- Email: [email protected]
LEAD IN PETROL
1264
Formaldehyde, like all other chemicals, is potentially a toxic substance. However, it is also a normal metabolite of most mammalian biological systems,l and there are biotransformation mechanisms available in man which can metabolise formaldehyde to formic acid2 and hence to carbon dioxide and water.3 The dermatological problems associated with formaldehyde are well documented, but to imply that formaldehyde be compared to asbestos, a known human carcinogen, is, on present evidence, unnecessarily alarmist. Where interrelations between chemical exposure and cancer in man have occurred they have usually been first identified in working populations exposed to the risk materials. It is highly unlikely that a chemical carcinogen will avoid detection in the manufacturing/user group and appear, in the first instance, in the general public. Study of the working population should give some idea of potential risk. At a 1980 CIIT seminar on formaldehyde the results of four retrospective studies on several thousands of people engaged in the manufacture of formaldehyde and in its use (embalmers and morticians) were presented. No overall excess of deaths from cancer or deaths from respiratory disease was discovered in the populations studied. Further epidemiological studies were recommended and large investigations of formaldehyde workers are in progress in the U.S.A. (National Cancer Institute/Formaldehyde Institute) and the U.K. (Medical Research Council). The published results of these surveys should help to identify any specific health hazard of under known exposure conditions. of the problems reported as being associated with Many formaldehyde have resulted from exposure to formaldehyde at unknown, "but high", levels or to atmospheric levels well in excess of the current threshold limit value of 2 p.p.m. Such exposures should be avoided.
formaldehyde
Agricultural Division, Imperial Chemical Industries Ltd, Billingham, Cleveland TS23 1LE
D. D. BRYSON, Chairman, Medical Sub-committee, Formaldehyde Health Impact Study Team
SlR,—Your April 25 editorial should have been entitled "Formaldehyde Misconceptions". The basic one was the imputation of irritant effects of high doses (much greater than 5 -0and up to 30 - 0 p.p.m.) to doses less than 3-00 p.p.m. You also imply that at low doses there is substantial evidence for immunological sensitisation. You were wrong to state that the threshold limit value (TLV) for formaldehyde has been reduced to 2 -0p.p.m. in the United States. Furthermore, though the National Institute for Occupational Safety and Health (NIOSH) did, in 1976, recommend a 10p.p.m. TLV, on the basis of a suspect group of in-house reports and a paper by Schuck et al. not containing formaldehyde measurements, the TLV has remained unchanged at 3 - p.p.m.4,5 The "skin sensitivity", attributed to formaldehyde in your editorial, drawing on Glass’s work,6 was attributed by Glass himself to urea-formaldehyde resin. This resin (or other constituents) may be irritating, but formaldehyde at low doses was not found to be either an irritant or an immunological sensitiser. The view that formaldehyde vapour, in low or even moderate doses, sensitises the airways immunologically has not been substantiated and needs experimental confirmation in man. The myth of textile dermatitis from immunological sensitisation to formaldehyde was exploded long ago-by Marcussen,1,8 who could not separate irritant from putatively allergic effects at levels down to 1. Akabane J. Aldehydes and related compounds. Int Encycl Pharmacol Ther section 20(2): 523. 2. Williams RT. Detoxication mechanisms, toxic substances and other organic compounds, 2nd ed. New York: Wiley, 1959: 18-19. 3. Neely WB. The metabolic fate of formaldehyde-14c. Biochem Pharmacol 1964; 13: 1137-42. 4. Berger JM, Lamm SH. In: Professional Consultants in Occupational Health, Inc., ed A comprehensive report on human exposure to formaldehyde at low, or trace concentrations. Washington, DC: U.S. Consumer Product Safety Commission, 1980 August, 1980. 5. National Institute for Occupational Safety and Health. Criteria for recommended standard... occupational exposure to formaldehyde. NIOSH publn 77-126, 1976. 6. Glass WI. An outbreak of fomaldehyde dermatitis. NZ Med J 1961; 60: 423-27 7. Marcussen PV. Dermatitis caused by formaldehyde resins in textiles. Dermatologica
1962; 125: 101-11. 8. Marcussen PV. Comparison of the intradermal test and patch test using nickel sulfate and formaldehyde: a quantitative approach J Invest Dermatol 1963; 40: 263-66.
10-5 dilutions of 4% formalin; by Cronin,’ who noted the very low incidence of possible cases; by Skogh, 10 who noted that the eczema sites were those commonly macerated by hyperhidrosis and occurred very frequently in climacteric women; and by others4.;.1212 including Marcussen, who noted that the use of antiperspirant coagulators in Europe paralleled the rise of textile dermatitis. While persons appear sensitive to many dyes, dye-fast substances, colouring agents, and other substances in textiles, immunological sensitivity to formaldehyde by itself in clothing has yet to be established as a substantial clinical entity rather than a rare
idiosyncrasy. Many measurements of formaldehyde have been done by students of Mr Peter A. Breysse, an industrial hygienist. The complaints studied did
not
show
a
dose-response effect in any of the series
published in his newsletter, nor has he done a controlled study. Breysse himself has not attributed complaints exclusively to formaldehyde,11as he is often interpreted as saying. He has focused on the general problem of indoor air contamination and its effects in homes built, in response to warnings of an energy crisis during the Carter administration, to resemble energy-tight plastic bags. None of the symptoms listed in the editorial have ever been attributed scientifically in the indoor environment "at levels well below 1 p.p.m.". They have been associated, because only formaldehyde has been measured. Formaldehyde has not been shown, in the studies you cite, to be a probable cause of the symptomslz,r3 "Attribution" means that some association with strength, statistically or otherwise, has been shown: this is not the case for formaldehyde, particularly below 3’0 0 p.p.m. Rats exposed to intolerable levels of formaldehyde for lifetimes had cancers at the sites of classic inflammation in the nose at or near the initial site of exposure, but nowhere else in any excess. These tumours are very rare in man and virutally non-reported in formaldehyde workers. These animal neoplasms may be considered the results of the peculiar circumstances of the bioassay, one of which circumstances was an upper respiratory viral infection early on, another being a no effect level at 2 - 0 p.p.m. Formaldehyde is indeed "now becoming recognised as a problem for the whole community" but this may in large part be due to the wholesale dissemination of misinformation in respect of common indoor exposure levels, such as the programme launched two years ago by the U.S. Consumer Product Safety Commission. Scientists and physicians should scrutinise the formaldehyde poisoning story, paying special attention to the dose, the association, and the methods used to draw conclusions-and then decide for themselves. Professional Consultants in
Occupational Health, Inc.,
J. M. BERGER
Avenue, Suite 205, Bethesda, Maryland 20014, U.S.A. 7720 Wisconsin
S. H. LAMM
LEAD IN PETROL
SIR,-The comments by Dr Russell Jones on the evils of lead in petrol (May 23, p. 1160) suggest a paucity of knowledge on the subject, equatable perhaps with my own on dermatology. The Government’s recent decision to reduce lead in petrol from 0.4 g/l to 0 15 g/1 by the end of 1985 was based upon the recommendations in the Lawther report (sections 208 and 209).’ This D.H.S,S. working party found that the contribution of lead from motor vehicles to the body burden was small, between 5 and 15%, relative the contribution from other sources, but nevertheless recommended a reduction "subject to an appraisal of any other possible effects on health of altering the constituents of petrol" (section 211[ 5]). Reducing lead in petrol to 0 -15 g/1 could result inaa to
9. Cronin E. Formalin textile dermatitis. BrJ Derm 1963; 75: 267-73. 10. Skogh M. Axillary eczema in women Acta Derm-Venereol 1959; 39: 369-71 11. Breysse PA, The health cost of"tight" homes. JAMA 1981; 245: 267-68 12. Berger JM, Lamm SH. In: Professional Consultants In Occupational Health, Inc. ed A medical and scientific assessment of regulatory positions on formaldehyde, health and cancer. Washington, DC. US Consumer Product Safety Commission, 1981 13. National Research Council. Formaldehyde and other aldehydes. Washington. DC National Academy Press, 1981 1. Lead and health: Report by D.H.S.S. working party London: HM Stationery Office, 1980.
on
lead in the environment
1265
greater requirement for additional aromatic compounds to make up for the lost octane numbers, which might well give rise to a potential carcinogenic risk. Contrary to Russell Jones’ understanding, lead is not an accumulative poison in a physiological sense. It accumulates in bone, after the second decade of life, where it remains physiologically inactive. It does not accumulate in the physiologically active soft tissues,2because input is very largely balanced by excretory output.3Because encephalopathy may arise at blood lead concentrations well in excess of 80 g/dl, it does not follow that adverse neurotoxic effects will be evident at 15-20 µg/dl, values commonly found in the general population. Were this to be so then all neurotoxins, including aspirin and general anaesthetics, would have to be considered unacceptable and should be summarily banned. Like others before him, Russell Jones, in his reference to the placental barrier and the potential for the development of mental retardation in later life, fails to differentiate between unacceptably high levels of lead absorption and the low levels to which we are all subjected by the natural consequence of our birth on a planet where lead is ubiquitous and inescapable. Although he appears to blame lead in petrol it is interesting that he refers to a study on lead in water4 as his example for mental retardation. The amount of tetraethyl lead in urban atmospheres has been found to be only 1-4% of the total lead. Values in excess of this may exist in the vicinity of petrol stations.These very low values are not considered to be of health significance. Russell Jones should know that the fat soluble tetra-alkyl lead compounds have no effect on the brain; only the trialkyl lead compounds, formed by decomposition in the liver, exert a specific toxic action on brain cells. These are both water and fat soluble and appear in greater concentrations in the liver and kidneys, upon which they appear to have no toxic effect, than in the The lead content in petrol was reduced from 0 · 4 to 015 g/1 in West Germany in January, 1976. Two years later the blood lead concentrations in population groups in Frankfurt, selected for their greater potential exposure to lead from motor vehicle exhausts, had stabilised at a reduction of lead in blood of 1-2 lagldl, equivalent to less than 10% of the total blood lead.8This is the probable extent of the effect that we can expect to see in the British population following the Government’s decision. The recent E.E.C. report on 17 500 blood samples from within member States showed an average lead level of 13 µg/dl, a figure considerably lower than those that were commonly observed ten years ago.9 During this same decade the total use of lead in petrol showed only marginal fluctuations in European countries. There is no reason to suppose that the reduction of lead in petrol to 0 · 15 g/1, or its abolition, will give rise to any recognisable health benefits.
brain.’,,7
’
Associated Octel Company Ltd, Ellesmere Port, South Wirral L65 4HF
.
P. S. I. BARRY
SEX AND SURVIVAL IN ACUTE LEUKAEMIA
SIR,—Dr Eden’s letter (May 9, p. 1053) referring to the article of Dr Sather and colleagues (April 4, p. 739) raises some very important points, and he may well be correct in his implication that, after induction therapy, some more intensive consolidation is 2. Barry
PSI. A comparison of concentrations of lead in human tissues. Br J Ind Med 1975;
32: 119-39. 3 Kehoe RA. The Harben lectures, 1960: The metabolism of lead in man in health and disease. J Roy Inst Publ Hlth 1961; 24: 81-96, 101-120, 129-143, 177-203. 4 Moore M, Meredith P, Goldberg A. A retrospective analysis of blood lead in mentally retarded children. Lancet 1977; i: 717-19. 5 Harrison RM, Perry R. The analysis of tetraalkyl lead compounds and their significance as urban air pollutants. Atmos Envir 1977; 2: 847-52. 6. Cremer JE. Biochemical studies on the toxicity of tetraethyl lead andother organo-lead compounds. Br J Ind Med 1959; 16: 191-99. 7 Springman F, Bingham E, Stemmer KL. The acute effects of lead alkyls. Arch Envir Hlth 1963; 6: 469-72. 8. Sinn W. Relationship between lead concentrations in the air and blood lead levels of people living and working in the centre ofa city (Frankfurt blood lead study) I, Experimental method and examination of differences; II, Correlations and conclusions. Int Arch Occup Envir Hlth 1980; 47: 93-118; 1981: 48: 1-23. 9 Commission of the European Communities. Progress report on the implementation of the council directive 77/312/EEC of 29 March 1977 on biological screening of the population for lead. COM(81) 88 final. Brussels: EEC, 1981.
necessary before cranial irradiation, to reduce the incidence of testicular disease. We have, however, done fourteen bilateral wedge biopsies of the testes in boys at the completion of induction therapy. Thirteen of the patients had common acute lymphatic leukaemia and one T cell leukaemia. None of these-boys had evidence of occult disease at this stage. We did not have an opportunity to stain specifically for TdT positivity, and this may well have revealed leukaemic cells. The boy with T cell leukaemia and three other patients have relapsed in the bone marrow. None of them had clinically overt testicular disease at the time of relapse. It remains very difficult therefore to select those cases likely to be at risk of testicular relapse. The problem of testicular damage by drugs is another important one. It has been suggested that adequate radiation to the testes and subsequent systemic chemotherapy will rescue children with isolated testicular relapse, but we have recently had a patient in whom recurrent testicular disease developed despite 2400 rads and full systemic therapy. Another two patients died of recurrent disease 6 and 12 months after isolated testicular relapse treated with radiation. These 12 boys at post mortem had very limited infiltration of all organs except the testes, which were densely involved. Work in Manchester on mice (unpublished) suggests that unless there is direct trauma to the testes infiltration does not occur. Other animal models may show different results. Necropsy data on children dying’early are obviously a selected population and do not reflect the overall picture. We suggest that attempts to eradicate possible residual disease in the testes should therefore be in the form of a carefully planned controlled trial. A comparison of an intensive drug regimen which does not of itself produce significant changes in testicular morphology with the current standard management regimen would seem a sensible starting point. Departments of Paediatric Oncology and Pathology, Royal Manchester Children’s Hospital, Manchester M27 1HA
P. H. MORRIS M. LENDON
JONES
AETIOLOGY OF CEREBRAL ANEURYSMS
SIR,—The paper by Dr Pope and his colleagues (May 2, p. 973) on type III collagen deficiency and cerebral aneurysms contains the apparent assumption that such aneurysms have a congenital aetiology. They report a reduction in type III collagen in seven out of twelve patients "with congenital cerebral aneurysms" and imply that such a deficit results in aneurysm formation before birth. There is little evidence to support this view. Defects in the medial layer of an anterior cerebral artery were described by Bruce et al. at the site ofacerebral aneurysm, but were later shown by Du Boulay2to be a physiological mechanism to avoid buttonhole stenosis of the branch during vasoconstriction. Other findings, including the high age at which rupture of aneurysms occurs (40- 60 years)3 and the very low incidence of cerebral aneurysms found at necropsy in children,confirms that the vast majority of aneurysms are acquired during life. Bell and SymonS found that cigarette smokers have an increased incidence of subarachnoid haemorrhage, and other workhas shown an association with influenza A. Pope et al. do not seem to have considered an acquired defect in collagen synthesis as being the cause of aneurysm formation and give very few details of the patients studied. Department of Medicine, University Hospital of Wales, Cardiff CF4 4XW
DAVID B.
JONES
1. Bruce A, Pine JHH, McDonald WK. Aneurysm of the anterior cerebral artery with unusual prolongation of life after rupture. Rev Neurol Psychiat 1908; 6: 449-62. 2. Du Boulay GH Some observations on the natural history of intracranial aneurysms. Br J Radiol 1965, 38: 721-57. 3 Locksley HB Natural history of subarachnoid haemorrhage, intracranial aneurysms and arteriovenous malformations. J Neurosurg 1966; 25: 219-39 4. Uttley D Subarachnoid haemorrhage. Br J Hosp Med 1978; 19: 138-54. 5. Bell BA, Symon L. Smoking and subarachnoid haemorrhage. Br Med J 1979, i. 577-78. 6. Jones DB. An association between influenza A virus and subarachnoid haemorrhage. Postgrad Med J 1979, 55: 853-55
Formaldehyde, like all other chemicals, is potentially a toxic substance. However, it is also a normal metabolite of most mammalian biological systems,l and there are biotransformation mechanisms available in man which can metabolise formaldehyde to formic acid2 and hence to carbon dioxide and water.3 The dermatological problems associated with formaldehyde are well documented, but to imply that formaldehyde be compared to asbestos, a known human carcinogen, is, on present evidence, unnecessarily alarmist. Where interrelations between chemical exposure and cancer in man have occurred they have usually been first identified in working populations exposed to the risk materials. It is highly unlikely that a chemical carcinogen will avoid detection in the manufacturing/user group and appear, in the first instance, in the general public. Study of the working population should give some idea of potential risk. At a 1980 CIIT seminar on formaldehyde the results of four retrospective studies on several thousands of people engaged in the manufacture of formaldehyde and in its use (embalmers and morticians) were presented. No overall excess of deaths from cancer or deaths from respiratory disease was discovered in the populations studied. Further epidemiological studies were recommended and large investigations of formaldehyde workers are in progress in the U.S.A. (National Cancer Institute/Formaldehyde Institute) and the U.K. (Medical Research Council). The published results of these surveys should help to identify any specific health hazard of under known exposure conditions. of the problems reported as being associated with Many formaldehyde have resulted from exposure to formaldehyde at unknown, "but high", levels or to atmospheric levels well in excess of the current threshold limit value of 2 p.p.m. Such exposures should be avoided.
formaldehyde
Agricultural Division, Imperial Chemical Industries Ltd, Billingham, Cleveland TS23 1LE
D. D. BRYSON, Chairman, Medical Sub-committee, Formaldehyde Health Impact Study Team
SlR,—Your April 25 editorial should have been entitled "Formaldehyde Misconceptions". The basic one was the imputation of irritant effects of high doses (much greater than 5 -0and up to 30 - 0 p.p.m.) to doses less than 3-00 p.p.m. You also imply that at low doses there is substantial evidence for immunological sensitisation. You were wrong to state that the threshold limit value (TLV) for formaldehyde has been reduced to 2 -0p.p.m. in the United States. Furthermore, though the National Institute for Occupational Safety and Health (NIOSH) did, in 1976, recommend a 10p.p.m. TLV, on the basis of a suspect group of in-house reports and a paper by Schuck et al. not containing formaldehyde measurements, the TLV has remained unchanged at 3 - p.p.m.4,5 The "skin sensitivity", attributed to formaldehyde in your editorial, drawing on Glass’s work,6 was attributed by Glass himself to urea-formaldehyde resin. This resin (or other constituents) may be irritating, but formaldehyde at low doses was not found to be either an irritant or an immunological sensitiser. The view that formaldehyde vapour, in low or even moderate doses, sensitises the airways immunologically has not been substantiated and needs experimental confirmation in man. The myth of textile dermatitis from immunological sensitisation to formaldehyde was exploded long ago-by Marcussen,1,8 who could not separate irritant from putatively allergic effects at levels down to 1. Akabane J. Aldehydes and related compounds. Int Encycl Pharmacol Ther section 20(2): 523. 2. Williams RT. Detoxication mechanisms, toxic substances and other organic compounds, 2nd ed. New York: Wiley, 1959: 18-19. 3. Neely WB. The metabolic fate of formaldehyde-14c. Biochem Pharmacol 1964; 13: 1137-42. 4. Berger JM, Lamm SH. In: Professional Consultants in Occupational Health, Inc., ed A comprehensive report on human exposure to formaldehyde at low, or trace concentrations. Washington, DC: U.S. Consumer Product Safety Commission, 1980 August, 1980. 5. National Institute for Occupational Safety and Health. Criteria for recommended standard... occupational exposure to formaldehyde. NIOSH publn 77-126, 1976. 6. Glass WI. An outbreak of fomaldehyde dermatitis. NZ Med J 1961; 60: 423-27 7. Marcussen PV. Dermatitis caused by formaldehyde resins in textiles. Dermatologica
1962; 125: 101-11. 8. Marcussen PV. Comparison of the intradermal test and patch test using nickel sulfate and formaldehyde: a quantitative approach J Invest Dermatol 1963; 40: 263-66.
10-5 dilutions of 4% formalin; by Cronin,’ who noted the very low incidence of possible cases; by Skogh, 10 who noted that the eczema sites were those commonly macerated by hyperhidrosis and occurred very frequently in climacteric women; and by others4.;.1212 including Marcussen, who noted that the use of antiperspirant coagulators in Europe paralleled the rise of textile dermatitis. While persons appear sensitive to many dyes, dye-fast substances, colouring agents, and other substances in textiles, immunological sensitivity to formaldehyde by itself in clothing has yet to be established as a substantial clinical entity rather than a rare
idiosyncrasy. Many measurements of formaldehyde have been done by students of Mr Peter A. Breysse, an industrial hygienist. The complaints studied did
not
show
a
dose-response effect in any of the series
published in his newsletter, nor has he done a controlled study. Breysse himself has not attributed complaints exclusively to formaldehyde,11as he is often interpreted as saying. He has focused on the general problem of indoor air contamination and its effects in homes built, in response to warnings of an energy crisis during the Carter administration, to resemble energy-tight plastic bags. None of the symptoms listed in the editorial have ever been attributed scientifically in the indoor environment "at levels well below 1 p.p.m.". They have been associated, because only formaldehyde has been measured. Formaldehyde has not been shown, in the studies you cite, to be a probable cause of the symptomslz,r3 "Attribution" means that some association with strength, statistically or otherwise, has been shown: this is not the case for formaldehyde, particularly below 3’0 0 p.p.m. Rats exposed to intolerable levels of formaldehyde for lifetimes had cancers at the sites of classic inflammation in the nose at or near the initial site of exposure, but nowhere else in any excess. These tumours are very rare in man and virutally non-reported in formaldehyde workers. These animal neoplasms may be considered the results of the peculiar circumstances of the bioassay, one of which circumstances was an upper respiratory viral infection early on, another being a no effect level at 2 - 0 p.p.m. Formaldehyde is indeed "now becoming recognised as a problem for the whole community" but this may in large part be due to the wholesale dissemination of misinformation in respect of common indoor exposure levels, such as the programme launched two years ago by the U.S. Consumer Product Safety Commission. Scientists and physicians should scrutinise the formaldehyde poisoning story, paying special attention to the dose, the association, and the methods used to draw conclusions-and then decide for themselves. Professional Consultants in
Occupational Health, Inc.,
J. M. BERGER
Avenue, Suite 205, Bethesda, Maryland 20014, U.S.A. 7720 Wisconsin
S. H. LAMM
LEAD IN PETROL
SIR,-The comments by Dr Russell Jones on the evils of lead in petrol (May 23, p. 1160) suggest a paucity of knowledge on the subject, equatable perhaps with my own on dermatology. The Government’s recent decision to reduce lead in petrol from 0.4 g/l to 0 15 g/1 by the end of 1985 was based upon the recommendations in the Lawther report (sections 208 and 209).’ This D.H.S,S. working party found that the contribution of lead from motor vehicles to the body burden was small, between 5 and 15%, relative the contribution from other sources, but nevertheless recommended a reduction "subject to an appraisal of any other possible effects on health of altering the constituents of petrol" (section 211[ 5]). Reducing lead in petrol to 0 -15 g/1 could result inaa to
9. Cronin E. Formalin textile dermatitis. BrJ Derm 1963; 75: 267-73. 10. Skogh M. Axillary eczema in women Acta Derm-Venereol 1959; 39: 369-71 11. Breysse PA, The health cost of"tight" homes. JAMA 1981; 245: 267-68 12. Berger JM, Lamm SH. In: Professional Consultants In Occupational Health, Inc. ed A medical and scientific assessment of regulatory positions on formaldehyde, health and cancer. Washington, DC. US Consumer Product Safety Commission, 1981 13. National Research Council. Formaldehyde and other aldehydes. Washington. DC National Academy Press, 1981 1. Lead and health: Report by D.H.S.S. working party London: HM Stationery Office, 1980.
on
lead in the environment
1265
greater requirement for additional aromatic compounds to make up for the lost octane numbers, which might well give rise to a potential carcinogenic risk. Contrary to Russell Jones’ understanding, lead is not an accumulative poison in a physiological sense. It accumulates in bone, after the second decade of life, where it remains physiologically inactive. It does not accumulate in the physiologically active soft tissues,2because input is very largely balanced by excretory output.3Because encephalopathy may arise at blood lead concentrations well in excess of 80 g/dl, it does not follow that adverse neurotoxic effects will be evident at 15-20 µg/dl, values commonly found in the general population. Were this to be so then all neurotoxins, including aspirin and general anaesthetics, would have to be considered unacceptable and should be summarily banned. Like others before him, Russell Jones, in his reference to the placental barrier and the potential for the development of mental retardation in later life, fails to differentiate between unacceptably high levels of lead absorption and the low levels to which we are all subjected by the natural consequence of our birth on a planet where lead is ubiquitous and inescapable. Although he appears to blame lead in petrol it is interesting that he refers to a study on lead in water4 as his example for mental retardation. The amount of tetraethyl lead in urban atmospheres has been found to be only 1-4% of the total lead. Values in excess of this may exist in the vicinity of petrol stations.These very low values are not considered to be of health significance. Russell Jones should know that the fat soluble tetra-alkyl lead compounds have no effect on the brain; only the trialkyl lead compounds, formed by decomposition in the liver, exert a specific toxic action on brain cells. These are both water and fat soluble and appear in greater concentrations in the liver and kidneys, upon which they appear to have no toxic effect, than in the The lead content in petrol was reduced from 0 · 4 to 015 g/1 in West Germany in January, 1976. Two years later the blood lead concentrations in population groups in Frankfurt, selected for their greater potential exposure to lead from motor vehicle exhausts, had stabilised at a reduction of lead in blood of 1-2 lagldl, equivalent to less than 10% of the total blood lead.8This is the probable extent of the effect that we can expect to see in the British population following the Government’s decision. The recent E.E.C. report on 17 500 blood samples from within member States showed an average lead level of 13 µg/dl, a figure considerably lower than those that were commonly observed ten years ago.9 During this same decade the total use of lead in petrol showed only marginal fluctuations in European countries. There is no reason to suppose that the reduction of lead in petrol to 0 · 15 g/1, or its abolition, will give rise to any recognisable health benefits.
brain.’,,7
’
Associated Octel Company Ltd, Ellesmere Port, South Wirral L65 4HF
.
P. S. I. BARRY
SEX AND SURVIVAL IN ACUTE LEUKAEMIA
SIR,—Dr Eden’s letter (May 9, p. 1053) referring to the article of Dr Sather and colleagues (April 4, p. 739) raises some very important points, and he may well be correct in his implication that, after induction therapy, some more intensive consolidation is 2. Barry
PSI. A comparison of concentrations of lead in human tissues. Br J Ind Med 1975;
32: 119-39. 3 Kehoe RA. The Harben lectures, 1960: The metabolism of lead in man in health and disease. J Roy Inst Publ Hlth 1961; 24: 81-96, 101-120, 129-143, 177-203. 4 Moore M, Meredith P, Goldberg A. A retrospective analysis of blood lead in mentally retarded children. Lancet 1977; i: 717-19. 5 Harrison RM, Perry R. The analysis of tetraalkyl lead compounds and their significance as urban air pollutants. Atmos Envir 1977; 2: 847-52. 6. Cremer JE. Biochemical studies on the toxicity of tetraethyl lead andother organo-lead compounds. Br J Ind Med 1959; 16: 191-99. 7 Springman F, Bingham E, Stemmer KL. The acute effects of lead alkyls. Arch Envir Hlth 1963; 6: 469-72. 8. Sinn W. Relationship between lead concentrations in the air and blood lead levels of people living and working in the centre ofa city (Frankfurt blood lead study) I, Experimental method and examination of differences; II, Correlations and conclusions. Int Arch Occup Envir Hlth 1980; 47: 93-118; 1981: 48: 1-23. 9 Commission of the European Communities. Progress report on the implementation of the council directive 77/312/EEC of 29 March 1977 on biological screening of the population for lead. COM(81) 88 final. Brussels: EEC, 1981.
necessary before cranial irradiation, to reduce the incidence of testicular disease. We have, however, done fourteen bilateral wedge biopsies of the testes in boys at the completion of induction therapy. Thirteen of the patients had common acute lymphatic leukaemia and one T cell leukaemia. None of these-boys had evidence of occult disease at this stage. We did not have an opportunity to stain specifically for TdT positivity, and this may well have revealed leukaemic cells. The boy with T cell leukaemia and three other patients have relapsed in the bone marrow. None of them had clinically overt testicular disease at the time of relapse. It remains very difficult therefore to select those cases likely to be at risk of testicular relapse. The problem of testicular damage by drugs is another important one. It has been suggested that adequate radiation to the testes and subsequent systemic chemotherapy will rescue children with isolated testicular relapse, but we have recently had a patient in whom recurrent testicular disease developed despite 2400 rads and full systemic therapy. Another two patients died of recurrent disease 6 and 12 months after isolated testicular relapse treated with radiation. These 12 boys at post mortem had very limited infiltration of all organs except the testes, which were densely involved. Work in Manchester on mice (unpublished) suggests that unless there is direct trauma to the testes infiltration does not occur. Other animal models may show different results. Necropsy data on children dying’early are obviously a selected population and do not reflect the overall picture. We suggest that attempts to eradicate possible residual disease in the testes should therefore be in the form of a carefully planned controlled trial. A comparison of an intensive drug regimen which does not of itself produce significant changes in testicular morphology with the current standard management regimen would seem a sensible starting point. Departments of Paediatric Oncology and Pathology, Royal Manchester Children’s Hospital, Manchester M27 1HA
P. H. MORRIS M. LENDON
JONES
AETIOLOGY OF CEREBRAL ANEURYSMS
SIR,—The paper by Dr Pope and his colleagues (May 2, p. 973) on type III collagen deficiency and cerebral aneurysms contains the apparent assumption that such aneurysms have a congenital aetiology. They report a reduction in type III collagen in seven out of twelve patients "with congenital cerebral aneurysms" and imply that such a deficit results in aneurysm formation before birth. There is little evidence to support this view. Defects in the medial layer of an anterior cerebral artery were described by Bruce et al. at the site ofacerebral aneurysm, but were later shown by Du Boulay2to be a physiological mechanism to avoid buttonhole stenosis of the branch during vasoconstriction. Other findings, including the high age at which rupture of aneurysms occurs (40- 60 years)3 and the very low incidence of cerebral aneurysms found at necropsy in children,confirms that the vast majority of aneurysms are acquired during life. Bell and SymonS found that cigarette smokers have an increased incidence of subarachnoid haemorrhage, and other workhas shown an association with influenza A. Pope et al. do not seem to have considered an acquired defect in collagen synthesis as being the cause of aneurysm formation and give very few details of the patients studied. Department of Medicine, University Hospital of Wales, Cardiff CF4 4XW
DAVID B.
JONES
1. Bruce A, Pine JHH, McDonald WK. Aneurysm of the anterior cerebral artery with unusual prolongation of life after rupture. Rev Neurol Psychiat 1908; 6: 449-62. 2. Du Boulay GH Some observations on the natural history of intracranial aneurysms. Br J Radiol 1965, 38: 721-57. 3 Locksley HB Natural history of subarachnoid haemorrhage, intracranial aneurysms and arteriovenous malformations. J Neurosurg 1966; 25: 219-39 4. Uttley D Subarachnoid haemorrhage. Br J Hosp Med 1978; 19: 138-54. 5. Bell BA, Symon L. Smoking and subarachnoid haemorrhage. Br Med J 1979, i. 577-78. 6. Jones DB. An association between influenza A virus and subarachnoid haemorrhage. Postgrad Med J 1979, 55: 853-55