Biomedical subjects
Publications and source records attributed to L Tomatis.
The incorporation of bromodeoxyuridine (BUdR) into newborn rat tissue DNA has been determined after i.p. injection of 5-bromo-2'-deoxy-[6-3H]uridine. Incorporation of the unchanged nucleoside was shown by hydrolysis and ion exchange chromatography of extracted DNA. In all tissues examined, more than 90% of the radioactivity incorporated was in the form of bromodeoxyuridine.
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Vinylidene chloride (VDC) monomer dissolved in olive oil was given orally to female BD IV rats (150 mg/kg body weight) on the 17th day of gestation. Their offspring were treated weekly with 50 mg/kg body weight VDC by stomach tube from the time of weaning for life span. Liver and meningeal tumours were more frequently observed in treated than in untreated animals, but the total number of tumour-bearing animals was not significantly different between treated and untreated animals. Chloroprene (CP) monomer dissolved in olive oil was given orally to female BD IV rats (100 mg/kg body weight) on the 17th day of gestation and their offspring were treated weekly with 50 mg/kg body weight by stomach tube from the time of weaning for life span. Total incidence of tumours was similar in treated and untreated animals. The data presented provide limited evidence of the carcinogenicity of VDC and no evidence of the carcinogenicity of CP when given by the oral route to rats.
During January 10-11, 1978 in Lyon, France, a joint National Institute of Environmental Health Sciences/International Agency for Research on Cancer ad hoc Working Group considered and discussed the feasibility of coordinating epidemiological studies on the long-term hazards associated with the chlorinated dibenzo-p-dioxins and chlorinated dibenzofurans (PCDDs and and PCDFs). Nineteen invited scientists from eight countries presented introductory working papers summarizing the most up-to-date and relevant information available from their individual programs. This report represents the collective views and scientific opinions of the Working Group. The greater part of this document comprises epidemiological studies related to episodes of human exposures. The review begins with a brief section concerning possible routes of human exposure, an overview of the pertinent chemical characteristics, and the salient toxicological properties of the structurally similar PCDDs/PCDFs. The Working Group report ends with recommendations for future activities.
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An international ad hoc Working Group of experts in cancer research met at the International Agency for Research on Cancer (IARC) in January 1979 to evaluate the data on human and experimental animal carcinogenicity for 54 chemicals, groups of chemicals, and industrial processes. Monographs for these chemicals were published in Vols. 1 to 20 of the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Based on evidence from human studies, 18 of the 54 chemicals or industrial processes are human carcinogens. A further 18 chemicals are probably carcinogenic for humans, although the data were considered not adequate to establish a causal association. To reflect differing degrees of evidence of carcinogenicity within this group, the chemicals were further subdivided, with 6 chemicals exhibiting a high degree of evidence and 12 chemicals exhibiting a lower degree. Data on the remaining 18 chemicals were considered insufficient to allow any evaluation of carcinogenicity. The report summarizes the background, purpose, and overall conclusions of the Working Group. The evidence supporting the evaluations is given in the "Appendix."
Repeated s.c. administration of chloroethylene oxide, a reactive metabolite of the carcinogen vinyl chloride, induced local tumors in mice, with an incidence comparable to that of bis(chloromethyl)ether, a structurally related human and animal carcinogen, when both compounds were applied at maximum tolerated chronically toxic doses; no tumors distant from the injection site were produced. Bis(chloromethyl)ether, chloroethylene oxide, and its rearrangement product chloroacetaldehyde, a highly toxic compound, were further tested in an initiation-promotion experiment. Application to the skin of a single dose of either bis(chloromethyl)ether or chloroethylene oxide, followed by 3-times-weekly applications of 12-O-n-tetradecanoylphorbol-13-acetate for 42 weeks, produced skin tumors in mice; chloroacetaldehyde under comparable conditions produced no increase in benign or malignant tumors. A good correlation between the chemical reactivity, on the basis of hydrolysis constants in aqueous media, and the carcinogenicity of the three compounds was noted. Our results support the hypothesis that epoxidation of the thylenic double bond in vinyl chloride yields an ultimate carcinogenic metabolite, chloroethylene oxide, a highly reactive compound which appears also to be largely responsible for the known genetic changes caused by the parent compound.
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Using a novel in vitro technique, whereby microsomal enzymes were embedded in an agar layer to prolong their viability, 1,1-bis(p-chlorophenyl) ethylene(DDNU), a mammalian metabolite of 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), was converted by microsomal mono-oxygenases of mouse liver into 1,1-bis(p-chlorophenyl)-1,2-ethanediol (DDNU-diol). The putative epoxide intermediate, 1,1-bis(p-chlorophenyl)ethylene oxide (DDNU-oxide), a new compound, was synthesized; it showed weak alkylating activity with 4-(4-nitrobenzyl)pyridine but was not mutagenic in Salmonella typhimurium strains TA100 and TA98. DDT and 13 of its metabolites or putative synthetic derivatives, including 1,1-bis(p-chlorophenyl)-2,2-dichloroethylene (DDE), 1 1,1-bis(p-chlorophenyl)-2-chloroethylene (DDMU), 1,1-bis(p-chlorophenyl)-2-chloroethane (DDMS)-DDNU, 2,2-bis(p-chlorophenyl)ethanol (DDOH), bis(p-chlorophenyl)acetic acid (DDA) and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethanol (Kethane), caused no mutagenic effects in S. typhimurium strains TA100 or TA98, either in the presence or absence of a mouse-liver microsomal fraction. 1,1-Bis(p-chlorophenyl)-2,2,2-trichloroethyl acetate (Kelthane acetate) was a direct-acting mutagen in strain TA100, whereas 1,1-bis(p-chlorophenyl)-2,2-dichloroethane (DDD) was mutagenic in TA98, only in the presence of a mouse-liver microsomal system. The results are discussed in relation to possible pathways whereby DDT is activated to mutagenic and/or carcinogenic metabolites.
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An international ad hoc Working Group of experts in cancer research met at the International Agency for Research on Cancer (IARC) in January 1979 to evaluate the data on human and experimental animal carcinogenicity for 54 chemicals, groups of chemicals, and industrial processes. Monographs for these chemicals were published in Volumes 1-20 of the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. On the basis of evidence from human studies, 18 of the 54 chemicals and industrial processes are human carcinogens. A further 18 chemicals are probably carcinogenic for humans, although the data were considered not adequate to establish a causal association. To reflect differing degrees of evidence of carcinogenicity within this group, it was further subdivided; for six chemicals there was a high degree of evidence, and for 12 there was a lower degree. Data on the remaining 18 chemicals were considered insufficient to allow any evaluation of carcinogenicity. The report summarizes the background, purpose, and overall conclusions of the Working Group. The evidence supporting the evaluations is given in the Appendix. This volume includes a cumulative index of chemicals for Volumes 1-20 of the IARC Monographs, as well as an index by possible target organ in humans. A condensed version of this report will appear in the December 1979 issue of Cancer Research.
That exposure of pregnant animals to chemical carcinogens results in the occurrence of tumors in the progeny is well documented. Evidence has been accumulated on at least 38 chemicals pertaining to different chemical groups. The experimental evidence was followed by observations in humans regarding the increased risk of cancer in daughters of women who received stilbestrol during pregnancy. Additional experimental evidence is accumulating on the possibility that exposure during pregnancy results in an increased incidence of tumors for more than one generation of untreated descendants. Studies done on mice with DMBA and on rats with MNU and ENU showed that exposure to the carcinogens during pregnancy resulted in a high incidence of tumors in animals of the first generation and in an increased incidence of tumors at specific sites in untreated animals of the second and third generations.
In 1971 the International Agency for Research on Cancer initiated a program on the evaluation of the carcinogenic risk of chemicals to humans, which concentrated on the production of monographs on individual chemicals. A review of this ongoing program is presented here as a contribution to the discussion of primary prevention of cancer. A total of 368 chemicals were evaluated in the first 16 volumes of the International Agency for Research on Cancer monographs. For 26 chemicals (or industrial processes), a positive association between exposure and the occurrence of cancer in humans was observed. For 221 chemicals, some evidence of carcinogenicity was found in at least one species of experimental animals. However, no evaluation of the carcinogenic risk of these chemicals to humans was made, either because no epidemiological studies or case reports were available or because the results of available human studies were inconclusive. For the remaining 121 chemicals, the available data were inadequate for an evaluation of the presence or absence of a carcinogenic effect in experimental animals or humans. The criteria on which the carcinogenicity of chemicals to humans and/or experimental animals was assessed, from the initiation of this program in 1971 until 1977, have recently been revised and are briefly discussed.
Styrene monomer dissolved in olive oil was given orally to female O20 mice (1,350 mg/kg), C57 Bl mice (300 mg/kg) and BD IV rats (1,350 mg/kg) on the 17th day of gestation. Their offspring were treated weekly with styrene by stomach tube from the time of weaning throughout their life-span. The weekly doses used were 1,350 mg/kg for O20 mice, 300 mg/kg for C57 Bl mice, and 500 mg/kg for BD IV rats. Following the continuous oral administration of styrene for over 100 weeks, an increased and earlier appearance of lung tumors was observed in O20 mice. A few tumors rarely seen in controls were observed in BD IV styrene-treated rats, and a slightly increased incidence of liver tumors was found in C57 Bl mice. In both cases, however, the total incidence of tumors was not significantly different from that of the controls. The present results provide weak evidence of the carcinogenicity of styrene in one of the two strains of mice tested, when it is given at a high dose level.
A single dose of 40 mg/kg of N-nitrosoethylurea (ENU) was administered to BDVI rats on the 16th day of pregnancy. The first generation descendants (F1) were mated on a brother-to-sister system to produce a second generation (F2) which was then mated to produce a third generation. A high incidence of nervous tissue tumors and a few kidney tumours were observed in F1 descendants. A few nervous tissue tumours were observed in F3 but not in F2 descendants. These results partially confirm previous observations obtained with 7,12-dimethylbenz(a)anthracene in mice and nitrosomethylurea in rats and indicate that prenatal exposure to a chemical carcinogen may result in an increased cancer risk which can persist for more than one generation.
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A survey was carried out on legislation in 14 industrialized countries relating to the prevention of occupational cancers. Two types of legislation were considered in particular: that dealing specifically with chemical carcinogens in the working environment, and that relating to compensation for occupational cancers. The survey revealed that legislation prohibiting the manufacture of chemicals known to be carcinogenic in humans or known to represent a possible cancer hazard to humans exists only in a limited number of the 14 countries considered and does not cover the same chemicals in each country. Legislation concerning monetary compensation is more common in these countreis than is legislation providing for primary prevention. There are two fundamental deficiencies in even the more comprehensive legislation. First, some chemicals for which carcinogenicity in humans has been proved are still produced in large quantities and are not covered by legislation. Second, the criteria used to determine which chemicals may be hazardous to humans when only experimental evidence of carcinogenicity exists are overexclusive, while the allowed concentrations of some of the chemicals recognized as possibly hazardous to humans appear to be very high.