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Ethylene metabolism and carcinogenicity
70
Information section Fd Chem. Toxic. Vol. 24, No. 1 ETHYLENE METABOLISM AND CARCINOGENICITY
Ethylene has traditionally been regarded as a simple asphyxiant, for which no TLV is necessary to control industrial exposure. This classification was supported by the preliminary results of a CIIT 2-yr rat study, in which no toxic or carcinogenic effects were found after inhalation of 300, 1000 or 3000 ppm. However, there have been indications that certain species, notably mice, may metabolize ethylene to the carcinogenic and mutagenic ethylene oxide (EO). CIIT scientists published a summary of the final ethylene bioassay results last year, concluding that there was "no evidence that ethylene at these concentrations causes chronic toxicity or is oncogenic in Fischer-344 rats" (Hamm et al. Fund. appl. Toxic. 1984, 4, 473). According to the 'executive summary' of the full report (published separately), unusual malignant lung tumours were found in two rats exposed to 1000 ppm and one exposed to 3000 ppm, but their low incidence and the lack of other related changes in the bronchial epithelium suggested they may have occurred spontaneously. The incidence of mononuclear cell leukaemia is not discussed in this summary, but the full report (available only on microfiche) indicates that it was somewhat increased in both sexes at the top dose level. The number of animals affected (out of 90) rose from 12 and 8 in male and female controls to 21 and 11, respectively, at 3000 ppm. The total number of organs or tissues affected rose to 106 in males and 83 in females from only 62 and 26, respectively, in controls Whether it increased at lower doses too is uncertain, since only limited histological examination of the lower dose groups was conducted. In view of the ability of EO to induce this form of cancer ( N I O S H Current Intelligence Bulletin 1981, no. 5, 22 May) it is strange that the incidence of leukaemias is not discussed in the report's executive summary or by Hamm et al. Although one of the CIIT scientists, Derek Guest, was unable to detect any conversion of ethylene to EO in an in vitro preparation of rat-liver microsomes (Hamm et al. loc. cit.), two other metabolic studies indicate that rats and mice can indeed metabolize ethylene to EO and that both chemicals can lead to the alkylation of proteins and DNA. In a German study, the monooxygenase enzyme system was shown to be responsible for the conversion in rats of inhaled ethylene to exhaled EO (Filser & Bolt, Mutation Res. 1983, 120, 57). The other study, carried out by Dan
Segerb~ick of Stockholm University, showed that ethylene and EO produced the same pattern of alkylations among amino acids in haemoglobin from mice exposed to the radiolabelled compounds, and that both chemicals alkylated DNA from the liver, spleen and testes (the only organs examined). The alkylation products were always the 2-hydroxyethyl derivative of an amino acid of DNA base. Furthermore, for both chemicals the ratio between the degree of alkylation of DNA in any of the three organs and the degree of haemoglobin alkylation was always approximately the same (Chemico-Biol. Interactions 1983, 45, 139). Segerb~ick concludes that measurement of the degree of alkylation of haemoglobin in red blood cells (a method that could be used in animal studies or for human monitoring) would give "a good estimate of the DNA dose". Two of his colleagues at the University of Stockholm, Siv Osterman-Golkar and Lars Ehrenberg, have suggested that measurement of haemoglobin alkylation would be a more sensitive indicator of the genotoxic potential of EO (and therefore ethylene) than would animal studies such as the CIIT study (Drug. Metab. Rev. 1982, 13, 647). In supporting the use of alkylation studies, they also note that ethylene has a low solubility in water and would therefore be expected to give negative results in standard Ames tests--which is apparently what it has done ( H a m m e t al. loc. cit.; Osterman-Golkar & Ehrenberg loc. cit.). The assessment of ethylene's potential carcinogenic or genotoxic hazard for humans therefore relies, at least in part, on the extent to which ethylene is converted by human enzymes to EO (if at all). In the absence of this data, studies of haemoglobin alkylation in workers exposed to ethylene would be a very useful contribution to this assessment, along with investigations of the possibility of chromosome damage, which has been observed in some groups exposed to EO (Cited in F.C.T. 1984, 22, 86). It may be remembered that American concern over EO's genotoxic and carcinogenic potential prompted OSHA, in June 1984, to lower the permissible exposure level to 1 ppm (Federal Register 1984, 49, 25734).
[Christine Rostron--BIBRA]
Information section Fd Chem. Toxic. Vol. 24, No. 1 ETHYLENE METABOLISM AND CARCINOGENICITY
Ethylene has traditionally been regarded as a simple asphyxiant, for which no TLV is necessary to control industrial exposure. This classification was supported by the preliminary results of a CIIT 2-yr rat study, in which no toxic or carcinogenic effects were found after inhalation of 300, 1000 or 3000 ppm. However, there have been indications that certain species, notably mice, may metabolize ethylene to the carcinogenic and mutagenic ethylene oxide (EO). CIIT scientists published a summary of the final ethylene bioassay results last year, concluding that there was "no evidence that ethylene at these concentrations causes chronic toxicity or is oncogenic in Fischer-344 rats" (Hamm et al. Fund. appl. Toxic. 1984, 4, 473). According to the 'executive summary' of the full report (published separately), unusual malignant lung tumours were found in two rats exposed to 1000 ppm and one exposed to 3000 ppm, but their low incidence and the lack of other related changes in the bronchial epithelium suggested they may have occurred spontaneously. The incidence of mononuclear cell leukaemia is not discussed in this summary, but the full report (available only on microfiche) indicates that it was somewhat increased in both sexes at the top dose level. The number of animals affected (out of 90) rose from 12 and 8 in male and female controls to 21 and 11, respectively, at 3000 ppm. The total number of organs or tissues affected rose to 106 in males and 83 in females from only 62 and 26, respectively, in controls Whether it increased at lower doses too is uncertain, since only limited histological examination of the lower dose groups was conducted. In view of the ability of EO to induce this form of cancer ( N I O S H Current Intelligence Bulletin 1981, no. 5, 22 May) it is strange that the incidence of leukaemias is not discussed in the report's executive summary or by Hamm et al. Although one of the CIIT scientists, Derek Guest, was unable to detect any conversion of ethylene to EO in an in vitro preparation of rat-liver microsomes (Hamm et al. loc. cit.), two other metabolic studies indicate that rats and mice can indeed metabolize ethylene to EO and that both chemicals can lead to the alkylation of proteins and DNA. In a German study, the monooxygenase enzyme system was shown to be responsible for the conversion in rats of inhaled ethylene to exhaled EO (Filser & Bolt, Mutation Res. 1983, 120, 57). The other study, carried out by Dan
Segerb~ick of Stockholm University, showed that ethylene and EO produced the same pattern of alkylations among amino acids in haemoglobin from mice exposed to the radiolabelled compounds, and that both chemicals alkylated DNA from the liver, spleen and testes (the only organs examined). The alkylation products were always the 2-hydroxyethyl derivative of an amino acid of DNA base. Furthermore, for both chemicals the ratio between the degree of alkylation of DNA in any of the three organs and the degree of haemoglobin alkylation was always approximately the same (Chemico-Biol. Interactions 1983, 45, 139). Segerb~ick concludes that measurement of the degree of alkylation of haemoglobin in red blood cells (a method that could be used in animal studies or for human monitoring) would give "a good estimate of the DNA dose". Two of his colleagues at the University of Stockholm, Siv Osterman-Golkar and Lars Ehrenberg, have suggested that measurement of haemoglobin alkylation would be a more sensitive indicator of the genotoxic potential of EO (and therefore ethylene) than would animal studies such as the CIIT study (Drug. Metab. Rev. 1982, 13, 647). In supporting the use of alkylation studies, they also note that ethylene has a low solubility in water and would therefore be expected to give negative results in standard Ames tests--which is apparently what it has done ( H a m m e t al. loc. cit.; Osterman-Golkar & Ehrenberg loc. cit.). The assessment of ethylene's potential carcinogenic or genotoxic hazard for humans therefore relies, at least in part, on the extent to which ethylene is converted by human enzymes to EO (if at all). In the absence of this data, studies of haemoglobin alkylation in workers exposed to ethylene would be a very useful contribution to this assessment, along with investigations of the possibility of chromosome damage, which has been observed in some groups exposed to EO (Cited in F.C.T. 1984, 22, 86). It may be remembered that American concern over EO's genotoxic and carcinogenic potential prompted OSHA, in June 1984, to lower the permissible exposure level to 1 ppm (Federal Register 1984, 49, 25734).
[Christine Rostron--BIBRA]