Showing papers by "International Agency for Research on Cancer published in 1979"

Mutagenic and alkylating metabolites of halo-ethylenes, chlorobutadienes and dichlorobutenes produced by rodent or human liver tissues. Evidence for oxirane formation by P450-linked microsomal mono-oxygenases.

Abstract: Mutagenicity, expressed as the number of his + revenants per μmole of test compound per hour of exposure, was estimated in two strains of S. typhimurium in the presence of a postmitochondrial mouse-liver supernatant, following exposure to vapours of one of a series of halo-olefins. Their activity was in the following descending order: 3,4-dichlorobutene-1 > 1-chlorobutadiene (technical grade) > 2-chlorobutadiene > vinyl bromide > vinylidene chloride > vinyl chloride; marginal mutagenicity was detected in the presence of 1,1,2-trichloroethylene and 1,1-difluoroethylene, and none with tetrachloroethylene and vinyl acetate. Liver fractions from humans converted vinyl chloride, vinyl bromide, vinylidene chloride and 2-chlorobutadiene into mutagens. In the plate incorporation assay, 1,4-dichlorobutene-2 was mutagenic per se, and addition of microsomal fractions from human or mouse liver enhanced the mutagenicity; a synthetic putative metabolite, 1,4-dichloro-2,3-epoxybutane was less mutagenic than the parent olefin in strain TA100. Treatment of rats with phenobarbital or 3-methylcholanthrene caused an up to 2-fold increase in the liver microsome-mediated mutagenicities of vinyl chloride and vinylidene chloride in S. typhimurium TA1530; while treatment with pregnenolone-16α-carbonitrile, aminoacetonitrile or disulfiram decreased the mutagenic effects. Vinyl chloride, and probably vinyl bromide, were shown to be epoxidized by mouse-liver microsomes; volatile alkylating metabolites were trapped by reaction with excess 4-(4-nitrobenzyl)pyridine and analysed spectrally. 2-Chlorobutadiene also yielded an alkylating intermediate, but 1,1-difluoroethylene, 1,1-dichloroethyleneand 1,1,2-trichloroethylene did not. 2-Chloro- and 1-chlorobutadiene, 3,4-dichlorobutene-1, 1,4-dichlorobutene-2 and its 2,3-epoxy derivative showed alkylating activity with 4-(4-nitrobenzyl)pyridine, which was not related quantitatively to mutagenic activity in S. typhimurium TA100 in the absence of a metabolic activation system. These data support the hypothesis that an oxidation of the double bond in certain halo-olefins, which is dependent on microsomal mono-oxygenases is a common pathway in the formation of biologically reactive intermediates. The relevance of the metabolites formed during such oxidative processes to the mutagenic, toxic and carcinogenic activities in vivo of some of the parent compounds is discussed.

Cancer morbidity and causes of death among danish brewery workers

Abstract: Cancer morbidity and causes of death were examined in a retrospective cohort study of 14,313 male members of the Danish Brewery Workers' Union in order to determine health effects of heavy beer drinking, in particular in the aetiology of colorectal cancer. Brewery workers hold the right to consume 6 bottles (2,100 ml) of light pilsener beer (alcohol content 3.7 g1/00 ml) on the premises of the brewery per working day. The cohort included 1,063 mineral-water factory workers with no free ration of beer. Cancer morbidity and mortality were compared with those of the general population after adjustment for age, sex, area and time trends. Cancer morbidity, 1943–1972, was increased for cancer of the pharynx (RR = 2.09), oesophagus (RR=2.09), liver (RR=1.51) and larynx (RR = 1.98). The risk of these tumours was highest among workers who had had a ration of free beer during 30 or more years of employment. An increased risk of lung cancer (RR-1.16) corresponds with the risk among persons of low socio-economic class. These tumour sites accounted for a 9% excess of all malignant neoplasms among members of the BWU. No increased risk for either cancer of the colon (RR = 1.07) or cancer of the rectum (RR = 1.02) was observed. In contrast to studies on “alcoholics”, only deaths from the above-mentioned cancers, liver cirrhosis (RR=1.77) and motor vehicle accidents (RR = 1.33) were in excess; total mortality was only slightly above expectation (RR = 1.06). The present investigation suggests that the statistical association between beer and colo-rectal cancer is of a non-causal nature. It is concluded that the heavy consumption of “weak” alcoholic beverages may increase the risk of upper aero-digestive tract cancers, and that part of the disease pattern associated with “alcoholism” is unrelated to alcohol consumption.

Oesophageal cancer and alcohol consumption; importance of type of beverage.

Abstract: The role of alcohol consumption in oesophageal cancer in Normandy has been studied by a retrospective study of 312 male cases and 869 controls. The linear relationship between the logarithm of risk and overall daily alcohol consumption was confirmed after adjustment for tobacco. The role of each specific alcoholic beverage was further investigated by computing relative risks for individuals consuming a given beverage and for those drinking other beverages only, within each overall alcohol consumption category. It is concluded: (1) that there is a linear relationship between the logarithm of risk of oesophageal cancer and overall daily ethanol consumption, whatever the beverage; (2) that the effect is more marked for strong beverages (digestives) than for lighter beverages; (3) that there is an additional risk related to apple brandy and cider.

Critical importance of microsome concentration in mutagenesis assay with V79 Chinese hamster cells.

Abstract: For optimum mutagenesis in V79 Chinese hamster cells, the amount of liver postmitochondrial fraction in the assay was found to be of critical importance, depending on the chemicals being tested. Benzo[a]pyrene (BP) required lower (1–5%) concentrations of the liver 15 000 × g supernatant (S15) from methylcholanthrene pretreated rats for a maximum induction of cytotoxicity and mutagenicity, as determined by 8-azaguanine- and ouabain-resistance. A sharp peak of mutagenicity and cytotoxicity was induced by 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (7,8-diol BP) at a concentration of 1% of the S15 fraction. Little or no response was induced by these compounds with the S15 concentrations of more than 10%. Similarly, aflatoxin B1 induced a sharp peak of mutagenicity and cytotoxicity at a concentration of 2% of the liver S15 fraction from Aroclor-pretreated rats. Under the same condition, non-carcinogenic aflatoxin G2 did not induce cytotoxicity and mutagenicity. Analysis of BP metabolites by high-pressure liquid chromatography indicates that with the 30% S15 fraction, more than 80% of BP was metabolized during the first 15 min, while with the 2% S15 fraction, 7,8-diol BP increased continuously throughout the 120-min incubation period, suggesting a strong metabolic competition to rapidly remove BP and 7,8-diol BP with a high concentration of the S15. In contrast with these compounds, N-nitrosodimethylamine induced mutagenicity and cytotoxicity which increased linearly in proportion to the increasing amount of the S15 fraction from phenobarbitone- and Aroclor-pretreated rats. Various nitrosamines with different lipophilicity were examined at a high (30%) and low (2%) concentration of the S15 fraction from Aroclor-pretreated rats, in which ratios of mutation frequencies at 30% and 2% correlated inversely with lipophilicity of the compound. This result suggests that the lipid solubility of test compounds may be one factor which determines the concentration of post-mitochondrial supernatant for optimum mutagenesis.

Formation and Loss of Alkylated Purines from DNA of Hamster Liver after Administration of Dimethylnitrosamine

Abstract: The methylation of hamster liver DNA was studied as a function of dose of dimethylnitrosamine. 7-Methylguanine levels were proportional to a dose over the range of 10 μg/kg to 25 mg/kg when measured 5 to 24 hr after treatment. This product was lost from the DNA at a rate greater than expected from spontaneous depurination at neutral pH, suggesting that enzyme-catalyzed excision takes place. O 6 -Methylguanine levels were not proportional to doses over this range but were much lower than expected (based on 7-methylguanine levels) when measured 5 to 24 hr after doses of dimethylnitrosamine below 0.5 mg/kg. It is suggested that this result may be due to the presence of an enzyme capable of removing O 6 -methylguanine from DNA efficiently, provided the level of methylation was low. The presence of such an enzyme in hamster liver extracts was demonstrated by incubation with methylated DNA. The extracts brought about a significant decrease in the content of O 6 -methylguanine present in acid-precipitable DNA. However, when doses of dimethylnitrosamine above 0.5 mg/kg were used, removal of O 6 -methylguanine occurred much more slowly, and the capacity of hamster liver to carry out removal of O 6 -methylguanine from DNA in vivo was considerably lower than that of rat liver. The possible relevance of these findings to the relative susceptibility of these species to liver cancer induction by single doses of dimethylnitrosamine is discussed.

Mutagenecity of vinyl chloride, vinylidene chloride and chloroprene in V79 Chinese hamster cells

Abstract: The mutagenicity of vinyl chloride, vinylidene chloride (1,1-dichloroethylene) and chloroprene (2-chloro-1,3-butadiene) was tested in V79 Chinese hamster cells in the presence of a 15 000 × g liver supernatant from phenobarbitone-pre-treated rats and mice. Mutations in terms of 8-azaguanine and ouabain resistance were induced in a dose-related fashion by exposure to vapour of vinyl chloride in the presence of liver supernatant from phenobarbitone-pretreated rats. Vapours of vinylidene chloride and chloroprene induced a doserelated toxicity in the presence of liver supernatant from phenobarbitone-pretreated rats, but these two compounds were not mutagenic in V79 Chinese hamster cells under the present assay conditions. The results are discussed with regard to the metabolic activation of the compounds and to the correlation with their carcinogenicity in man and experimental animals.

Some factors determining the concentration of liver proteins for optimal mutagenicity of chemicals in the Salmonella/microsome assay.

Abstract: In plate assays in the presence of S. typhimurium TA100 and various amounts of liver 9000 X g supernatant (S9) from either untreated, phenobarbitone- (PB) or Aroclor-treated rats, the S9 concentration required for optimal mutagenicity of aflatoxin B1 (AFB) depended both on the source of S9 and on the concentration of the test compound. In these assays, the water-soluble procarcinogen, dimethylnitrosamine (DMN) was mutagenic in S. typhimurium TA1530 only in the presence of a 35-fold higher concentration of liver S9 from PB-treated rats than that required for AFB, a lipophilic compound. In liquid assays, a biphasic relationship was observed in the mutagenicities in S. typhimurium TA100 of benzo[a]pyrene (BP) and AFB and the concentration of liver S9. For optimal mutagenesis of BP, the concentration of liver S9 from rats treated with methylcholanthrene (MC) was 4.4% (v/v); for AFB it was 2.2% (v/v) liver S9 from either Aroclor-treated or untreated rats. At higher concentrations of S9 the mutagenicity of BP and of AFB was related inversely to the amount of S9 per assay. The effect of Aroclor treatment on the microsomemediated mutagenicity of AFB was assay-dependent: in the liquid assay, AFB mutagenicity was decreased, whereas in the plate assay it did not change or was increased. As virtually no bacteria-bound microsomes were detected by electron microscopy, after the bacteria had been incubated in a medium containing 1-34% (v/v) MC-treated rat-liver S9, it is concluded that, in mutagenicity assays, mutagenic metabolites generated by microsomal enzymes from certain pro-carcinogens have to diffuse through the assay medium before reaching the bacteria. Thus the mutagenicity of BP was dependent on both the concentration of rat-liver microsomes and that of total cytosolic proteins and other soluble nucleophiles such as glutathione. At a concentration of 4.4% (v/v) liver S9, the mutagenicity of BP was about 3.6 times higher than in assays containing a 4-fold higher concentration of cytosolic fraction. Studies on the glutathione-dependent reduction of BP mutagenicity in plate assays has shown that, in the presence of liver S9 concentrations greater than that required for optimal mutagenicity, the reduction in mutagenicity was related directly to the concentration of liver S9. Thus, in the Salmonella/microsome assay, when the concentration of rat-liver S9 was increased over and above the amount required for the optimal mutagenicity of BP, the mutagenic metabolites of BP were inactivated (by being trapped with cytosolic nucleophiles and/or by enzymic conjugation with glutathione); this effect increased more rapidly than their rate of formation. The concentration of liver S9 for optimal mutagenicity of test compounds requiring activation catalyzed by mono-oxygenases seems, therefore, to be related to the departure from linearity of the relationship between the rate of formation of mutagenic metabolites and the concentration of liver S9.

A comparison of the prognostic value of antibody-dependent lymphocyte cytotoxicity and other ebv antibody assays in Chinese patients with nasopharyngeal carcinoma

Abstract: Antibody titres to EBV-associated antigens in Chinese NPC patients were analysed according to length of survival after diagnosis and to disease stage. Geometric mean titres of ADLC antibody were highest in the long-term survivors, whereas VCA, EA and EBNA antibody titres showed an inverse relationship to survival. High VCA, EA and EBNA titres were less frequent, and high ADLC titres were more frequent in long-term survivors than in intermediate or short-term survivors. The association of geometric mean titres of EBV antibodies with prognosis could not be entirely explained by stage of disease. A functional role for the ADLC antibody is suggested by the association of a high ADLC antibody titre with a good prognosis regardless of stage of disease.

Epstein-Barr virus specific IgA serum antibodies in nasopharyngeal and other respiratory carcinomas.

Abstract: In order to better understand the relationship between IgA and IgG antibodies to Epstein-Barr virus (EBV) in nasopharyngeal carcinoma (NPC), we analyzed 230 NPC sera but also a series of sera from patients with other carcinomas selected for their high EBV/IgG antibody titres. We were surprised to find that 21 out of 46 sera from bronchopulmonary carcinomas (BPC) and 6 out of 7 carcinomas of nasal fossae were IgA anti-VCA positive, and 9 BPC sera and 5 nasal fossae sera were also positive for IgA and anti-EA. Bronchial undifferentiated small-cell carcinomas may represent a particular group associated with high EBV profile.

Limitations and advantages of epidemiological investigations in environmental carcinogenesis

Abstract: Epidemiology is that part of medical science which uses information about the frequency and distribution of diseases to search for determinants.’ The word “determinants” is used advisedly as it embraces not only the underlying cause of the disease but also other factors and circumstances which favor or hinder the action of the agent responsible. Dealing with human experience, epidemiology is axiomatically more apposite to the detection of the environmental causes of cancer than any indirect system (such as bacterial mutation or the experimental animal). Bedevilled by the effect of a long but variable latent period between first exposure and the appearance of a cancer, epidemiological techniques nevertheless identify causes, permit evaluation of interaction and the effect of control measures, and can assist in differentiating between the effects of product variants and in the assessment of the effect of low doses in humans. These techniques cannot predict whether a new exposure is likely to be carcinogenic. This paper sets out the advantages and disadvantages of the epidemiological method and draws attention to the fact that, essential though epidemiological investigations are, there are very few trained chronic disease epidemiologists. Further, the closing door of confidentiality is making a widely used epidemiological technique, the cohort study, impossible or unnecessarily complicated and expensive.

Carcinogen Metabolism with Human and Experimental Animal Tissues: Inter-individual and Species Differences

Abstract: Liver fractions obtained from surgery tissue samples of different human subjects were shown to convert vinyl chloride or related halo-olefins and several N -nitroso derivatives into alkylating and mutagenic intermediates. Although large inter-individual variations were observed, the average activity was in general lower or close to that of mouse or rat liver fractions. However, with N -nitroso- N '-methyl-piperazine, human liver samples were up to 40 times more active than rat liver. When hepatic benzo( a )pyrene (BP)-hydroxylase activity in samples from different human subjects was plotted against the liver microsome-mediated mutagenicity, a statistically significant positive correlation was obtained between the rates of oxidative BP-metabolism and mutagenicity in the presence of N -nitrosomorpholine or vinyl chloride as substrate. Such a correlation may have significance for developing methods to evaluate the drug- and carcinogen-metabolising capacity of different human individuals. Therefore, BP-hydroxylase activity in normal and tumorous lung tissue from 76 patients with lung tumours was measured. A 60-fold inter-individual variation was noted; in most cases the rates of BP-hydroxylation in tumorous lung tissue was lower than in normal tissue of the same patient. When BP-hydroxylase activity in the tumorous tissue (expressed as % activity of the normal tissue of the same patient) was plotted versus the number of cigarettes smoked per day prior to surgery, a negative correlation was apparent. These interim results suggest that differences in carcinogenic metabolism may condition in part the response of human individuals when exposed to the same level of environmental carcinogens.

Present and Future Developments in Environmental Carcinogenesis

Abstract: The background to recent developments in environmental carcinogenesis and geographical pathology are summarized as providing an introduction to the requirements of modern societies, including the important pioneering role played by the Union Internationale Contre le Cancer in its formative years. Data from a variety of sources including studies on high risk groups, geographical variations in incidence, as well as changes in cancer patterns, especially in migrants, have increasingly confirmed the important role - whether direct or indirect - played by environmental factors in many human cancers. In certain societies, the environmental stimuli causing between 30% to 50% of human cancers have been identified, of which cancers due to the cultural environment form by far the largest group. These include mouth, oesophagus, lung, liver and skin. The importance of cancers related to occupational and iatrogenic stimuli are discussed not only in terms of aetiology, but also in relation to conceptual preventative approaches. The possible role of environmental and other agents in cancers of unknown origin are reviewed, and the concept of “lifestyle” discussed. The implications of recent observations in terms of primary cancer prevention and future research are examined in relation to the necessity to distinguish between hazards to which man has already been exposed, and exposure to new potential hazards. The value of an approach integrating laboratory and epidemiological techniques is emphasized, including “metabolic epidemiology” and better extrapolation, both qualitative and quantitative.

Tissue Specificity in Metabolic Activation

Abstract: Organ specificity of certain carcinogenic chemicals can be determined by the half-lives of ultimate carcinogens which may act to prevent their distribution in the body by covalent reactions, in organs (cells) in which they are generated. Evidence is summarized for several systemically acting carcinogenic N -nitrosamines, N -(α-acyloxy)alkyl- N -alkylnitrosamines and 3,3-dimethyl-1-phenyltriazene; an alternative model of organ specificity involving the formation of a transportable alkylating species is discussed. In human liver specimens, large inter-individual differences in the activity of carcinogen-activating enzymes were noted. Benzo[α]pyrene-hydroxylase (AHH)-activity and microsome-mediated mutagenicity was measured using the hepato-carcinogens, N -nitrosomorpholine, N -nitroso-N'-methylpiperazine and vinyl chloride as substrates. When AHH-activity in liver specimens from human subjects was plotted against the respective microsome-mediated mutagenicity in S. typhimurium , a positive correlation was obtained for the rate of oxidative benzo[α]pyrene metabolism and mutagenicity in the presence of N -nitrosomorpholine, N -nitroso-N'-methylpiperazine or vinyl chloride. Thus, differences in tissue-specific activation processes of chemical carcinogens a) appear to be contributing factors in the production of tumours in certain organs only and b) may also condition the carcinogenic response in human individuals when exposed to the same level of environemental carcinogens.

Triplex gene dosage effect of TPI and G3PD in a human lymphoblastoid cell line with partial trisomy 12p13 and 18p

Abstract: The EBV-induced lymphoblastoid line established from a patient carrying a duplication of the distal part of chromosome 12 short arm (12p13) retained the original partial trisomy and displayed the same triplex gene dosage effect for TPI and G3PD as found in the patient's RBC and WBC.

Further studies of antibody levels to herpes simplex virus, cytomegalovirus, measles virus, and adenovirus type 5 in Burkitt's lymphoma patients.

Abstract: Sera collected from Burkitt's lymphoma (BL) patients before and after tumor manifestation were tested for antibodies to herpes simplex virus (HSV), cytomegalovirus (CMV), measles virus (MV) and adenovirus type 5,using the immunofluorescent (IF) techniques in all instances except for MV where complement fixation (CF) was used. It was found that none of these viruses showed higher antibody levels in BL patients than in controls, either before or after the appearance of the tumor. The patients came from the West Nile District of Uganda.

On-going Research and Needs in Cancer Epidemiology — a World-wide Survey

Abstract: The 908 epidemiological studies undertaken in 70 countries and reported in 1977 to the Clearing-House of On-going Research in Cancer Epidemiology, operated jointly by the International Agency for Research on Cancer and the Deutsches Krebsforschungszentrum, have been analysed Descriptive epidemiology is undertaken in a fairly wide range of countries Analytical studies are much more frequent in North America, the nordic countries and in the United Kingdom where there are a considerable number of investigations under way in industrial and non-industrial high-risk groups as well as case-control studies Studies on breast and respiratory tract cancer are frequent but common sites like pancreas, malignant melanoma and prostate are currently largely ignored The investment in epidemiological effort is trivial in relation to study opportunities and needs The major impediments to epidemiological cancer research comprise: 1) an absence of trained investigators due to failure to teach chronic disease epidemiology at graduate and undergraduate level, and to create a career structure; 2) differing concepts of epidemiology; 3) secrecy of death certificates in certain countries, and other barriers preventing linkage of exposed persons and their subsequent disease experience