alone. The data show that B[e]P is a very weak tumor initiator, a weak complete carcinogen, a moderate tumor promoter, possibly a weak co-tumor-initiator when given with B[a]P, and a potent anit-tumor-initiator when given with DMBA. The anti-tumor initiating and co-tumor-initiating effects of B[e]P appear to be related to its ability to modify the conversion of the tumor initiator into an electrophilic intermediate(s) which are capable of covalently binding to DNA. In addition, B[e]P induced epidermal cellular proliferation which may be related to its promoting ability.

Regenerative proliferation of mouse epidermal cells following application of a carcinogenic skin irritant (MCA). Micro-flow fluorometric DNA measurements and 3H-TdR incorporation studies of isolated basal cells.

0.025 ml of a 1% solution of the complete skin carcinogen 20-methylcholanthrene (MCA) dissolved in benzene was applied to the back skin of hairless mice. At different time intervals up to 3 days after the carcinogen application groups of animals were injected i.p. with 30 muCi 3H-TdR 30 min before they were killed. Single cell suspensions of epidermal basal cells were prepared by a combined enzymatic and mechanical separation method, and the DNA frequency distribution pattern from each cell suspension was measured by means of micro-flow fluorometry. Smears for autoradiography were made from each cell suspension and the labeling index and mean grain count assessed. After a short initial delay, MCA induced an increase in the labeling index similar to that observed after non-specific cell injury and cell loss. Thereafter, the cells were considerably delayed in their progression through the S phase, with a low exit from S resulting in a transient emptying of the G2 compartment, without indications of any significant delay of the passage through G2 phase. The cells that had been injured by the MCA application in or just before S phase proceeded into the G2 phase and mitosis more than 24 h after the initiation of DNA synthesis. The cell kinetic reaction of epidermis to a single application of MCA is thus very different from that caused by a nonspecific cell damage, e.g. application of the vesicant agent cantharidin or removal of surface cells by cellophane tape stripping.

Retinoids block phenotypic cell transformation produced by sarcoma growth factor

MURINE SARCOMA VIRUS (MSV)-transformed cells lack available receptors for epidermal growth factor (EGF)1,2. We have shown that this altered phenotype is the result of the endogenous production of growth factors by the MSV-trans-formed cells themselves. The major activity, isolated and purified from transformed cells, has been found in a 12,000-molecular weight peak and competed with EOF in an EGF-receptor-binding assay3. This growth factor, called sarcoma growth factor (SGF), stimulates cell division, causes normal cells to grow in soft agar and produces rapid, reversible morphological transformation of cells in monolayer culture3. There is no evidence that SGF acts as a complete carcinogen, producing permanent cell transformation; its properties resemble classical chemical promoters of carcinogenesis, like 12-O-tetradecanoylphorbol-13-acetate (TPA)4–6, the highly active component of croton oil. Whereas TPA is an exogenous plant derivative acting on an animal or a cell, SGF is an endogenous, virally induced growth promoter. In this respect it is interesting that retinoids (vitamin A and synthetic analogues)7 block the action in vivo of exogenous and endogenous promoters, preventing carcinogens from producing new tumours, but do not reverse the growth of many established tumours7–10. Retinoids prevent cancer of the lung7,11, skin9, bladder12 and mammary gland13 in experimental animals, block cell transformation induced by chemicals14 and radiation14,15 in culture, and reverse the anchorage-independent growth of transformed mouse fibroblasts16. If SGF is part of the natural tumour-promoting system and retinoids are part of the natural defence against that system, then one should be able to demonstrate a direct antagonism in cell culture. This, report establishes that this happens.

The effect of the co-carcinogen TPA on chemical mutagenesis in bacteria

Environmental carcinogens are physical, chemical, and biological exogenous agents that cause cancer after having penetrated into the organism. Cancer is basically a disease caused by chronic exposure to low-dose carcinogens. Mutagenesis and tumor promotion are rate-limiting steps. Accordingly, carcinogens have been distinguished into mutagens and promoters, albeit complete carcinogens can be both. Oncogenic viruses, radiation, and many xenochemicals are environmental carcinogens acting through specific molecular and cellular pathways. They are, however, also characterized by a set of common general mechanisms including the induction of inflammation, immunosuppression, and hormonal disruption of fetal and neonatal tissues. Molecular mechanisms involve direct DNA alterations leading to mutagenesis and epigenetic alterations through free radical production leading to indirect mutagenesis and tumor promotion. A basic property of chemical environmental carcinogens − for example, polycyclic aromatic hydrocarbons, N-nitroso compounds, aromatic and heterocyclic amines, dioxins, polychlorobiphenyls, and other organochlorines − is their lipophilicity, so they can enter cells, where they can be fully or partially metabolized by the cytochrome P450 system or other enzymes such as peroxidases. These detoxifying enzymes act in addition to phase II conjugating enzymes such as N-acetyl transferases and sulfotransferases. As a result of these metabolic processes, procarcinogens can be either detoxified or activated into reactive carcinogens. It has been shown that adipose tissue can act as a reservoir where environmental carcinogens and procarcinogens can bioaccumulate and from which they can be released in the blood circulation to target peripheral tissues for carcinogenesis. Because they contribute not only to the promoting and cocarcinogenic effects of many environmental pollutants but also to the mutagenic effects of many of them, both the aryl hydrocarbon receptor and the inducible cytochrome P450 systems are central in chemical environmental carcinogenesis. Despite the fact that endogenous carcinogens may contribute to the genesis of a limited number of cancers, hypothesis is that the recently observed growing incidence of cancer could be mostly caused by chemical environmental carcinogens.

Effect of Trichloropropene Oxide on the Ability of Polyaromatic Hydrocarbons and Their “K-Region” Oxides To Initiate Skin Tumors in Mice and To Bind to DNA In Vitro2

The potent epoxide hydrase inhibitor, 1,1,1-trichloro-2,3-propene oxide (TCPO), enhanced the tumor-initiating ability of benzo[alpha]pyrene (BP) and 3-methylcholanthrene (MCA) but had no effect on 9,10-dimethyl-1,2-anthracene (DMBA) initiation in a two-stage system of tumorigenesis in female Charles River CD-1 mice. The tumor-initiating ability of dibenz[alpha,h]-anthracene (DBA) was decreased by prior topical treatment with 10 mumoles of TCPO. The tumor latency period of BP and MCA was decreased by TCPO but had no effect on DMBA or DBA. Topical treatment with 10 mumoles of TCPO did not initiate tumors in a two-stage system in mouse skin nor did it cause any histopathologic changes in the skin. The "K-region" epoxides of BP, DMBA, and MCA were weak tumor initiators when compared to the parent compounds. TCPO only slightly increased or had no effect on the tumor-initiating activity of the above epoxides. Pretreatment with Croton oil 18 hours prior to initiation with BP-4,5-epoxide also slightly enhanced the tumorigenic response in mouse skin. DBA-5,6-epoxide, when tested as a complete carcinogen at high doses (1 mg daily/10 days), was found to be a weak carcinogen but with activity comparable to that of DBA. TCPO only slightly increased the in vitro epidermally mediated covalent binding of the above parent polycyclic hydrocarbons to DNA.

Cocarcinogenic activity of peroxy compounds.

Peracetic acid was a potent tumor promoter and a weak complete carcinogen on the skin of female ICR Swiss mice. "Decomposed peracetic acid" was inactive as a tumor promoter, as were 3% [hydrogen peroxide and 5%] urea peroxide; 1% perbenzoic acid and m-chloroperbenzoic acid were active tumor prototers.

Early Morphologic Alterations in Mouse Skin After Topical Application of 3-Methylcholanthrene and Its Metabolites2

The effects of topical administration of 3-methylcholanthrene (MCA) or its metabolites on BALB/cKi mice were reported on inflammatory skin reactions, the alterations in epidermal thickness, the number of nucleated cells, pyknotic nuclei and/or nuclear fragments, and mitotic figures in the interfollicular epidermis (IFE). In the two-stage carcinogenesis system, MCA, the powerful complete carcinogen, induced an ordered sequence of cell changes strikingly similar to those caused by tumor-promoting agents such as the phorbol esters. These changes were absent after application of the "K-region" oxide of MCA. Other MCA metabolites also failed to induce notable inflammation, epidermal hyperplasia, and/or hypertrophy. Several MCA derivatives, however, caused a thinning of IFE paralleled by an increase in the relative number of pyknotic nuclei and a decrease in the total number of epithelial cells. The inhibitor of polycyclic hydrocarbon metabolism alpha-naphthoflavone did not prevent MCA-mediated skin reactions but, under suitable conditions, apparently potentiated the hyperplastic effects of MCA. The findings indicate that important events in the promotion phase of MCA-mediated skin carcinogenesis might be associated with the parent compound rather than with one of its metabolites.

Carcinogenicity in mice of some fatty acid methyl esters. 1. Skin application.

Two oxygen‐containing derivatives of unsaturated fatty acids, methyl 12‐oxo‐trans‐10 octadecenoate and methyl hydroxyoctadecadienoate, both highly active in the newt test for carcinogenicity, have been tested as complete carcinogens and as promoting agents by application to the skin of ST/a mice. Through observation for two years the tumourigenic effect was recorded and compared with that of methyl oleate and of adequate positive control substances: 7,12‐dimethylbenz[α]anthracene and croton oil. Both methyl oxooctadecenoate and hydroxyoctadecadienoate showed a significant potency to promote the induction of skin papillomas. The genesis of malignant skin tumours was promoted by methyl oleate and oxooctadecenoate, and all the three methyl esters had a weak activity as complete carcinogens to the skin. As a systemic effect all the esters promoted the induction of malignant lymphomas, most markedly methyl oxooctadecenoate. Even without preceding initiation this ester and methyl oleate had some activity in lymphoma cancerogenesis. The various observations show that, when tested by our experimental procedures, methyl oxooctadecenoate is the ester most active in the induction of tumours, and the effect is essentially that of a promoter. The relation between molecular configuration and carcinogenicity of fatty acids is discussed.

Chlorinated dibenzodioxins and dibenzofurans.

Research ArticleOpen AccessChlorinated dibenzodioxins and dibenzofurans.is corrected byErratum J E Huff, and J S Wassom J E Huff Search for more papers by this author and J S Wassom Search for more papers by this author Published:1 September 1973https://doi.org/10.1289/ehp.7305283Cited by:7AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited ByHuff J, Weisburger E and Fung V (2018) Multicomponent criteria for predicting carcinogenicity: dataset of 30 NTP chemicals., Environmental Health Perspectives, 104:suppl 5, (1105-1112), Online publication date: 1-Oct-1996. Huff J (1992) 2,3,7,8-TCDD: A potent & complete carcinogen in experimental animals, Chemosphere, 10.1016/0045-6535(92)90506-M, 25:1-2, (173-176), Online publication date: 1-Jul-1992. Van Den Berg M, Olie K and Hutzinger O (2008) Polychlorinated dibenzofurans (PCDFs), Toxicological & Environmental Chemistry, 10.1080/02772248509357079, 9:3, (171-217), Online publication date: 1-Feb-1985. Veerkamp W, Wever J and Hutzinger O (1981) The metabolism of some chlorinated dibenzofurans by rats, Chemosphere, 10.1016/0045-6535(81)90235-6, 10:4, (397-403), Online publication date: 1-Jan-1981. Huff J, Moore J, Saracci R and Tomatis L (2018) Long-term hazards of polychlorinated dibenzodioxins and polychlorinated dibenzofurans., Environmental Health Perspectives, 36, (221-240), Online publication date: 1-Jun-1980. Wassom J, Huff J and Loprieno N (1977) A review of the genetic toxicology of chlorinated dibenzo-p-dioxins, Mutation Research/Reviews in Genetic Toxicology, 10.1016/0165-1110(77)90001-X, 47:3-4, (141-160), Online publication date: 1-Jan-1977. Madge D (1977) Effects of trichlorophenoxyacetic acid and chlorodioxins on small intestinal function, General Pharmacology: The Vascular System, 10.1016/0306-3623(77)90007-6, 8:5-6, (319-324), Online publication date: 1-Jan-1977. Related articlesErratumDec 1, 1973, 12:00:00 AMEnvironmental Health Perspectives Vol. 5September 1973Metrics About Article Metrics Publication History Originally published1 September 1973Published in print1 September 1973 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact ehponline@niehs.nih.gov. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Composition Studies on Tobacco. XLIV. Tumor-Promoting Activity of Subfractions of the Weak Acid Fraction of Cigarette Smoke Condensate<xref ref-type="fn" rid="FN2">2</xref>

Subfractions of the weak acid fraction of cigarette smoke condensate (CSC) were tested for tumorigenic activity in mice previously painted with 125 μg 7,12-dimethylbenz[a]anthracene (DMBA). In one experiment, the pH of the test solutions ranged from 5.7–6.0. In a second experiment, the pH range was 5.0–5.5. Before fractionation the weak acids were more active in the second experiment with the lower pH. The residue remaining after steam distillation was consistently active. The steam distillates and a synthetic steam distillate gave inconsistent results and probably do not contribute importantly to the carcinogenicity of CSC for mouse skin. In high concentrations, the unfractionated weak acids produced 2 tumors in a group of 50 mice that had not been previously exposed to DMBA. The weak acid fraction is thus a very weak complete carcinogen. Even so, a comparison of the tumor yields produced by DMBA alone, by the weak acids alone, and by combinations of both agents suggests that the weak acids acted as promoting agents. It was concluded that the promoting activity of the weak acid fraction of CSC depended primarily on the nonvolatile constituents and only slightly on volatile phenols and other constituents of the steam distillate.

The mechanism of carcinogenesis by the neutral fraction of cigarette smoke condensate.

Sixteen groups, each of 50 Swiss female SPF mice, were treated thrice weekly with various combinations of 3,4-benzopyrene (BP) and/or the neutral fraction of cigarette smoke (NF) in acetone applied to the skin. Some groups received one carcinogen, some the other and some a mixture of the two. Skin tumour incidence rates were found to increase both with the dose of NF and with the dose of BP. With BP alone a threshold dose was found beyond which a very heavy incidence rate of malignant skin tumours occurred. After correction of the results for intercurrent deaths it was found that when NF and BP are applied together as a mixture they do not act independently in the production of malignant skin tumours but interact positively. This suggests that some of the components of NF act as cocarcinogens rather than as complete carcinogens. Treatment with NF appeared to increase the incidence of malignant lymphomas. The data were not suitable for deciding whether the various treatments influenced the rates of incidence of internal tumours of other types, for example, lung tumours.