The contribution of the International Agency for Research on Cancer to the prevention of cancer.
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Carcinogens, Environmental↗
Biomedical subjects
L Tomatis
Publications and source records attributed to L Tomatis.
Diet, nutrition and cancer: concluding remarks and future perspectives.
Several dietary exposures may increase the risk of cancer, while others may have a protective effect. The degrees of evidence for a casual relationship between these exposures and human cancer vary considerably, as do their suitability for prevention. Investigations on the mechanisms by which food components contribute to either increase or decrease cancer risks therefore deserve priority, as their results would allow a quantitative evaluation of risks and of their preventability. Dietary factors are likely to contribute directly or indirectly to the induction of cancer in a variety of organs--namely, oesophagus, stomach, colon and rectum, liver, breast and endometrium, as well as the oral cavity and larynx. In addition, certain dietary factors may contribute to the prevention of cancer at other sites, as, for instance, the lung and prostate. Dietary interventions may therefore have a very considerable impact on prevention. This is certainly not the least reason for the attraction that intervention studies exert on scientists. Attractive as they may be, however, they should not encourage short-cuts, in the belief that understanding of the means for the prevention of cancer might be easier than understanding of the mechanisms of its induction. This very timely symposium has exposed the controversies that still exist about certain basic assumptions on the role of dietary factors in human cancer, and has underlined the importance of a multidisciplinary approach to understanding of the underlying mechanisms.
Diet↗
Workshop on ataxia-telangiectasia heterozygotes and cancer.
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Ataxia Telangiectasia↗
Exposures associated with cancer in humans.
The IARC programme on the evaluation of the risk of chemicals to humans was initiated in the late 1960s in response to the request made to the Agency for information on environmental carcinogens. The programme, which has been implemented with the advice and the collaboration of a large number of international experts, is focused on the production of monographs on individual chemicals, groups of chemicals or complex exposures. The programme will shortly include also the evaluation of risks related to some of the most widely spread cultural habits. It has been, and still is, the policy of the programme to consider only published information in relation to biological data relevant to the evaluation of carcinogenic risks. One of the main limitations with regard to the possibility of accurately evaluating cancer risks was shown to be the shortage of information on the level of exposure to carcinogenic risk factors. To overcome such limitations it would appear that a close and continuous collaboration between experimentalists and epidemiologists be maintained.
Carcinogens, Environmental↗
Incorporation and persistence of 5-bromodeoxyuridine in newborn rat tissue DNA.
One-day-old BDVI rats were given a mixture 5-[3H]bromodeoxyuridine (BrUdR) and [14C]thymidine (each at 20 mg/kg; 12.8 and 3.53 mCi/mmol, respectively) by intraperitoneal injection. DNA was isolated by a phenol procedure from various pooled tissues up to 21 days later and the levels of BrUdR and thymidine incorporation were determined after formic acid hydrolysis and Dowex-50 chromatography. Incorporation increased to a maximum at 12 h then decreased, the decrease of both products occurring in parallel in all tissues examined but differing in kinetics from tissue to tissue. After 12 h, the relative amounts of 3H and 14C showed no consistent or marked decreases and this suggests that BrUdR is not actively removed from DNA by a repair process under these experimental conditions. This was also the case after a much lower dose of these agents (9 micrograms/kg [3H]BrUdR 22.6 Ci/mmol; 1.3 mg/kg [14C]thymidine 53 mCi/mmol) when the 3H/14C ratios in DNA from various tissues were increased relative to the higher dose and showed only slight differences between 15 h and 21 days after administration.
Aging↗
Persistence of methylated purines in the DNA of various rat fetal and maternal tissues and carcinogenesis in the offspring following a single transplacental dose of N-methyl-N-nitrosourea.
Formation and loss of methylated purines in DNA of various fetal and maternal tissues were measured up to 7 days following intravenous administration of N-[14C]methyl-N-nitrosourea to rats on the 21st day of gestation. Methylation products were detected in all tissues examined, the level in maternal liver being higher than in other tissues. The concentrations of 7-methylguanine and 3-methyladenine decreased faster in fetal than in corresponding maternal tissues, due to a higher rate of DNA synthesis in fetal tissues, as determined by incorporation of labelled thymidine. Removal of the promutagenic DNA lesion O6-methylguanine was most efficient in maternal and fetal liver; but it was very poorly repaired in kidney and brain. The persistence of O6-methylguanine relative to 7-methylguanine was highest in the DNA of fetal brain. The principal targets for the transplacental carcinogenic effect of N-methyl-N-nitrosourea under these experimental conditions were fetal neurogenic tissue and kidney; and malignant tumors developed at these sites in 31-34% and 15-16% of male and female descendants, respectively. These results support the concept that a complex interaction between DNA alkylation, repair and replication is the molecular basis of initiation of carcinogenesis by alkylating agents.
Adenine↗
Quantitative comparison of carcinogenicity, mutagenicity and electrophilicity of 10 direct-acting alkylating agents and of the initial O6:7-alkylguanine ratio in DNA with carcinogenic potency in rodents.
The quantitative relationship between carcinogenicity in rodents and mutagenicity in Salmonella typhimurium was examined, by using 10 monofunctional alkylating agents, including N-nitrosamides, alkyl methanesulfonates, epoxides, beta-propiolactone and 1,3-propane sultone. The compounds were assayed for mutagenicity in two S. typhimurium strains (TA1535 and TA100) and in plate and liquid assays. The mutagenic activity of the agents was compared with their alkylating activity towards 4-(4'-nitrobenzyl)pyridine and with their half-lives (solvolysis constants) in an aqueous medium. No correlations between these variables were found, nor was mutagenic activity correlated with estimates of carcinogenicity in rodents. There was a positive relationship between carcinogenicity and the initial ratios of 7-:O6-alkylguanine formed or expected after their reaction with double-stranded DNA in vitro. The results suggest that alkylation of guanine at position O6 (or at other O atoms of DNA bases) may be a critical DNA-base modification that determines the overall carcinogenicity of these alkylating agents in rodents.
Alkylating Agents↗
Combined effects of fast-neutron irradiation and subcutaneously applied carbon tetrachloride or chloroform in C57Bl6 mice.
Male and female C57Bl6 mice received a single whole-body dose of irradiation with 170 rad or 330 rad of fast neutrons. Nine weeks later they were given a single subcutaneous injection of carbon tetrachloride or chloroform. Chloroform did not influence the occurrence of tumours, but carbon tetrachloride markedly increased the incidence of radiation-induced liver carcinomas.
Animals↗
Comparison between carcinogenicity and mutagenicity based on chemicals evaluated in the IARC monographs.
The qualitative relationship between carcinogenicity and mutagenicity (DNA-damaging activity), based on chemicals which are known to be or suspected of being carcinogenic to man and/or to experimental animals, is analyzed using 532 chemicals evaluated in Volumes 1-25 of the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. About 40 compounds (industrial processes) were found to be either definitely or probably carcinogenic to man, and 130 chemicals have been adequately tested in rodents and most of them also in various short-term assays. For a comparison between the carcinogenicity of a chemical and its behavior in short-term tests, systems were selected that have a value for predicting carcinogenicity. These were divided into mutagenicity in (A) the S. typhimurium/microsome assay, (B) other submammalian systems and (C) cultured mammalian cells; (D) chromosomal abnormalities in mammalian cells; (E) DNA damage and repair; (F) cell transformation (or altered growth properties) in vitro. The following conclusions can be drawn. In the absence of studies in man, long-term animal tests are still today the only ones capable of providing evidence of the carcinogenic effect of a chemical. The development and application of an appropriate combination of short-term tests (despite current limitations) can significantly contribute to the prediction/confirmation of the carcinogenic effects of chemicals in animals/man. Confidence in positive tests results is increased when they are confirmed in multiple short-term tests using nonrepetitive end points and different activation systems. Assays to detect carcinogens which do not act via electrophiles (promoters) need to be developed. The results of a given short-term test should be interpreted in the context of other toxicological data. Increasing demand for quantitative carcinogenicity data requires further examination of whether or not there is a quantitative relationship between the potency of a carcinogen in experimental animals/man, and its genotoxic activity in short-term tests. At present, such a relationship is not sufficiently established for it to be used for the prediction of the carcinogenic potency of new compounds.
Animals↗
Mutagenicity and carcinogenicity of environmental chemicals.
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Animals↗
Cell shape and organization of cytoskeleton and surface fibronectin in non-tumorigenic and tumorigenic rat liver cultures.
Morphological changes associated with neoplastic transformation of epithelial cells were studied in a series of IAR cell lines derived from rat liver. The series included three independently obtained, non-tumorigenic lines and five derived, tumorigenic lines. The morphology of cell surfaces was observed by scanning electron microscopy; the distribution of actin, tubulin and fibronectin was determined by indirect immunofluorescence. All the non-tumorigenic lines had a typical epithelioid morphology: isolated cells of these lines spread on the substratum had a discoid shape and contained circular, marginal bundles of microfilaments and microtubules. In denser areas, the cells formed monolayered sheets with characteristic marginal bundles of microfilaments near the free edges. Decreased spreading of isolated cells on the substratum was the characteristic feature that distinguished tumorigenic lines from their non-tumorigenic parent lines. In particular a decrease in the size of the ring-like, peripheral lamella and its disintegration into several discrete lamellar zones were often observed; as a result, the cell shape was altered from discoid to polygonal or elongated. The altered distribution of microfilament bundles and microtubules was characteristic in elongated cells; the pattern of the cytoskeletal elements of these cells resembled that of polarized fibroblasts. Complete disappearance of microfilament bundles was observed in cells of only one tumorigenic line. Various degrees of disorganization of monolayered cell sheets were observed in tumorigenic cultures, accompanied by an altered distribution of microfilament bundles. The alterations in the fibronectin-containing structures were more complex: there were often fewer fibronectin "spots' and fibrils at the lower surfaces of cells of tumorigenic cultures as compared with those of non-tumorigenic ones; there were more fibrils in dense cultures of certain lines but fewer in others. It is concluded that alterations in the ability to spread on the substratum and to form cell-cell contacts are common features of morphologically transformed fibroblastic and epithelial cultures. However, the actual changes in the cytoskeletal structures that accompany these alterations are different in transformed cultures of various tissue types.
Animals↗
Quantitative comparisons between carcinogenicity, mutagenicity and electrophilicity of direct-acting N-nitroso compounds and other alkylating agents.
The quantitative relationship between carcinogenicity in rodents and mutagenicity in S. typhimurium was examined using 10 monofunctional alkylating agents, including N-nitrosamides, alkylmethane sulfonates and epoxides. The compounds were assayed for mutagenicity in two S. typhimurium strains (TA1535, TA100) and in plate and liquid assays. Mutagenic activity was compared with alkylating activity, half-life (solvolysis constant) and carcinogenic activity in rodents (TD50). No correlations between these variables were found. However, there was a good positive relationship between the TD50 values of the carcinogens and the initial ratios of N-7-alkylguanine to 0(6)-alkylguanine formed after reaction with double-stranded DNA in vitro (r = 0.88, p less than 0.01; n = 9). From these results, it is concluded that the N-7/0(6)-alkylguanine ratio is quantitatively related to the carcinogenic activity for this class of compounds and it may therefore be used to predict the carcinogenic potency of new compounds within this class.
Alkylating Agents↗
Increased cancer incidence in the progeny of male rats exposed to ethylnitrosourea before mating.
Results from previous experiments have indicated tha persistence of an increased cancer risk in subsequent generations following prenatal exposure to a chemical carcinogen. In the present experiment, the possible role of prezygotic events in determined cancer risk was investigated in the progeny of male rats treated with ethylnitrosourea (ENU) before mating with untreated females. Eight BDVI male rats were given a single i.p. dose of 80 mg/kg bw ENU and each rat was then caged at weeks 1, 2, 3 and 4 after treatment with three untreated females. Fertility was lower and preweaning mortality higher in the experimental group, as compared to controls, particularly at the 4th-week mating. Survival rates after weaning were similar in the progeny of treated males and controls, as was the total incidence of tumours. However, analysis of tumour incidence at the various organ sites showed an increased incidence of neurogenic tumours in the progeny of ENU-treated males, as compared to that of controls.
Animals↗
Massive arterial air embolism due to rupture of pulsatile assist device: successful treatment in the hyperbaric chamber.
We present the case of a patient who had rupture of a pulsatile assist device (PAD) accompanied by massive air embolism, and the treatment that brought it to a successful outcome. After rupture of the skin of the PAD balloon, a massive amount of air was injected into the ascending aorta. The patient was placed in Trendelenburg position and cooled in deep hypothermia with cardiopulmonary bypass. He was given 1 gm of methylprednisolone intravenously, and the aortic valve replacement and double vein bypass graft were performed. After completion of the operation, the patient was partially rewarmed to 30 degrees C central temperature and transported by ambulance to a hyperbaric chamber where he was compressed to 6 atmospheres absolute 9 hours after the accident with clinical signs of severe brain dysfunction. The patient recovered completely and was discharged from the hospital on the tenth postoperative day.
Assisted Circulation↗
Mutagenicity of extracts of pickled vegetables collected in Linhsien County, a high-incidence area for esophageal cancer in Northern China.
Extracts of pickled vegetables commonly consumed in Linhsien County, a high-incidence area for esophageal cancer in Northern China, were studied for mutagenicity. The liquid residue from ethereal extracts produced a dose-dependent increase of mutants in Salmonella typhimurium TA98 and TA100 strains; mutagenicity required the presence of a fortified liver microsomal activation system induced by Aroclor 1254 in adult male BD VI inbred rats. An amount of extract equivalent to 2.8 g fresh pickled vegetables produced sixfold (75 revertants/g) and twofold (45 revertants/g) increases in revertant frequencies in strains TA98 and TA100, respectively. Roussin's red methyl ester, a tetranitroso compound, [(NO)2Fe(CH3S)]2, not previously reported to occur in nature, was isolated and identified from the ethereal extracts. The synthetic compound was mutagenic in strain TA100 in the presence of a liver activation system, producing 25 revertants/mumol. Findings on the presence of mutagenic compounds in pickled vegetables were discussed in relation to their possible etiologic role in cancer of the esophagus in Linhsien County.
China↗
An evaluation of the genetic toxicity of epichlorohydrin. A report of an expert group of the International Commission for Protection against Environmental Mutagens and Carcinogens.
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Animals↗
Carcinogenicity of dapsone of mice and rats.
Dapsone (4,4'-diamino-diphenyl sulfone) has been tested for possible carcinogenicity in long-term animal experiments. BDIV rats and C₇ Bl mice received a 3.5% aqueous suspension of dapsone by intragastric intubation. Treatment was started in pregnant females during the last part of pregnancy, continued during lactation, then given to the offspring after weaning, five times a week for 104 weeks. The dose administered was 100 mg/kg to both rats and mice; total doses ranged from 10-16 g per rat and 1.2-1.4 g per mouse. Separate groups of animals received a combined treatment of dapsone with urethane or benzo (alpha) pyrene, to investigate the possible additive or synergistic action of dapsone with known carcinogens, as well as the possible inhibiting effect of dapsone on carcinogenesis. Unusual tumors, viz. spleen sarcomas (related to severe fibrosis of the spleen) were detected in male rats, and higher morbidity from C-cell thyroid carcinomas was observed in treated rats of both sexes than in control rats. There was no evidence that dapsone can modify the action of other chemical carcinogens. It was noted that: (1) although the increase in the incidence of tumours in dapsone-treated animals over that observed in untreated controls is statistically significant, the increase is relatively low; (2) the tumours appeared after lifetime treatment with maximum tolerated doses; (3) in rats, spleen sarcomas were observed mostly in males; this may indicate a possible hormone-dependence of the observed carcinogenic effect. The present results therefore provide only limited evidence of carcinogenicity of dapsone in rats.
Animals↗