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Yet more about beryllium
ARTICLES OF GENERAL rN-TEREST
573
Parisi, loc. cit.) while at 20-30 m-equiv./litre, Mg causes cardiac arrest (Nutrition Reviews 1968, 26, 139). Excessive serum concentrations may be produced by parenteral Mg therapy, which is commonly employed in the treatment of toxaemia of pregnancy. Lipsitz & English (Pediatrics, Springfield, 1967, 40, 856) have attributed depression in infants to hypermagnesaemia induced in their mothers. These authors studied 16 infants whose toxaemic mothers had received Mg sulphate injections immediate before delivery, in doses equivalent to 13-50 % of the total Mg content of the body. In normal mothers, serum Mg averaged 1-8 m-equiv./litre, and the cord blood concentration was about 1-9 m-equiv./litre, whereas in the treated mothers the corresponding concentrations were in the ranges 3-14 and 3.111.5 m-equiv./litre. Four of the 16 infants had no adverse symptoms, while three were severely flaccid, with respiratory depression and poor reflexes, and died. The remainder had symptoms varying in severity and lasting from 3 hr to 2 days. After birth the infants' serum Mg fell progressively, but remained higher than normal for 24 hr, and in one infant for 80 hr. Some of the toxic effects of hypermagnesaemia may be attributable to the adverse effects of Mg-Ca imbalance. Ottenjann et al. (Klin. Wschr. 1969, 47, 1204) have reported that acute hypermagnesaemia in 20 subjects inhibited the expected stimulation of gastric secretion by a Ca infusion. During the infusion of Mg the serum Mg rose in the subjects from an average of 1.62 to 3.41 m-equiv./litre, while the serum Ca rose during the Ca infusion from 4.83 to 6.83 m-equiv./litre. Ca treatment alone raised the volume of gastric secretion from21.6to 33.7 ml/15 min, and reduced its pH. During the Ca and Mg treatment, the gastric secretory rate fell again to 22"7 ml/15 min, and the pH returned to normal.
Drug-altered metabolism of Mg Drugs may alter the rate of exchange of Mg in muscle and bone. Vachon & Marchand
(J. Pharm. exp. Ther. 1970, 172, 122) have found that in rats given an intravenous injection of morphine sulphate (2 mg/kg) the serum concentration of Mg rose, reaching a peak 1 hr later. A dose-response curve could be observed with morphine doses up to 16 mg/kg. When the narcotic antagonist nalorphine (4 mg/kg) was given at the same time as the morphine (8 mg/kg), hypermagnesaemia was prevented. Nalorphine alone was slightly hypermagnesaemic in its effect. Further investigations in morphine-treated rats given intravenous Mg sulphate labelled with 2SMg showed an increase in the specific activity of the serum, bone and muscle, but no change in Mg excretion compared with rats not treated with morphine. The effect of the morphine may therefore be attributed to an alteration of the bone and soft-tissue exchange of Mg, and not to its known antidiuretic activity.
YET MORE ABOUT BERYLLIUM We have seen that occupational exposure to beryllium (Be) compounds may result in acute or chronic respiratory disorders (Cited in F.C.T. 1969, 7, 83; ibid 1970, 8, 575). The relationship between Be exposure, prior respiratory illness and the later development of respiratory-tract cancers has been examined by Mancuso (Envir. Res. 1970, 3, 251), who undertook cohort studies of the total population of each of two major companies involved in Be extraction for the period 1937-1948, and extended the investigation to 1967. In this study a relationship appeared between the duration of employment in Be extraction and
574
ARTICLES OF GENERAL INTEREST
the specific cause of death. Workers employed for 0-25-1.25 yr showed a higher incidence of lung cancer than those employed 1-5 yr or longer. The incidence of lung cancer was much higher among workers with prior respiratory illness, principally acute bronchitis and pneumonitis, than among the entire group of workers over the same period. The study therefore indicates that Be workers are more liable to contract lung cancer if they have already suffered occupational respiratory-tract illness. The diagnosis of chronic beryUiosis usually depends on circumstantial evidence, since the abnormalities of lung function are non-specific and clinically and pathologically it is difficult to distinguish the condition from sarcoidosis. Since only a small proportion of exposed workers develops Be disease, it is probable that hypersensitivity is involved, a supposition favoured by the fact that susceptible workers often show hypergammaglobulinaemia. Serum concentrations of immunoglobulins IgG, IgM and IgA have been measured in subjects with chronic berylliosis (Resnick et al. Am. Rev. resp. Dis. 1970, 101, 504). Most subjects with chronic Be dermatitis or pulmonary berylliosis had hypergammaglobulinaemia, with increased serum IgG, but these findings were less frequent in persons whose acute Be poisoning had resolved. The serum IgG titre was raised in five of six subjects with chronic and in four of seven with acute berylliosis, and in four of five subjects with Be dermatitis. However, 18 of 22 workers with a history of long exposure to Be but no clinical signs of Be intoxication also had a raised IgG titre. Possibly, therefore, a determination of serum IgG might indicate hypersensitivity which would render a worker liable to Be intoxication; but further differentiation will be necessary before apparently false-positive results can be discounted. Zschunke & Folesky (Hautarzt 1969, 20, 403) have also reported raised serum-globulin levels in healthy workers employed in handling Be. In other workers suffering from subacute eczema due to Be nitrate, they found disturbances in the activities of isocitrate and malate dehydrogenases, serum and erythrocyte phosphohexose isomerase and acid and alkaline phosphatases. These authors conclude that patch testing with Be salts could be a frequent cause of sensitization, and in susceptible persons could lead to acute exacerbation of both Be granuloma and pulmonary disease. They consider that sensitivity testing with Be salts should therefore be discontinued. The relationship between the development of Be granulomas and delayed hypersensitivity in exposed individuals has been studied by Hanifin et al. (J. invest. Derm. 1970, 55, 284), who also contrasted Be granulomas with those produced by silica. The latter, consisting of perivascular clusters of macrophages containing ingested silica, form in any exposed individuals and their size is roughly proportional to the amount of silica. Be, on the other hand, induces organized epithelioid-cell granulomas only in sensitive subjects. The size of the lesions, which are, as we have said, morphologically similar to those of sarcoidosis, is largely independent of the amount of Be salt present, and Be is detectable only in a few phagocytes at the periphery of the granuloma. It appears that delayed hypersensitivity is related to granulomatous sensitivity to Be, and Hanifin et al. (loc. cit.) showed that lymphocytes from Be-hypersensitive subjects underwent 'blastogenic' transformation, typically associated with delayed hypersensitivity to a number of antigens, when exposed to Be salts in vitro. Monocytes from these sensitive subjects matured into macrophages more rapidly than those from normal subjects, and the resulting macrophages, after phagocytizing particulate Be oxide, induced blastogenic transformation of sensitive lymphocytes. The systemic effects of injected salts are unlikely to be of general interest, but the toxicologist requires as wide a picture as possible of the activity of a toxic element. The report of
ARTICLES OF GENERAL INTEREST
575
Pham-Huu-Chanh et al. (Th~rapie 1970, 25, 663) on the cardiovascular effects of Be in the anaesthetized dog indicates that a single intravenous dose of 200-300 mg Be sulphate/kg produces only a slight fall in arterial blood pressure, and a transient slight increase in heart rate. Repeated injections significantly reduce arterial pressure, sometimes to a lethal level; in surviving animals there is a rebound rise of blood pressure. This response is not modified by artificial respiration, bilateral vagotomy or atropinization. In the decerebrate animal a single intravenous dose of 100 mg Be sulphate/kg markedly reduces blood pressure, though it has little effect in the intact animal. The hypotensive effect of Be is potentiated by yohimbine, nicotine, sparteine and veratrine, and by catecholamine depletion, and is not antagonized by antihistamines. Pham-Huu-Chanh et aL (Ioc. cit.) suggest that the hypotensive effect of Be may be partly due to vasodilatation, and possibly to myocardial depression.
AFLATOXIN--A HARDY ANNUAL Reports on aflatoxin (AF) have continued to be published at a considerable rate since our last review (Cited in F.C.T. 1970, 8, 695) but progress in our understanding of the health hazard presented by this toxin remains fairly slow. Many strains of the Aspergillus flavus group can produce AF, which has been shown to be, for some animals, one of the most potent carcinogens known. In a study of some 28 of these strains, Hesseltine et al. (Mycologia 1970, 62, 123) were unable to distinguish between them on grounds of gross morphology or biochemistry and found that the presence and ratios of the various types of AF appeared to be the best basis for classification. One of the more notable of the recent contributions to the evergrowing AF literature is a topical survey of the problem given by Dr. J. M. Barnes as the Second StenhouseWilliams Memorial Lecture to the Society for Applied Bacteriology (Barnes, J. appl. Bact. 1970, 33, 285). Dr. Barnes points out that there is little point in trying to analyse food eaten at any particular time in order to find out whether it contains AF because chance plays too great a part in determining the degree to which any particular harvests or batches of stored food may be contaminated. Information must be obtained at a much earlier stage, with adequate surveys of food harvesting and storage, so that the populations that may be most heavily exposed to food regularly or intermittently contaminated with fungi may be identified. However, many reports on the levels of AF contamination in food products are still compiled and remain of some passing interest. Cheese has always seemed a likely candidate to play host to AF and, indeed, AF production by Aspergilli has been demonstrated in Cheddar cheese by Lie & Marth (J. Dairy Sci. 1967, 50, 1708). However, more recently, samples of Roquefort, Camembert and domestic blue cheese were all found to be free from AF (Shih & Marth, ibid 1969, 52, 1681). Similarly in a German study (Kiermeier & Grolt, Z. Lebensmittehmters. u. -Forsch. 1970, 143, 81 ; idem, ibid 1970, 142, 120), no AF was found in 169 samples of 19 cheese varieties, but artificial infection with A. flavus resulted in large amounts of AF Bz on Tilsit cheese under favourable environmental conditions, although on Camembert and Romadur the growth of the fungus was inhibited. Clearly the right conditions for AF contamination are present in some hot and humid cheese factories. A further German paper (Spicher, Brot Gebiick 1969, 23, 149) has shown that AF may occasionally be formed in some wholemeal and mixed breads. However, the state of deterioration of the bread was such that it was unlikely to have been eaten.
573
Parisi, loc. cit.) while at 20-30 m-equiv./litre, Mg causes cardiac arrest (Nutrition Reviews 1968, 26, 139). Excessive serum concentrations may be produced by parenteral Mg therapy, which is commonly employed in the treatment of toxaemia of pregnancy. Lipsitz & English (Pediatrics, Springfield, 1967, 40, 856) have attributed depression in infants to hypermagnesaemia induced in their mothers. These authors studied 16 infants whose toxaemic mothers had received Mg sulphate injections immediate before delivery, in doses equivalent to 13-50 % of the total Mg content of the body. In normal mothers, serum Mg averaged 1-8 m-equiv./litre, and the cord blood concentration was about 1-9 m-equiv./litre, whereas in the treated mothers the corresponding concentrations were in the ranges 3-14 and 3.111.5 m-equiv./litre. Four of the 16 infants had no adverse symptoms, while three were severely flaccid, with respiratory depression and poor reflexes, and died. The remainder had symptoms varying in severity and lasting from 3 hr to 2 days. After birth the infants' serum Mg fell progressively, but remained higher than normal for 24 hr, and in one infant for 80 hr. Some of the toxic effects of hypermagnesaemia may be attributable to the adverse effects of Mg-Ca imbalance. Ottenjann et al. (Klin. Wschr. 1969, 47, 1204) have reported that acute hypermagnesaemia in 20 subjects inhibited the expected stimulation of gastric secretion by a Ca infusion. During the infusion of Mg the serum Mg rose in the subjects from an average of 1.62 to 3.41 m-equiv./litre, while the serum Ca rose during the Ca infusion from 4.83 to 6.83 m-equiv./litre. Ca treatment alone raised the volume of gastric secretion from21.6to 33.7 ml/15 min, and reduced its pH. During the Ca and Mg treatment, the gastric secretory rate fell again to 22"7 ml/15 min, and the pH returned to normal.
Drug-altered metabolism of Mg Drugs may alter the rate of exchange of Mg in muscle and bone. Vachon & Marchand
(J. Pharm. exp. Ther. 1970, 172, 122) have found that in rats given an intravenous injection of morphine sulphate (2 mg/kg) the serum concentration of Mg rose, reaching a peak 1 hr later. A dose-response curve could be observed with morphine doses up to 16 mg/kg. When the narcotic antagonist nalorphine (4 mg/kg) was given at the same time as the morphine (8 mg/kg), hypermagnesaemia was prevented. Nalorphine alone was slightly hypermagnesaemic in its effect. Further investigations in morphine-treated rats given intravenous Mg sulphate labelled with 2SMg showed an increase in the specific activity of the serum, bone and muscle, but no change in Mg excretion compared with rats not treated with morphine. The effect of the morphine may therefore be attributed to an alteration of the bone and soft-tissue exchange of Mg, and not to its known antidiuretic activity.
YET MORE ABOUT BERYLLIUM We have seen that occupational exposure to beryllium (Be) compounds may result in acute or chronic respiratory disorders (Cited in F.C.T. 1969, 7, 83; ibid 1970, 8, 575). The relationship between Be exposure, prior respiratory illness and the later development of respiratory-tract cancers has been examined by Mancuso (Envir. Res. 1970, 3, 251), who undertook cohort studies of the total population of each of two major companies involved in Be extraction for the period 1937-1948, and extended the investigation to 1967. In this study a relationship appeared between the duration of employment in Be extraction and
574
ARTICLES OF GENERAL INTEREST
the specific cause of death. Workers employed for 0-25-1.25 yr showed a higher incidence of lung cancer than those employed 1-5 yr or longer. The incidence of lung cancer was much higher among workers with prior respiratory illness, principally acute bronchitis and pneumonitis, than among the entire group of workers over the same period. The study therefore indicates that Be workers are more liable to contract lung cancer if they have already suffered occupational respiratory-tract illness. The diagnosis of chronic beryUiosis usually depends on circumstantial evidence, since the abnormalities of lung function are non-specific and clinically and pathologically it is difficult to distinguish the condition from sarcoidosis. Since only a small proportion of exposed workers develops Be disease, it is probable that hypersensitivity is involved, a supposition favoured by the fact that susceptible workers often show hypergammaglobulinaemia. Serum concentrations of immunoglobulins IgG, IgM and IgA have been measured in subjects with chronic berylliosis (Resnick et al. Am. Rev. resp. Dis. 1970, 101, 504). Most subjects with chronic Be dermatitis or pulmonary berylliosis had hypergammaglobulinaemia, with increased serum IgG, but these findings were less frequent in persons whose acute Be poisoning had resolved. The serum IgG titre was raised in five of six subjects with chronic and in four of seven with acute berylliosis, and in four of five subjects with Be dermatitis. However, 18 of 22 workers with a history of long exposure to Be but no clinical signs of Be intoxication also had a raised IgG titre. Possibly, therefore, a determination of serum IgG might indicate hypersensitivity which would render a worker liable to Be intoxication; but further differentiation will be necessary before apparently false-positive results can be discounted. Zschunke & Folesky (Hautarzt 1969, 20, 403) have also reported raised serum-globulin levels in healthy workers employed in handling Be. In other workers suffering from subacute eczema due to Be nitrate, they found disturbances in the activities of isocitrate and malate dehydrogenases, serum and erythrocyte phosphohexose isomerase and acid and alkaline phosphatases. These authors conclude that patch testing with Be salts could be a frequent cause of sensitization, and in susceptible persons could lead to acute exacerbation of both Be granuloma and pulmonary disease. They consider that sensitivity testing with Be salts should therefore be discontinued. The relationship between the development of Be granulomas and delayed hypersensitivity in exposed individuals has been studied by Hanifin et al. (J. invest. Derm. 1970, 55, 284), who also contrasted Be granulomas with those produced by silica. The latter, consisting of perivascular clusters of macrophages containing ingested silica, form in any exposed individuals and their size is roughly proportional to the amount of silica. Be, on the other hand, induces organized epithelioid-cell granulomas only in sensitive subjects. The size of the lesions, which are, as we have said, morphologically similar to those of sarcoidosis, is largely independent of the amount of Be salt present, and Be is detectable only in a few phagocytes at the periphery of the granuloma. It appears that delayed hypersensitivity is related to granulomatous sensitivity to Be, and Hanifin et al. (loc. cit.) showed that lymphocytes from Be-hypersensitive subjects underwent 'blastogenic' transformation, typically associated with delayed hypersensitivity to a number of antigens, when exposed to Be salts in vitro. Monocytes from these sensitive subjects matured into macrophages more rapidly than those from normal subjects, and the resulting macrophages, after phagocytizing particulate Be oxide, induced blastogenic transformation of sensitive lymphocytes. The systemic effects of injected salts are unlikely to be of general interest, but the toxicologist requires as wide a picture as possible of the activity of a toxic element. The report of
ARTICLES OF GENERAL INTEREST
575
Pham-Huu-Chanh et al. (Th~rapie 1970, 25, 663) on the cardiovascular effects of Be in the anaesthetized dog indicates that a single intravenous dose of 200-300 mg Be sulphate/kg produces only a slight fall in arterial blood pressure, and a transient slight increase in heart rate. Repeated injections significantly reduce arterial pressure, sometimes to a lethal level; in surviving animals there is a rebound rise of blood pressure. This response is not modified by artificial respiration, bilateral vagotomy or atropinization. In the decerebrate animal a single intravenous dose of 100 mg Be sulphate/kg markedly reduces blood pressure, though it has little effect in the intact animal. The hypotensive effect of Be is potentiated by yohimbine, nicotine, sparteine and veratrine, and by catecholamine depletion, and is not antagonized by antihistamines. Pham-Huu-Chanh et aL (Ioc. cit.) suggest that the hypotensive effect of Be may be partly due to vasodilatation, and possibly to myocardial depression.
AFLATOXIN--A HARDY ANNUAL Reports on aflatoxin (AF) have continued to be published at a considerable rate since our last review (Cited in F.C.T. 1970, 8, 695) but progress in our understanding of the health hazard presented by this toxin remains fairly slow. Many strains of the Aspergillus flavus group can produce AF, which has been shown to be, for some animals, one of the most potent carcinogens known. In a study of some 28 of these strains, Hesseltine et al. (Mycologia 1970, 62, 123) were unable to distinguish between them on grounds of gross morphology or biochemistry and found that the presence and ratios of the various types of AF appeared to be the best basis for classification. One of the more notable of the recent contributions to the evergrowing AF literature is a topical survey of the problem given by Dr. J. M. Barnes as the Second StenhouseWilliams Memorial Lecture to the Society for Applied Bacteriology (Barnes, J. appl. Bact. 1970, 33, 285). Dr. Barnes points out that there is little point in trying to analyse food eaten at any particular time in order to find out whether it contains AF because chance plays too great a part in determining the degree to which any particular harvests or batches of stored food may be contaminated. Information must be obtained at a much earlier stage, with adequate surveys of food harvesting and storage, so that the populations that may be most heavily exposed to food regularly or intermittently contaminated with fungi may be identified. However, many reports on the levels of AF contamination in food products are still compiled and remain of some passing interest. Cheese has always seemed a likely candidate to play host to AF and, indeed, AF production by Aspergilli has been demonstrated in Cheddar cheese by Lie & Marth (J. Dairy Sci. 1967, 50, 1708). However, more recently, samples of Roquefort, Camembert and domestic blue cheese were all found to be free from AF (Shih & Marth, ibid 1969, 52, 1681). Similarly in a German study (Kiermeier & Grolt, Z. Lebensmittehmters. u. -Forsch. 1970, 143, 81 ; idem, ibid 1970, 142, 120), no AF was found in 169 samples of 19 cheese varieties, but artificial infection with A. flavus resulted in large amounts of AF Bz on Tilsit cheese under favourable environmental conditions, although on Camembert and Romadur the growth of the fungus was inhibited. Clearly the right conditions for AF contamination are present in some hot and humid cheese factories. A further German paper (Spicher, Brot Gebiick 1969, 23, 149) has shown that AF may occasionally be formed in some wholemeal and mixed breads. However, the state of deterioration of the bread was such that it was unlikely to have been eaten.