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1839. Carcinogenicity of calcium chromate
690
THE CHEMICAL ENVIRONMENT
Earlier observations have shown that beryllium (Be) selectively inhibits the synthesis of deoxyribonucleic acid (DNA) in a number of in vitro systems (Cited h7 F.C.T. 1966, 4, 630). These results have now been confirmed in the regenerating livers of intact animals. Utilizing the marked affinity of Be for rat-liver nuclei, Witschi (cited above) injected Be intravenously into partially hepatectomized rats and measured the effect of such treatment on in vivo nuclear metabolism. When Be was given in doses too small to cause liver necrosis after 28 hr (30/~moles/kg at 5, 14, 20 and 28 hr before sacrifice) it stopped net D N A synthesis and inhibited the incorporation of 14C-labelled thymidine into DNA. The degree of inhibition was found to be dose-dependent. On the other hand, Be had no effect on the incorporation of leucine into total liver protein or of orotic acid into total liver ribonucleic acid (RNA), either in the partially hepatectomized rats or in rats with intact livers used in a preliminary study. Be has been shown to bind to rat-liver nuclei in both normal livers (ibm 1968, 6, 539) and regenerating livers (Truhaut et al. Annls Biol. clin. 1965, 23, 45). It has been claimed (Cited hi F.C.T. 1965, 3, 867) that Be binds to D N A and alters its physicochemical properties, but this has only been demonstrated h7 vitro. The fact that Be is most effective as an inhibitor of D N A synthesis when given shortly after partial hepatectomy suggests that it is more likely to exert an effect on the processes that lead to the initiation of D N A synthesis than to act directly on the synthesis itself. So far no results have been forthcoming as to specific interactions of Be with enzyme systems involved in D N A synthesis, but there is some evidence for an antagonism between Be and magnesium. Although no direct relationship can yet be established between the results obtained so far and the necrogenic action of Be, one can speculate that interference by Be in D N A synthesis may be related to its sarcogenic and carcinogenic effects in experimental animals.
1839. Carcinogenicity of calcium chromate Roe, F. J. C. & Carter, R. L. (1969). Chromium carcinogenesis: Calcium chromate as a potent carcinogen for the subcutaneous tissues of the rat. Br. J. Cancer 23, 172. Chromium has been implicated as a possible carcinogen due to the high incidence of lung cancer in workers engaged in the extraction of chromium from its crude ore. The first step in processing the crude ore involves the formation of calcium chromate (I) and this appears to be one important stage where potential carcinogens may be encountered. Continuing a prolonged investigation into the carcinogenicity of chromium-containing compounds, the authors cited above administered 20 once-weekly intramuscular injections of 1 suspended in 0-2 ml arachis oil into the right flank of 24 young male rats. Each animal received a total dose of 19 mg I and was sacrificed after 63 wk. Sixteen control rats received 20 once-weekly injections of 0.2 ml arachis oil alone. Spindle cell and pleomorphic cell sarcomas developed at the site of injection in 75 % of the test rats but no neoplasms were found at other sites in either the test or control rats. The tumours which developed were locally invasive but did not metastasize. The mean period of induction of the tumours was 323 days, the first tumour appearing after 203 days. There seems to be no doubt that I is capable of producing sarcomas under the right experimental conditions. Payne (A.M.A. Archs ind. Hlth 1960, 21, 530) demonstrated the production of sarcomas in mice at the site of subcutaneous injection of I, although attempts to produce pulmonary tumours in rats by intratracheal administration of I were unsuccessful (Hueper & Payne, Archs envir. Hlth 1962, 5, 445). Speaking at the meeting of the American Industrial Health Association in St. Louis in May 1968, Dr. S. Laskin reported the induction
THE CHEMICAL ENVIRONMENT
691
of squamous carcinomas of the lung in six and adenocarcinomas of the lung in two out of 100 rats exposed to 1 in the form of a pellet attached to the bronchial mucosa. [Work at BIBRA has demonstrated that many materials are capable of eliciting a neoplastic response that is unrelated to their carcinogenicity (Gangolli et al. Fd Cosmet. Toxicol. 1967, 5, 601). Without details of the initial tissue reaction following intramuscular injection of calcium chromate (not given in the present paper) it is impossible to interpret these findings in terms of the compound's true carcinogenicity. But there appears to be sufficient evidence from other sources to implicate calcium chromate as one of the putative carcinogens responsible for the well-documented cancer hazard associated with the chromateproducing industry.]
1840. Black sheep in the copper family Wiener, G., Field, A. C. & Wood, Jean (1969). The concentration of minerals in the blood of genetically diverse groups of sheep. I. Copper concentration of different seasons in Blackface, Cheviot, Welsh Mountain and crossbred sheep at pasture. J. agric. Sci., Camb. 72, 93. Wiener, G. & Field, A. C. (1969). Copper concentrations in the liver and blood of sheep of different breeds in relation to swayback history. J. comp. Path. Ther. 79, 7. In recent years there has been growing interest in the mineral levels in sheep, and studies have indicated that the blood levels of minerals vary widely in individual animals. In a few cases the variability can be attributed to hereditary differences, which in turn can be linked with the incidence of particular disorders. Wiener and his associates (first paper cited above) measured the copper (Cu) concentrations in the blood of sheep at different times during 1965 in a grassland flock comprising the Scottish Blackface, Cheviot and Welsh Mountain breeds and their crosses. The two factors which were found to have most influence on the concentrations were breed and swayback history. Blackface had consistently the lowest values and Welsh the highest, while in most cases the levels in crossbreeds were at or near the concentration of the parental breed with the highest value. In general, the values were higher in the summer than in the winter but tended to be more variable in the winter. Ewes which had produced swayback lambs in 1964 had lower levels of Cu in their blood than ewes which had produced normal lambs, the difference being much more marked in winter. Ewes which were barren had higher blood concentrations of Cu than ewes which had lambed, while those producing twins had a slightly lower level than those producing a single offspring. In a further study in a similar flock of sheep, the same group (Wiener & Field, cited above) attempted to relate the concentration of Cu in the liver to genetic factors and investigated the relationships between liver and blood concentrations of Cu in each breed. The three different breeds showed the same relative values for liver concentrations as were found for blood, but unlike the concentration found in the blood of crossbreeds the Cu level in the liver of crossbreeds was nearly intermediate between the levels of the two parental breeds. No significant difference was apparent in the Cu levels of the livers of ewes that had produced swayback lambs. In general, Cu concentrations in the liver were three times as variable as those in the blood, suggesting that genetic factors play a smaller part in determining the Cu levels in the former tissue than in the latter.
THE CHEMICAL ENVIRONMENT
Earlier observations have shown that beryllium (Be) selectively inhibits the synthesis of deoxyribonucleic acid (DNA) in a number of in vitro systems (Cited h7 F.C.T. 1966, 4, 630). These results have now been confirmed in the regenerating livers of intact animals. Utilizing the marked affinity of Be for rat-liver nuclei, Witschi (cited above) injected Be intravenously into partially hepatectomized rats and measured the effect of such treatment on in vivo nuclear metabolism. When Be was given in doses too small to cause liver necrosis after 28 hr (30/~moles/kg at 5, 14, 20 and 28 hr before sacrifice) it stopped net D N A synthesis and inhibited the incorporation of 14C-labelled thymidine into DNA. The degree of inhibition was found to be dose-dependent. On the other hand, Be had no effect on the incorporation of leucine into total liver protein or of orotic acid into total liver ribonucleic acid (RNA), either in the partially hepatectomized rats or in rats with intact livers used in a preliminary study. Be has been shown to bind to rat-liver nuclei in both normal livers (ibm 1968, 6, 539) and regenerating livers (Truhaut et al. Annls Biol. clin. 1965, 23, 45). It has been claimed (Cited hi F.C.T. 1965, 3, 867) that Be binds to D N A and alters its physicochemical properties, but this has only been demonstrated h7 vitro. The fact that Be is most effective as an inhibitor of D N A synthesis when given shortly after partial hepatectomy suggests that it is more likely to exert an effect on the processes that lead to the initiation of D N A synthesis than to act directly on the synthesis itself. So far no results have been forthcoming as to specific interactions of Be with enzyme systems involved in D N A synthesis, but there is some evidence for an antagonism between Be and magnesium. Although no direct relationship can yet be established between the results obtained so far and the necrogenic action of Be, one can speculate that interference by Be in D N A synthesis may be related to its sarcogenic and carcinogenic effects in experimental animals.
1839. Carcinogenicity of calcium chromate Roe, F. J. C. & Carter, R. L. (1969). Chromium carcinogenesis: Calcium chromate as a potent carcinogen for the subcutaneous tissues of the rat. Br. J. Cancer 23, 172. Chromium has been implicated as a possible carcinogen due to the high incidence of lung cancer in workers engaged in the extraction of chromium from its crude ore. The first step in processing the crude ore involves the formation of calcium chromate (I) and this appears to be one important stage where potential carcinogens may be encountered. Continuing a prolonged investigation into the carcinogenicity of chromium-containing compounds, the authors cited above administered 20 once-weekly intramuscular injections of 1 suspended in 0-2 ml arachis oil into the right flank of 24 young male rats. Each animal received a total dose of 19 mg I and was sacrificed after 63 wk. Sixteen control rats received 20 once-weekly injections of 0.2 ml arachis oil alone. Spindle cell and pleomorphic cell sarcomas developed at the site of injection in 75 % of the test rats but no neoplasms were found at other sites in either the test or control rats. The tumours which developed were locally invasive but did not metastasize. The mean period of induction of the tumours was 323 days, the first tumour appearing after 203 days. There seems to be no doubt that I is capable of producing sarcomas under the right experimental conditions. Payne (A.M.A. Archs ind. Hlth 1960, 21, 530) demonstrated the production of sarcomas in mice at the site of subcutaneous injection of I, although attempts to produce pulmonary tumours in rats by intratracheal administration of I were unsuccessful (Hueper & Payne, Archs envir. Hlth 1962, 5, 445). Speaking at the meeting of the American Industrial Health Association in St. Louis in May 1968, Dr. S. Laskin reported the induction
THE CHEMICAL ENVIRONMENT
691
of squamous carcinomas of the lung in six and adenocarcinomas of the lung in two out of 100 rats exposed to 1 in the form of a pellet attached to the bronchial mucosa. [Work at BIBRA has demonstrated that many materials are capable of eliciting a neoplastic response that is unrelated to their carcinogenicity (Gangolli et al. Fd Cosmet. Toxicol. 1967, 5, 601). Without details of the initial tissue reaction following intramuscular injection of calcium chromate (not given in the present paper) it is impossible to interpret these findings in terms of the compound's true carcinogenicity. But there appears to be sufficient evidence from other sources to implicate calcium chromate as one of the putative carcinogens responsible for the well-documented cancer hazard associated with the chromateproducing industry.]
1840. Black sheep in the copper family Wiener, G., Field, A. C. & Wood, Jean (1969). The concentration of minerals in the blood of genetically diverse groups of sheep. I. Copper concentration of different seasons in Blackface, Cheviot, Welsh Mountain and crossbred sheep at pasture. J. agric. Sci., Camb. 72, 93. Wiener, G. & Field, A. C. (1969). Copper concentrations in the liver and blood of sheep of different breeds in relation to swayback history. J. comp. Path. Ther. 79, 7. In recent years there has been growing interest in the mineral levels in sheep, and studies have indicated that the blood levels of minerals vary widely in individual animals. In a few cases the variability can be attributed to hereditary differences, which in turn can be linked with the incidence of particular disorders. Wiener and his associates (first paper cited above) measured the copper (Cu) concentrations in the blood of sheep at different times during 1965 in a grassland flock comprising the Scottish Blackface, Cheviot and Welsh Mountain breeds and their crosses. The two factors which were found to have most influence on the concentrations were breed and swayback history. Blackface had consistently the lowest values and Welsh the highest, while in most cases the levels in crossbreeds were at or near the concentration of the parental breed with the highest value. In general, the values were higher in the summer than in the winter but tended to be more variable in the winter. Ewes which had produced swayback lambs in 1964 had lower levels of Cu in their blood than ewes which had produced normal lambs, the difference being much more marked in winter. Ewes which were barren had higher blood concentrations of Cu than ewes which had lambed, while those producing twins had a slightly lower level than those producing a single offspring. In a further study in a similar flock of sheep, the same group (Wiener & Field, cited above) attempted to relate the concentration of Cu in the liver to genetic factors and investigated the relationships between liver and blood concentrations of Cu in each breed. The three different breeds showed the same relative values for liver concentrations as were found for blood, but unlike the concentration found in the blood of crossbreeds the Cu level in the liver of crossbreeds was nearly intermediate between the levels of the two parental breeds. No significant difference was apparent in the Cu levels of the livers of ewes that had produced swayback lambs. In general, Cu concentrations in the liver were three times as variable as those in the blood, suggesting that genetic factors play a smaller part in determining the Cu levels in the former tissue than in the latter.