- Email: [email protected]
ALUMINIUM TOXICITY IN RATS AND MAN
276 tool because other influential variables such as parity, and genetic background are all under control. Such studies have additionally automatically the economic advantage of avoiding the necessity for large numbers of subjects required in conventional epidemiological studies. Strong support should be given to twin studies, not only in connection with the question of the relation between smoking and mortality, but also in the investigation of
powerful
age, sex, maternal
chronic diseases. Philip Morris Research Center, P.O. Box 26583,
Richmond, Virginia 23261, U.S.A.
HELMUT R. R. WAKEHAM.
PERIPHERAL VENOUS SCANNING WITH 125I-TAGGED FIBRINOGEN
SIR,—Dr. Williams and Dr. Croft (April 29, p. 954) are in their objection to the inclusion of all patients with a positive lung scan ". The patients who were judged to have pulmona’-v embolism had pleuritic pain, breathlessness, with or without hxmoptysis, high erythrocyte-sedimentation rate, chest X-ray and lung-scan abnormalities suggesting pulmonary embolism, and, in some cases, electrocardiographic change "
correct
consistent with pulmonary embolism. Clinical progress, serial chest radiography, and lung scans all confirmed the diagnosis of pulmonary embolism. Patients with only an abnormal lung scan were not included in the series. We are well aware of the fallibility of the lung scan alone in patients with pre-existing lung disease, especially in the older age-group. Department of Radiology and A. F. MACDONALD Clinical Scanning Unit, Aberdeen. J. GADDIE. Royal Infirmary,
ALUMINIUM TOXICITY IN RATS AND MAN SiR—I was most interested to read the report by Berlyne et al.l in which they described aluminium (Al) intoxication in ursemic and non-uraemic rats given aluminium salts orally or parenterally. The continuing debate has interested me, since our group has shown2 that when patients with chronic renal failure are given AI(OH)a gel B.P. (’Aludrox’) in divided doses totalling 75-150 ml. per day (1-5-3-4 g. of Al per day) they may absorb up to 1. 2.
Berlyne, G. M., Yagil, R., Ben Ari, J., Weinberger, G., Knopf, E., Danovitch, G. M. Lancet, 1972, i, 564. Bailey, R. R., Eastwood, J. B., Clarkson, E. M., Luck, V. A., Hynson, W. V., O’Riordan, J. L. H., Woodhead, J. S., Clements, V. R., de Wardener, H. E. Clin. Sci. 1971, 41, 5p (abstr.); Clin. Sci. (in the press). DETAILS OF CONTROL AND
*
2 with
5/6
17 % of the administered dose of Al; this agent, which is of great value to nephrologists, can no longer be considered non-absorbable. However, the only convincing evidence for " Al toxicity " in man appears attributable to phosphate depletion,3 although a report by Parsons et al.4 suggests that an increased bone-Al content-not necessarily associ" ated with AI(OH)a therapy-may be important in Newcastle dialysis bone disease ". Berlyne et a1.5 previously concluded that AI(OH)3 administration may have been responsible for the increased -Al (neutron activation) observed in two of six serr non-dialysed uraemic patients given Al. None of these six patients, however, had the serum-Al estimated before treatment. These data were not convincing evidence that the raised serum-Al was actually due to the ingestion of Al(OH)3 (and this also applied to their observations with Al resins); although this would seem a most reasonable conclusion, in view of the recent report by de Wardener and co-workers.6 Some of the findings reported by Berlyne et al. do not accord with my own observations in 5/6 nephrectomised rats given Al salts; especially those animals given 1% AlClg drinking-water. The table shows that seven of ten urae1IÙc rats drinking AICla died within 6 days (mean survival 4-7±s.E.M. 0-4 days) of severe dehydration as evidenced by the clinical syndrome (similar to the observations of Berlyne et al. except that periorbital bleeding was not observed), very high serum sodium and chloride (animals venesected when moribund), haemoconcentration, striking weight loss (mean 41%), and increasing azotasmia with hyperphosphatxmia-the important point is that these seven urxmic rats (all of which were monitored in individual metabolic cages) would not, for some as yet unexplained reason, drink the AlCl3. The Al ingested by the uraemic rats that died was negligible. The remaining three ursemic rats and the eight control animals continued to drink the 1 % A1C13 for the 14-day observation period and survived. If the 1 % Aids was administered subcutaneously (s.c.) in a single daily dose for up to 14 days (mean quantity of injected Al per kg. for all rats 746:36 mg.) all animals (eight urxmic and eight controls) survived, although they became somewhat lethargic, possibly as a result of the necrosis at the injection sites. Interestingly in comparison to the uraemic animals who were given AICla in drinkingwater and died, the urxmic animals injected with this salt did not develop any deterioration of renal function, electrolyte disturbance, weight loss, or significant change in plasma3. Lotz, M., Zisman, E., Bartter, F. C. New Engl. J. Med. 1968, 278, 409. 4. Parsons, V., Davies, C., Goode, C., Ogg, C., Siddiqui, J. Br. med. J. 5.
1971, iv, 273. Berlyne, G. M., Ben-Ari, J., Pest, D., Weinberger, J., Stem, M., Gilmore, G. R., Levine, R. Lancet, 1970, ii, 494.
NEPHRECTOMISED RATS GIVEN
conjunctival infection; 3 with terminal epistaxis.
1% Aids DRINKING-WATER
t Assessed
on
individual initial weight.
277
AI(OH)3 (same dosage regimen as used administered s.c. daily for 14 days al.) all animals survived, but they similarly became ill and developed large necrotic lesions; all urasmic and control animals given AI(OH)3 daily by the intraperitoneal (i.p.) route died with a massive granulomatous peritonitis with
phosphate. by Berlyne
When
et
was
ascites. The observations made
by Professor Berlyne and his col-
leagues have been important in drawing doctors’ attention the possible dangers of AI(OH)3 and other Al compounds administered orally to man, but I am strongly of the opinion that their ursemic rats given Al salts to drink (at least 1% AlCIg) died of dehydration rather than Al toxicity and the animals given i.p. AI(OH)3 died of a severe peritonitis.
to
Renal Unit, Victoria Hospital and Department of Medicine, University of Western Ontario, London, Ontario, Canada.
Ross R. BAILEY.
transferring systems involving A.T.P. are similarly influenced by A13+, and we are exploring this. We have demonstrated interactions of A.T.P. and A13+ by electrometric methods, which suggest complexation, and these interactions are influenced by Mg2+. We believe that the finding by Thurston and Berlyne and their colleagues of A13+ incorporation into tissue accompanying use of aluminium hydroxide is sufficient reason to warrant a thorough study of its application by the drug industry and possibly also the food industry. This should not be negated by the rather restricted and short-term studies done previously. Our studies with hexokinase suggest that it, or possibly all phosphate-transferring systems involving A.T.P. and Mg2+, are possible biological target-sites for A13+. It is important to note that an investigator could miss an inhibition effect of this type if the conditions of the standard assay procedure were strictly conformed to with respect to maximisation of co-factor concentrations. Departments of Neurological Sciences and Biochemistry, Rush Medical College, 1725 West Harrison Street, Chicago, Illinois 60612, U.S.A.
W. H. HARRISON ELLEN CODD R. M. GRAY.
ALUMINIUM INHIBITION OF HEXOKINASE
SIR,-The possibility of aluminium toxicity when aluminium hydroxide is used in treatment of hyperphosphataemia of renal failure or as an insoluble antacid has been explored by Dr. Thurston (April 22, p. 881) and Dr. Berlyne (March 11, p. 564) and their colleagues, and the two groups have come to different conclusions. Thurston et al. disagree with the statement of Berlyne et al. that it is " advisable to suspend the widespread use of aluminium salts in man pending further studies of this problem ". This impasse results not from a disagreement on whether aluminium is incorporated to some extent into tissue, since both agree on this, but rather on whether the incorporation is sufficient to justify eliminating its use. This question will have to be resolved by long-term clinical investigations as well as by biochemical studies. Regarding the latter, there is an unfortunate paucity of information on biochemical effects of aluminium. In the light of this current interest in aluminium toxicity, we believe that some earlier unpublished observations we have on Al3-r inhibition of mammalian hexokinase may be pertinent to this problem. Having found an unanticipated A13+ inhibition of yeast hexokinase at levels as low as 1 x 10-5M, we tested mammalian hexokinase for AP+ inhibition using homogenates of various tissues of the guineapig. Employing a standard spectrophotometric method,l we found that 1 X 10-4M A13+ inhibited the hexokinase of all tissue studied, including heart (57%), kidney (79%), liver (100%), brain (66%), skin (100%), and spleen (37%). In an aqueous extract of kidney which represented soluble hexokinase we found 30% inhibition at 1 x 10-4MA13+ and 11% at 1O-5M AP-. It should be noted that we used a Mg2+ level in the assays which was suboptimal (rate limiting) with respect to the enzyme and A.T.P. (1 x 1O-4M MgCI2, 1 X 10-3M A.T.P.); this was a departure from the standard assay methods, which employ optimal concentrations of all co-factors. One reason for using lowered Mg2+ levels was that we had found previously with yeast hexokinase that A13+ inhibition was not observable unless Mg2+ was suboptimal, and that inhibition varied with the suboptimal levels-for example, 4 x 10-4M A13+ inhibited the enzyme 87% at 4 x 10-4M Mg2+ and 18% at 4 x 10-sM Mg2+, while 4 x 1O-81B,f AP+ inhibited the enzyme 59% at 4 x 10-4M Mg2+ and 13% at 4 x 10-M Mg2+. Also, it should be noted that suboptimal levels of Mg2+ are more reflective of the physiologic situation, numerous studies having indicated that Mg2+ levels are suboptimal with respect to the metabolic systems requiring it in tissue.2 The relationship shown between Mg2+ and A13+ raises the question of whether other Mg2+-requiring phosphate1. 2.
Bachelard, H. S., Goldfarb, P. S. G. Biochem.J. 1969, 112, 579. Rose, I. A. Proc. natn. Acad. Sci. U.S.A. 1968, 61, 1079.
RABIES
SiR,—Your editorial (July 15, p. 123), commenting on the survival of the boy who was proved on epidemiological, clinical, and laboratory evidence to have been infected with the rabies virus, makes interesting, indeed historic, reading. As I belong to an older generation of microbiologists, reared on Koch’s doctrines, may I be permitted to observe that it is unfortunate for strict scientific recording that the xtiological agent could not be isolated from the patient. During many years of laboratory work in a diagnostic laboratory, as a modus vivendi, I have had to resolve long ago to abide by the golden rule that serological results have to be regarded as only second-best evidence in diagnostic work. It is perhaps not illogical to have to admit (albeit sottovoce) that the extraordinary high titres (phenomenal, as Turner1 so aptly put it) reported by Hattwick and his colleagues appear rather convincing and pretty well conclusive, if only ... Royal Army Medical College, Millbank, London SW1P 4RJ.
ETHELWALD E. VELLA.
REORGANISATION OF THE SCOTTISH HEALTH SERVICE
SiR,—You will be aware of the present controversy within B.A.S.W. over the provision of a social work service to patients. The recommendation of the association is that " overall responsibility for providing a social work service to the community shall continue to lie with the Local Authority and responsibility for ensuring a social work service to patients shall lie with the Area Health Board which shall contract with the Local Authority Social Service Department to provide the service ". Because B.A.S.W. represents all social workers, medical social workers and psychiatric social workers are a minority group within it. Although there are clear indications that a very considerable number of this group feel strongly that the Health Service should have direct responsibility for the provision of a social work service to patients, B.A. S.W. has not thought it necessary to seek the individual views of those most closely affected by their policy on Health Service reorganisation. 1.
Trop. Dis. Bull. 1972, 69, 616.
powerful
age, sex, maternal
chronic diseases. Philip Morris Research Center, P.O. Box 26583,
Richmond, Virginia 23261, U.S.A.
HELMUT R. R. WAKEHAM.
PERIPHERAL VENOUS SCANNING WITH 125I-TAGGED FIBRINOGEN
SIR,—Dr. Williams and Dr. Croft (April 29, p. 954) are in their objection to the inclusion of all patients with a positive lung scan ". The patients who were judged to have pulmona’-v embolism had pleuritic pain, breathlessness, with or without hxmoptysis, high erythrocyte-sedimentation rate, chest X-ray and lung-scan abnormalities suggesting pulmonary embolism, and, in some cases, electrocardiographic change "
correct
consistent with pulmonary embolism. Clinical progress, serial chest radiography, and lung scans all confirmed the diagnosis of pulmonary embolism. Patients with only an abnormal lung scan were not included in the series. We are well aware of the fallibility of the lung scan alone in patients with pre-existing lung disease, especially in the older age-group. Department of Radiology and A. F. MACDONALD Clinical Scanning Unit, Aberdeen. J. GADDIE. Royal Infirmary,
ALUMINIUM TOXICITY IN RATS AND MAN SiR—I was most interested to read the report by Berlyne et al.l in which they described aluminium (Al) intoxication in ursemic and non-uraemic rats given aluminium salts orally or parenterally. The continuing debate has interested me, since our group has shown2 that when patients with chronic renal failure are given AI(OH)a gel B.P. (’Aludrox’) in divided doses totalling 75-150 ml. per day (1-5-3-4 g. of Al per day) they may absorb up to 1. 2.
Berlyne, G. M., Yagil, R., Ben Ari, J., Weinberger, G., Knopf, E., Danovitch, G. M. Lancet, 1972, i, 564. Bailey, R. R., Eastwood, J. B., Clarkson, E. M., Luck, V. A., Hynson, W. V., O’Riordan, J. L. H., Woodhead, J. S., Clements, V. R., de Wardener, H. E. Clin. Sci. 1971, 41, 5p (abstr.); Clin. Sci. (in the press). DETAILS OF CONTROL AND
*
2 with
5/6
17 % of the administered dose of Al; this agent, which is of great value to nephrologists, can no longer be considered non-absorbable. However, the only convincing evidence for " Al toxicity " in man appears attributable to phosphate depletion,3 although a report by Parsons et al.4 suggests that an increased bone-Al content-not necessarily associ" ated with AI(OH)a therapy-may be important in Newcastle dialysis bone disease ". Berlyne et a1.5 previously concluded that AI(OH)3 administration may have been responsible for the increased -Al (neutron activation) observed in two of six serr non-dialysed uraemic patients given Al. None of these six patients, however, had the serum-Al estimated before treatment. These data were not convincing evidence that the raised serum-Al was actually due to the ingestion of Al(OH)3 (and this also applied to their observations with Al resins); although this would seem a most reasonable conclusion, in view of the recent report by de Wardener and co-workers.6 Some of the findings reported by Berlyne et al. do not accord with my own observations in 5/6 nephrectomised rats given Al salts; especially those animals given 1% AlClg drinking-water. The table shows that seven of ten urae1IÙc rats drinking AICla died within 6 days (mean survival 4-7±s.E.M. 0-4 days) of severe dehydration as evidenced by the clinical syndrome (similar to the observations of Berlyne et al. except that periorbital bleeding was not observed), very high serum sodium and chloride (animals venesected when moribund), haemoconcentration, striking weight loss (mean 41%), and increasing azotasmia with hyperphosphatxmia-the important point is that these seven urxmic rats (all of which were monitored in individual metabolic cages) would not, for some as yet unexplained reason, drink the AlCl3. The Al ingested by the uraemic rats that died was negligible. The remaining three ursemic rats and the eight control animals continued to drink the 1 % A1C13 for the 14-day observation period and survived. If the 1 % Aids was administered subcutaneously (s.c.) in a single daily dose for up to 14 days (mean quantity of injected Al per kg. for all rats 746:36 mg.) all animals (eight urxmic and eight controls) survived, although they became somewhat lethargic, possibly as a result of the necrosis at the injection sites. Interestingly in comparison to the uraemic animals who were given AICla in drinkingwater and died, the urxmic animals injected with this salt did not develop any deterioration of renal function, electrolyte disturbance, weight loss, or significant change in plasma3. Lotz, M., Zisman, E., Bartter, F. C. New Engl. J. Med. 1968, 278, 409. 4. Parsons, V., Davies, C., Goode, C., Ogg, C., Siddiqui, J. Br. med. J. 5.
1971, iv, 273. Berlyne, G. M., Ben-Ari, J., Pest, D., Weinberger, J., Stem, M., Gilmore, G. R., Levine, R. Lancet, 1970, ii, 494.
NEPHRECTOMISED RATS GIVEN
conjunctival infection; 3 with terminal epistaxis.
1% Aids DRINKING-WATER
t Assessed
on
individual initial weight.
277
AI(OH)3 (same dosage regimen as used administered s.c. daily for 14 days al.) all animals survived, but they similarly became ill and developed large necrotic lesions; all urasmic and control animals given AI(OH)3 daily by the intraperitoneal (i.p.) route died with a massive granulomatous peritonitis with
phosphate. by Berlyne
When
et
was
ascites. The observations made
by Professor Berlyne and his col-
leagues have been important in drawing doctors’ attention the possible dangers of AI(OH)3 and other Al compounds administered orally to man, but I am strongly of the opinion that their ursemic rats given Al salts to drink (at least 1% AlCIg) died of dehydration rather than Al toxicity and the animals given i.p. AI(OH)3 died of a severe peritonitis.
to
Renal Unit, Victoria Hospital and Department of Medicine, University of Western Ontario, London, Ontario, Canada.
Ross R. BAILEY.
transferring systems involving A.T.P. are similarly influenced by A13+, and we are exploring this. We have demonstrated interactions of A.T.P. and A13+ by electrometric methods, which suggest complexation, and these interactions are influenced by Mg2+. We believe that the finding by Thurston and Berlyne and their colleagues of A13+ incorporation into tissue accompanying use of aluminium hydroxide is sufficient reason to warrant a thorough study of its application by the drug industry and possibly also the food industry. This should not be negated by the rather restricted and short-term studies done previously. Our studies with hexokinase suggest that it, or possibly all phosphate-transferring systems involving A.T.P. and Mg2+, are possible biological target-sites for A13+. It is important to note that an investigator could miss an inhibition effect of this type if the conditions of the standard assay procedure were strictly conformed to with respect to maximisation of co-factor concentrations. Departments of Neurological Sciences and Biochemistry, Rush Medical College, 1725 West Harrison Street, Chicago, Illinois 60612, U.S.A.
W. H. HARRISON ELLEN CODD R. M. GRAY.
ALUMINIUM INHIBITION OF HEXOKINASE
SIR,-The possibility of aluminium toxicity when aluminium hydroxide is used in treatment of hyperphosphataemia of renal failure or as an insoluble antacid has been explored by Dr. Thurston (April 22, p. 881) and Dr. Berlyne (March 11, p. 564) and their colleagues, and the two groups have come to different conclusions. Thurston et al. disagree with the statement of Berlyne et al. that it is " advisable to suspend the widespread use of aluminium salts in man pending further studies of this problem ". This impasse results not from a disagreement on whether aluminium is incorporated to some extent into tissue, since both agree on this, but rather on whether the incorporation is sufficient to justify eliminating its use. This question will have to be resolved by long-term clinical investigations as well as by biochemical studies. Regarding the latter, there is an unfortunate paucity of information on biochemical effects of aluminium. In the light of this current interest in aluminium toxicity, we believe that some earlier unpublished observations we have on Al3-r inhibition of mammalian hexokinase may be pertinent to this problem. Having found an unanticipated A13+ inhibition of yeast hexokinase at levels as low as 1 x 10-5M, we tested mammalian hexokinase for AP+ inhibition using homogenates of various tissues of the guineapig. Employing a standard spectrophotometric method,l we found that 1 X 10-4M A13+ inhibited the hexokinase of all tissue studied, including heart (57%), kidney (79%), liver (100%), brain (66%), skin (100%), and spleen (37%). In an aqueous extract of kidney which represented soluble hexokinase we found 30% inhibition at 1 x 10-4MA13+ and 11% at 1O-5M AP-. It should be noted that we used a Mg2+ level in the assays which was suboptimal (rate limiting) with respect to the enzyme and A.T.P. (1 x 1O-4M MgCI2, 1 X 10-3M A.T.P.); this was a departure from the standard assay methods, which employ optimal concentrations of all co-factors. One reason for using lowered Mg2+ levels was that we had found previously with yeast hexokinase that A13+ inhibition was not observable unless Mg2+ was suboptimal, and that inhibition varied with the suboptimal levels-for example, 4 x 10-4M A13+ inhibited the enzyme 87% at 4 x 10-4M Mg2+ and 18% at 4 x 10-sM Mg2+, while 4 x 1O-81B,f AP+ inhibited the enzyme 59% at 4 x 10-4M Mg2+ and 13% at 4 x 10-M Mg2+. Also, it should be noted that suboptimal levels of Mg2+ are more reflective of the physiologic situation, numerous studies having indicated that Mg2+ levels are suboptimal with respect to the metabolic systems requiring it in tissue.2 The relationship shown between Mg2+ and A13+ raises the question of whether other Mg2+-requiring phosphate1. 2.
Bachelard, H. S., Goldfarb, P. S. G. Biochem.J. 1969, 112, 579. Rose, I. A. Proc. natn. Acad. Sci. U.S.A. 1968, 61, 1079.
RABIES
SiR,—Your editorial (July 15, p. 123), commenting on the survival of the boy who was proved on epidemiological, clinical, and laboratory evidence to have been infected with the rabies virus, makes interesting, indeed historic, reading. As I belong to an older generation of microbiologists, reared on Koch’s doctrines, may I be permitted to observe that it is unfortunate for strict scientific recording that the xtiological agent could not be isolated from the patient. During many years of laboratory work in a diagnostic laboratory, as a modus vivendi, I have had to resolve long ago to abide by the golden rule that serological results have to be regarded as only second-best evidence in diagnostic work. It is perhaps not illogical to have to admit (albeit sottovoce) that the extraordinary high titres (phenomenal, as Turner1 so aptly put it) reported by Hattwick and his colleagues appear rather convincing and pretty well conclusive, if only ... Royal Army Medical College, Millbank, London SW1P 4RJ.
ETHELWALD E. VELLA.
REORGANISATION OF THE SCOTTISH HEALTH SERVICE
SiR,—You will be aware of the present controversy within B.A.S.W. over the provision of a social work service to patients. The recommendation of the association is that " overall responsibility for providing a social work service to the community shall continue to lie with the Local Authority and responsibility for ensuring a social work service to patients shall lie with the Area Health Board which shall contract with the Local Authority Social Service Department to provide the service ". Because B.A.S.W. represents all social workers, medical social workers and psychiatric social workers are a minority group within it. Although there are clear indications that a very considerable number of this group feel strongly that the Health Service should have direct responsibility for the provision of a social work service to patients, B.A. S.W. has not thought it necessary to seek the individual views of those most closely affected by their policy on Health Service reorganisation. 1.
Trop. Dis. Bull. 1972, 69, 616.