757 and the latest lawn-mowers have so many safety devices attached that they are almost too heavy to push. This year’s model electric mower can only be pushed forward, since O.S.H.A. has insisted on fitting a device that prevents the operator from pulling the machine backwards. Instead, a gadget has been installed that makes it impossible to turn the mower around except by slowly navigating it through a great semi-circle-a journey which almost invariably leads to the electric extension cord either slipping under the machine and becoming entangled in the blades, or else becoming wrapped around the limbs and neck of the operator. Nonetheless, O.S.H.A. underestimated the ingenuity of the average householder, and most have managed to dismantle every safety device within hours of purchase, thereby leaving a strippeddown version which is some 15 to 20 pounds lighter and much easier to use. O.S.H.A. has also contrived to attract a fair share of odium through its continued persecution of the owner of a small factory in the Far West. When the Government bureaucrats inspected the workshop of the factory (where fewer than ten people work), they found it to be without blemish, but the O.S.H.A. officials then demanded entrance to the owner’s home in order to look inside his refrigerator, where two of the workers kept their pre-packaged lunch and where one or two agents used in the manufacturing process were stored. On being denied entrance they brought a suit against the owner and over the past two years have conducted a continuing vendetta against him. The owner of the factory took the matter to court and fortunately O.S.H.A. was rebuffed. But the owner has spent several thousand dollars in legal fees with no hope of recovering the cost from the Government. This sort of petty harassment is becoming more frequent and the trouble lies, not so much with the hierarchy and directors of the various Government agencies, but with the lesser officials, many of whom seem to have emerged straight from Franz Kafka’s The Trial. RUMPUS ON RIVER POLLUTION
SOME time late last year the F.M.C. Corporation was found have inadvertently discharged excessive quantities of carbon tetrachloride into the Kanawha River at Charleston, West Virginia. Immediate steps were taken by the company to prevent a recurrence of this episode. The Kanawha is a tributary of the Ohio and some 300 miles downstream, the city of Cincinnati draws its water-supply from the larger river. Information concerning the spill hit the national press, and some reports asserted that carbon tetrachloride was a potent carcinogen; not unnaturally, there was a huge public outcry. But F.M.C:, having first sought expert advice and having been assured that the practice was safe, continued to discharge into the Kanawha effluents containing small quantities of carbon tetrachloride. The Environmental Protection Agency (E.P.A.) became involved, and although at first stating that the continued discharge of small quantities of carbon tetrachloride was harmless, it then did an about-face, and brought an action against the F.M.C. Corporation to forbid the discharge of any carbon tetrachloride into the river. The company warned that they would have to close the plant if this order was put into effect, but the E.P.A. sought an injunction against F.M.C., and a hearing is currently taking place before the U.S. District Court. The E.P.A. called as an expert witness an environmentalist from the Midwest, who testified that carbon tetrachloride was a potent carcinogen and that all those downstream had a greatly increased risk of developing cancer as a result of the discharges. This testimony conflicted with the opinion of most other experts, and certainly does not seem to fit in with the fact that carbon tetrachloride has been used in Britain and elsewhere as a dry-cleaning agent for many years. In any event, the furor seems somewhat inappropriate, since for years dozens of small towns in Pennsylvania, Ohio, and West Virginia have been pouring raw sewage into the Ohio and its tributaries, the upper reaches of which are likely to filter through a few glomeruli but undergo little else in the way of purification. to
i
j
!
Letters
to
the Editor
MORTALITY IN WOMEN ON ORAL CONTRACEPTIVES
SIR,-We would like to comment on the research results from the Royal College of General Practitioners and Professor Vessey and his colleagues published in this issue. Whilst much requires to be clarified through further retrospective and longterm prospective studies certain recommendations can be made in the light of present information. It has been shown in the R.C.G.P. study population that oral-contraceptive users compared with non-users have an increased risk of 1 per 5000 per year of dying from cardiovascular disease. The risk is concentrated, however, in women over the age of 35 years, especially if they smoke cigarettes and have used oral contraceptives continuously for 5 years or more. This relationship to duration of use requires confirmation. These observations will permit clinicians to identify women at special risk more accurately than before. There is no evidence to suggest that the risk for most women under the age of 35 years is great enough to warrant any change in clinical practice unless the well-known additional risk factors for cardiovascular disease are present. The division of the data at age 35 is arbitrary and it would be prudent to assume that there is a gradually increasing risk at an earlier age. These considerations are the basis for our recommendations: Women under 30 Years of Age We have no evidence to justify recommending any change of oral-contraceptive practice. It would be wise to emphasise the general advantage of stopping smoking. Women Aged 30-35 Years Because we have to assume a gradually increasing risk up to 35 years of age, we suggest that some women over 30 years ought to reconsider their use of oral contraceptives. We believe that women in this age-group who have used oral contraceptives continuously for more than 5 years and who are cigarette smokers should come into this category. If they would stop smoking it would probably be reasonable for them to continue the pill. If not it might be wiser for them to change to another method. Women over 35 Years There may well be circumstances where women over the age of 35 years would accept the additional risks involved and would wish to continue oral contraceptives. However, in general it would be wise for all oral-contraceptive users over 35 years of age to reconsider their method of contraception. Older women who smoke and/or have used oral contraceptives continuously for more than 5 years may well have extra risks which they and their doctor will wish to consider when weighing the balance of advantage and disadvantage. It appears that the pill takes several years to affect the cardiovascular system. There is therefore, no advantage in making any sudden change, and it would be reasonable for most women to consult their doctor as they come to the end of their current supplies of oral contraceptives. In no case should patients stop the pill without having adopted a satisfactory alternative method of contraception.
Type ofPill We are unable to determine from present evidence whether oral contraceptives containing lower doses of oestrogen confer any advantage over those containing 50 g. E. V. KUENSSBERG, Royal College of General Practitioners,
President
Royal College of Obstetricians and Gynæcologists
JOHN DEWHURST, President
758
** The following letter from Sir Eric Scowen, on behalf of the Committee on Safety of Medicines, was sent to doctors in the U.K. on Oct. 6.-ED. L "The Committee on Safety of Medicines has considered the two reports on mortality among women using oral contraceptives, published in The Lancet of October 8, 1977. The first described the results of a study by the Royal College of General Practitioners (R.C.G.P.) and the second a study conducted by the Oxford Department of Social and Community Medicine in collaboration with the Family Planning Association. The numbers in the studies are too small to allow precise conclusions to be reached about the over-all risk of using oral contraceptives or any residual risk which may remain from previous use. However, the findings in both studies are in line with the trend noted in earlier investigations that the risk of arterial thrombosis with oral contraceptives increases with age-particularly in the later part of reproductive life-and that this risk is aggravated by cigarette smoking. In one study the figures show an excess mortality from subarachnoid haemorrhage both in users and in ex-users of oral contraceptives. There is no similar finding in the other study. Further studies will therefore be needed before any conclusion can be reached. During the course of these studies major changes have occurred in the composition of oral contraceptive products due to a progressive reduction in their oestrogen content. In addition, some preparations containing the progestogen, megestrol acetate, in use at the start of the investigations have been removed from the market. It is therefore impossible at present to make any reasonable assessment of the findings discussed in the two reports in relation to the oral contraceptives now currently in use. In the view of the Committee of Safety of Medicines the present studies do not indicate the necessity for any change in the warnings and precautions for oral contraceptives, except to emphasise the importance of the increased risk for women in the later age group, especially those who are cigarette smokers.""
expected superiority of a corticosteroid in
by
our
group in Cardiff confirms
eczema, and
a
trial
that, for chronic hand
no active ingredients as effective 0.025% betametha("unguentum Merck") isone valerate over a one-month period. Clearly, the use of topical corticosteroids should be critically assessed by the prescriber who should realise that he is only temporarily damping down inflammation and that simpler (and cheaper) materials may be as effective. Pharmaceutical houses are similarly addicted. It is not their fault: they produce compounds which appear effective and which are prescribed extensively. Because topical corticosteroids have to be used over long periods and because the prescribers are hooked on them, large amounts are sold (sales of plain corticosteroid preparations in 1976-77 amounted to approximately LI0 million). For these reasons the pharmaceutical industry has been slow to realise that these products are far from ideal for the patient, and we are still some way off the production of compounds that have a more fundamental action than the suppression of inflammation. eczema at
least,
a
material
containing
was as
of Medicine, Welsh National School of Medicine, Cardiff CF4 4XN
Department
R. MARKS
SIR,-In your excellent editorial (Sept. 3, p. 487) you review the various undesirable effects of fluorinated steroids and conclude: "the hope must be that powerful anti-inflammatory agents can be developed which do not have ’fluorinated problems’ ". At the same time I read an equally authoritative article on corticosteroids in skin diseases by Dr D. D. Munro in the August issue of the Prescribers’ Journal. Munro states: "Most potent preparations are halogenated steroids, usually with one or more fluorine atoms, but neither the potency nor any complications are directly related to the fluorination, and equally potent non-halogenated compunds give rise to the same local and systemic side-effects". I am confused about these fundamentally opposite views on structure-activity relationships among the topical steróids. Elmdene Alcoholic Treatment Unit,
TOPICAL STEROIDS
SIR,-The "jungle topical steroids" is more hazardous than your editorial (Sept. 3, p. 487) suggests. Although masked infection, skin atrophy, pituitary-adrenal axis suppression, and habituation have all correctly been highlighted, other dangers exist. It is not only patients and their dermatoses who become "hooked" on steroids; doctors are also easily addicted to prescribing them. They see the rapid effects of the corticosteroids on their patient’s abnormal skin and vicariously experience the relief of symptoms. Topical corticosteroids suppress the inflammatory response of skin disease although we are not sure how.’ They do not fundamentally influence the natural history of skin disease. Consequently, relief lasts only as long as the application. The dramatic response of acutely inflamed skin to topical corticosteroids causes prescribers to forget the mild (but safe and useful) anti-inflammatory effects of simple bland creams and other preparations containing materials such as zinc and tar. How such bland preparations work is as mysterious as the mode of action of corticosteroids but some placebo preparations have an antimitotic effect for inflamed epidermis2 and others seem to have a vasoconstrictor action.3 There have been few studies contrasting the action of corticosteroids with simpler remedies. However, one such trial4 failed to show the
Bexley Hospital, Bexley, Kent DA5
2BW
SISIR K. MAJUMDAR
of
Wilson, L. C., Marks, R. in Mechanisms of Topical Corticosteroid Activity (edited by L. Wilson, and R. Marks). Edinburgh, 1976. 2. Tree, S., Marks, R. Br. J. Derm. 1975, 92, 195. 3. Woodford, R., Barry, B. W. ibid. 1973, 98, 53. 4. Medansky, R. S., Handler, R. M. Clin. Med. 1974, 81, 27. 1.
*** It is the fluorinated steroid that has mostly been misused, and it so happens it is only the fluorinated steroid that has a high inherent potency, interfering with the H.P.A. axis. Certainly, non-fluorinated steroids if used wrongly—e.g., with prolonged occlusion-have produced side-effects. For simplicity, all the difficulties were labelled "fluorinated problems", though it is not the fluorine component per se that is to blame.-ED.L. GLYCOSYLATED HÆMOGLOBIN IN DIABETES AND RENAL FAILURE your editorial (July 2, p. 22) you draw attention the increase of the glycosylated haemoglobin HbAlc in diabetes mellitus and the risk of reduced oxygen supply to the tissues. In renal failure, most patients have impaired glucose tolerance and those on chronic dialysis are usually dialysed against fluid with a high glucose content. It seems important therefore to study the level of HbA1c in patients on chronic dialysis in relation to their glucose metabolism. HbA1c was measured by the method of Trivelli et al, with minor modifications.1,2 In 18 normal subjects the HbAlc level
SIR,-In
to
1. Trivelli, L.
A., Ranney, H. M., Lai, H. T. New Engl. J. Med. 1971, 284,
353. 2.
Ranney,
H. M
Unpublished.
SOME time late last year the F.M.C. Corporation was found have inadvertently discharged excessive quantities of carbon tetrachloride into the Kanawha River at Charleston, West Virginia. Immediate steps were taken by the company to prevent a recurrence of this episode. The Kanawha is a tributary of the Ohio and some 300 miles downstream, the city of Cincinnati draws its water-supply from the larger river. Information concerning the spill hit the national press, and some reports asserted that carbon tetrachloride was a potent carcinogen; not unnaturally, there was a huge public outcry. But F.M.C:, having first sought expert advice and having been assured that the practice was safe, continued to discharge into the Kanawha effluents containing small quantities of carbon tetrachloride. The Environmental Protection Agency (E.P.A.) became involved, and although at first stating that the continued discharge of small quantities of carbon tetrachloride was harmless, it then did an about-face, and brought an action against the F.M.C. Corporation to forbid the discharge of any carbon tetrachloride into the river. The company warned that they would have to close the plant if this order was put into effect, but the E.P.A. sought an injunction against F.M.C., and a hearing is currently taking place before the U.S. District Court. The E.P.A. called as an expert witness an environmentalist from the Midwest, who testified that carbon tetrachloride was a potent carcinogen and that all those downstream had a greatly increased risk of developing cancer as a result of the discharges. This testimony conflicted with the opinion of most other experts, and certainly does not seem to fit in with the fact that carbon tetrachloride has been used in Britain and elsewhere as a dry-cleaning agent for many years. In any event, the furor seems somewhat inappropriate, since for years dozens of small towns in Pennsylvania, Ohio, and West Virginia have been pouring raw sewage into the Ohio and its tributaries, the upper reaches of which are likely to filter through a few glomeruli but undergo little else in the way of purification. to
i
j
!
Letters
to
the Editor
MORTALITY IN WOMEN ON ORAL CONTRACEPTIVES
SIR,-We would like to comment on the research results from the Royal College of General Practitioners and Professor Vessey and his colleagues published in this issue. Whilst much requires to be clarified through further retrospective and longterm prospective studies certain recommendations can be made in the light of present information. It has been shown in the R.C.G.P. study population that oral-contraceptive users compared with non-users have an increased risk of 1 per 5000 per year of dying from cardiovascular disease. The risk is concentrated, however, in women over the age of 35 years, especially if they smoke cigarettes and have used oral contraceptives continuously for 5 years or more. This relationship to duration of use requires confirmation. These observations will permit clinicians to identify women at special risk more accurately than before. There is no evidence to suggest that the risk for most women under the age of 35 years is great enough to warrant any change in clinical practice unless the well-known additional risk factors for cardiovascular disease are present. The division of the data at age 35 is arbitrary and it would be prudent to assume that there is a gradually increasing risk at an earlier age. These considerations are the basis for our recommendations: Women under 30 Years of Age We have no evidence to justify recommending any change of oral-contraceptive practice. It would be wise to emphasise the general advantage of stopping smoking. Women Aged 30-35 Years Because we have to assume a gradually increasing risk up to 35 years of age, we suggest that some women over 30 years ought to reconsider their use of oral contraceptives. We believe that women in this age-group who have used oral contraceptives continuously for more than 5 years and who are cigarette smokers should come into this category. If they would stop smoking it would probably be reasonable for them to continue the pill. If not it might be wiser for them to change to another method. Women over 35 Years There may well be circumstances where women over the age of 35 years would accept the additional risks involved and would wish to continue oral contraceptives. However, in general it would be wise for all oral-contraceptive users over 35 years of age to reconsider their method of contraception. Older women who smoke and/or have used oral contraceptives continuously for more than 5 years may well have extra risks which they and their doctor will wish to consider when weighing the balance of advantage and disadvantage. It appears that the pill takes several years to affect the cardiovascular system. There is therefore, no advantage in making any sudden change, and it would be reasonable for most women to consult their doctor as they come to the end of their current supplies of oral contraceptives. In no case should patients stop the pill without having adopted a satisfactory alternative method of contraception.
Type ofPill We are unable to determine from present evidence whether oral contraceptives containing lower doses of oestrogen confer any advantage over those containing 50 g. E. V. KUENSSBERG, Royal College of General Practitioners,
President
Royal College of Obstetricians and Gynæcologists
JOHN DEWHURST, President
758
** The following letter from Sir Eric Scowen, on behalf of the Committee on Safety of Medicines, was sent to doctors in the U.K. on Oct. 6.-ED. L "The Committee on Safety of Medicines has considered the two reports on mortality among women using oral contraceptives, published in The Lancet of October 8, 1977. The first described the results of a study by the Royal College of General Practitioners (R.C.G.P.) and the second a study conducted by the Oxford Department of Social and Community Medicine in collaboration with the Family Planning Association. The numbers in the studies are too small to allow precise conclusions to be reached about the over-all risk of using oral contraceptives or any residual risk which may remain from previous use. However, the findings in both studies are in line with the trend noted in earlier investigations that the risk of arterial thrombosis with oral contraceptives increases with age-particularly in the later part of reproductive life-and that this risk is aggravated by cigarette smoking. In one study the figures show an excess mortality from subarachnoid haemorrhage both in users and in ex-users of oral contraceptives. There is no similar finding in the other study. Further studies will therefore be needed before any conclusion can be reached. During the course of these studies major changes have occurred in the composition of oral contraceptive products due to a progressive reduction in their oestrogen content. In addition, some preparations containing the progestogen, megestrol acetate, in use at the start of the investigations have been removed from the market. It is therefore impossible at present to make any reasonable assessment of the findings discussed in the two reports in relation to the oral contraceptives now currently in use. In the view of the Committee of Safety of Medicines the present studies do not indicate the necessity for any change in the warnings and precautions for oral contraceptives, except to emphasise the importance of the increased risk for women in the later age group, especially those who are cigarette smokers.""
expected superiority of a corticosteroid in
by
our
group in Cardiff confirms
eczema, and
a
trial
that, for chronic hand
no active ingredients as effective 0.025% betametha("unguentum Merck") isone valerate over a one-month period. Clearly, the use of topical corticosteroids should be critically assessed by the prescriber who should realise that he is only temporarily damping down inflammation and that simpler (and cheaper) materials may be as effective. Pharmaceutical houses are similarly addicted. It is not their fault: they produce compounds which appear effective and which are prescribed extensively. Because topical corticosteroids have to be used over long periods and because the prescribers are hooked on them, large amounts are sold (sales of plain corticosteroid preparations in 1976-77 amounted to approximately LI0 million). For these reasons the pharmaceutical industry has been slow to realise that these products are far from ideal for the patient, and we are still some way off the production of compounds that have a more fundamental action than the suppression of inflammation. eczema at
least,
a
material
containing
was as
of Medicine, Welsh National School of Medicine, Cardiff CF4 4XN
Department
R. MARKS
SIR,-In your excellent editorial (Sept. 3, p. 487) you review the various undesirable effects of fluorinated steroids and conclude: "the hope must be that powerful anti-inflammatory agents can be developed which do not have ’fluorinated problems’ ". At the same time I read an equally authoritative article on corticosteroids in skin diseases by Dr D. D. Munro in the August issue of the Prescribers’ Journal. Munro states: "Most potent preparations are halogenated steroids, usually with one or more fluorine atoms, but neither the potency nor any complications are directly related to the fluorination, and equally potent non-halogenated compunds give rise to the same local and systemic side-effects". I am confused about these fundamentally opposite views on structure-activity relationships among the topical steróids. Elmdene Alcoholic Treatment Unit,
TOPICAL STEROIDS
SIR,-The "jungle topical steroids" is more hazardous than your editorial (Sept. 3, p. 487) suggests. Although masked infection, skin atrophy, pituitary-adrenal axis suppression, and habituation have all correctly been highlighted, other dangers exist. It is not only patients and their dermatoses who become "hooked" on steroids; doctors are also easily addicted to prescribing them. They see the rapid effects of the corticosteroids on their patient’s abnormal skin and vicariously experience the relief of symptoms. Topical corticosteroids suppress the inflammatory response of skin disease although we are not sure how.’ They do not fundamentally influence the natural history of skin disease. Consequently, relief lasts only as long as the application. The dramatic response of acutely inflamed skin to topical corticosteroids causes prescribers to forget the mild (but safe and useful) anti-inflammatory effects of simple bland creams and other preparations containing materials such as zinc and tar. How such bland preparations work is as mysterious as the mode of action of corticosteroids but some placebo preparations have an antimitotic effect for inflamed epidermis2 and others seem to have a vasoconstrictor action.3 There have been few studies contrasting the action of corticosteroids with simpler remedies. However, one such trial4 failed to show the
Bexley Hospital, Bexley, Kent DA5
2BW
SISIR K. MAJUMDAR
of
Wilson, L. C., Marks, R. in Mechanisms of Topical Corticosteroid Activity (edited by L. Wilson, and R. Marks). Edinburgh, 1976. 2. Tree, S., Marks, R. Br. J. Derm. 1975, 92, 195. 3. Woodford, R., Barry, B. W. ibid. 1973, 98, 53. 4. Medansky, R. S., Handler, R. M. Clin. Med. 1974, 81, 27. 1.
*** It is the fluorinated steroid that has mostly been misused, and it so happens it is only the fluorinated steroid that has a high inherent potency, interfering with the H.P.A. axis. Certainly, non-fluorinated steroids if used wrongly—e.g., with prolonged occlusion-have produced side-effects. For simplicity, all the difficulties were labelled "fluorinated problems", though it is not the fluorine component per se that is to blame.-ED.L. GLYCOSYLATED HÆMOGLOBIN IN DIABETES AND RENAL FAILURE your editorial (July 2, p. 22) you draw attention the increase of the glycosylated haemoglobin HbAlc in diabetes mellitus and the risk of reduced oxygen supply to the tissues. In renal failure, most patients have impaired glucose tolerance and those on chronic dialysis are usually dialysed against fluid with a high glucose content. It seems important therefore to study the level of HbA1c in patients on chronic dialysis in relation to their glucose metabolism. HbA1c was measured by the method of Trivelli et al, with minor modifications.1,2 In 18 normal subjects the HbAlc level
SIR,-In
to
1. Trivelli, L.
A., Ranney, H. M., Lai, H. T. New Engl. J. Med. 1971, 284,
353. 2.
Ranney,
H. M
Unpublished.
