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Seventeen Principles aboutCancer, or Something

THE Environmental Protection Agency (E.P.A.)of the U.S.A. is engaged in legal actions to suspendthe use of the insecticide mirex (and also aldrin,dieldrin, heptachlor, and chlordane). In thecourse of the legal proceedings the agency has publ-ished "17 Cancer Principles", and has moved tohave these recognised by the court. The principlesvary from the innocuous to the absurd. In briefthey state that cancer incidence is increasing, andthat cancer is mainly caused by exposure to exter-nal factors such as chemicals (a proposition thatfew would accept). The key principle, number four,contains the statement, "A chemical carcinogen isany agent that has been shown to cause benign ormalignant tumors in adequately conducted studiesin man or in animals. This ... causal effect may beevidenced by significantly increased tumors, or byshortening the latency period between exposureand the development of tumors."The statements go on lengthily to suggest that

tests using rats, mice, and hamsters are "acceptedby the scientific community as reliable, and

adopted by public policy-making agencies in theUnited States", but that "negative results are

grossly inadequate to give assurance of safety forhumans." Point sixteen states that "There is nomethod for establishing a no-effect level for humanexposure to carcinogens." The E.P.A. suggeststhat, since it has the necessary expertise, no otherbody should be called to give evidence on the sub-ject of carcinogens; the National Academy ofScience, in particular, should not be involved inthe case. Moreover, since the court has acceptednine of the seventeen principles in a previous case,these now have a legal status that makes it

improper to question them.

1. Pesticide Chemical News, 1975, 3, 10.

There is a danger that agencies of the EuropeanEconomic Community may adopt the E.P.A.’s

principles and approach. The consequences wouldbe a setback for the economic development of

Europe and for attempts to improve the quality oflife, and would make bureaucratic decision moreinfluential at the expense of free rational discuss-ion-all to no good purpose. First, as a medico-scientific statement the E.P.A. principles are aboutas useful as a law to prohibit cancer, or to maken=3. The attempt to define cancer and carcin-

ogens is na7ive and often wrong. For instance, thereis no "general increase in cancer" in the U.S.A.2The age-specific incidence of some cancers is risingwhile for others, such as stomach cancer, it is

falling. There is no evidence that the variation incancer incidence between countries is due to vari-ation in exposure to industrial chemicals. It is farmore likely to be due to variations in lifestyle-forinstance, variations in dietary fat intake.3 Majorchanges in cancer incidence are most unlikely tobe brought about by banning even a very largenumber of chemicals from industrial use. Anystatement on human cancer which fails to mention

cigarette smoking is irresponsible. The definitionattempted by the E.P.A. embraces an enormousnumber of substances. We can start with dietaryprotein and dietary fat, 4 5 since rats given deficientdiets tend to live longer, have fewer cancers, andrespond less to chemical carcinogens. We can go onto chloroform which causes cirrhosis and livertumours when given in huge doses to mice.6Phenobarbitone causes lumps (? benign hepatictumours) in the livers of certain mice, but we knowthat it does not produce cancers in rats or in alarge number of well-studied people with epilepsy.The list is almost endless, and the question is, howshall we come to rational decisions about com-

pounds that produce tumours in laboratoryanimals,’ 8 or that are mutagenic in the newer testsystems? The E.P.A. suggests that the proper wayto make such decisions for the U.S.A. is in thecourt of law, with the "17 Principles" having analmost legal value. Is such a procedure correct forEurope or the U.K.?

Lawyers are concerned with settling disputesbetween individuals or groups, according to anagreed set of rules, the Law. Unfortunately, cancerwill not obey man-made laws; we have to conformto its rules. A dispute between two major bureau-

2. Cutler, S. J., Devesa, S. S. in Host Environment Interactions in the Eti-ology of Cancer in Man (edited by R. Doll and I. Vodopija); p. 15. Inter-national Agency for Research on Cancer, Lyon, 1973.

3. De Waard, F. ibid. p. 121.4. McLean, A. E. M. ibid. p. 223.5. Symposium: Nutrition in the Causation of Cancer, Cancer Res. 1975, 35,

3238.6. Evaluation of Carcinogenic Risks to Man; vol. I, p. 61. International

Agency for Research on Cancer, Lyon, 1972 .

7. Lancet, 1973, ii, 1133.8. ibid. 1974, ii, 629.

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cracies underlies the apparent scientific questionswhich the "17 Principles" claim to answer. Thereis a struggle for power, prestige, and money. Onthe one hand is the industrial bureaucracy, withits scientific employees and adherents, who believethat industrial chemicals are generally not a sourceof hazard, or, where hazard is discovered, they willdeal with it themselves. The history of the waybladder cancers were dealt with in the dye andrubber industries is not entirely in favour of thisview. (The medical officer who discovers a hazardmay be regarded as a trouble-maker and a boat-rocker and his career can end abruptly.) However,one must say that many large corporations are

highly expert, and are in general against poisoningtheir work-force, and are frequently in favour ofnot poisoning the public if this can be managedwithout the loss of profit that would follow if thepublic were, for instance, to stop smoking cigar-ettes or drinking alcohol. Thalidomide showedthat the employees of a company may act in a

disastrous way to defend their continued existenceas a group. On the other hand there is the Govern-ment bureaucracy, its scientific staff, and scien-tists, who are generally financially dependent onfunds from Government, foundations, andcharities. If the public believes that it issurrounded by dangerous cancer-producingchemicals, often produced by industry, then thisscientific group will prosper. It is a potent shieldand defender of public safety, worthy of prestige,money, grants, and television interviews. Inaddition the devotees of the cause can feel greatsatisfaction in seeing themselves as little Davids

struggling against the giant Big Business, whilesafely supported by the biggest business of all,Government. There is no neutral scientific judge.We all speak from our own point of view and atti-tude, which will determine the extent to which wecredit the evidence from animal experiments or

epidemiology, or to which we trust other scientists.How should we approach the problem posed by theexistence of large numbers of chemicals, bothnatural and man-made, that we suspect of beingcapable of causing cancers?

First of all, the relative stability of Europeanpopulations, and in particular the existence ofNational Health Service and Registrar Generalrecords in the U.K., makes it possible to look forevidence in man.9 The excellent investigations ofphenobarbitone in Denmark show that human

beings treated with phenobarbitone do not developany significant excess of liver or other cancers. Inthis man resembles the rat rather than the mouse,which does acquire liver tumours when treated

.

with phenobarbitone.1o 11 Secondly, each case has

9. Royal College of Physicians. Smoking and Health Now. London, 1971.10. Clemmesen, J., Frederiksen, V., Plum, C. M. Lancet, 1974, n, 705.11. Clemmesen, J. ibid. 1975, i, 36.

to be assessed according to risks and benefits.Phenobarbitone has a high benefit and low risk.Alcohol carries major risks, but most people regardthe benefits as more important, and prohibition, aprevious crusade to eliminate an environmentalhealth hazard, was not exactly a success. Even

cigarettes are accepted by many individuals, des-pite their enormously high risk. A far lower levelof risk must be demanded when involuntary expo-sure is produced by wide use of, say, a food pre-servative. But what of nitrite, in bacon? The benefitis safety, because of the excellent preservativeeffect and inhibition of clostridial growth. The riskis as yet theoretical, in that minute amounts ofnitrosamines can be formed from nitrite and, whilewe know that nitrosamines in milligrammeamounts are carcinogenic, we have no ideawhether the microgramme per kg amounts foundin food 12 would cause more human suffering thanwould be caused by removal of nitrite. We needhuman evidence about the health of bacon-eaters.

The decision about the balance of benefit andrisk must be, in the end, a political one, since it isbased not on fact but on opinion about which risksare worth taking-especially when the risks are

taken by one social group and much of the benefitaccrues to other groups. (For instance, we allbenefit from risks taken by coal miners, fishermen,and deep-sea divers.) In the U.K. it seems thatdiscussions between the industrial scientific groupand the Government and academic group couldlead to agreed statements on the benefits and risksof various courses of action. But some difficult

questions would remain. How many cases of botu-lism should we accept, or should we ban bacon andaccept the social unrest and the rise of pig-smug-gling as a new industry? Or should we do nothing,or should we set in motion a survey to quantitatethe cancer risks of those who have a high nit-rate/nitrite intake?When we look at the E.P.A. statements and the

legal tangles in which the American agencies haveinvolved themselves, Europe must surely hope todo better than this. Voluntary agreements to limituse of D.D.T. in the U.K. have resulted in far lowerlevels of D.D.T. in body fat than were achieved bylegal action in the U.S.A.13 (in the Soviet UnionD.D.T. was officially banned long ago, but the fewanalyses we have show that the levels in foodstuffsare still as high as ours). We need safeguardsagainst irresponsible use of the power of industrialcompanies to produce very large amounts of newchemicals.14 We must try to prevent irresponsiblearousal of fear in the public. We need to spend

12. Crosby, N. T., Foreman, J. K., Palframan, J. F., Sawyer, R. Nature.1972, 238, 342.

13. Abbott, D. C., Collins, G. B., Goulding, R. Br. med. J. 1972, i, 553.14. Galbraith, J. K. Economics and the Public Purpose. Harmondsworth, 1975

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more time discussing these questions with the

public and the journalists who write for the public.This involves the medical profession, who need tokeep an informed opinion on environmental risks,and to tell their patients and the public whennothing should be done or when action is needed,and especially when we need public cooperation inthe gathering of information on the risks ofmodern life.

Late Complications of FemaleSterilisation

A HIGH’ percentage of women who have hadtubal sterilisation complain later of menorrhagia ordysmenorrhcea.1-8 MULDOON,6 for instance, foundthat, out of 374 patients followed for at least tenyears after operation, nearly 19% came to hysterec-tomy. The figures are not in dispute; but couldthere be an antecedent common cause? Are womenwho are sterilised more likely than average to com-plain later of increased or painful menstrual bleed-ing ? These symptoms, particularly increased bleed-ing, become more common with the passage oftime. Their incidence in unsterilised women

matched for race, age, social class, parity, and men-strual blood-loss is not known. Psychological fac-tors also operate, possibly by altering hormonalcontrol of the menstrual cycle via higher centres,and certainly by affecting the threshold for com-plaints (perhaps more readily in women who havebeen sterilised). Moreover, there is no way of di-

rectly measuring menstrual pain, and workers whohave measured menstrual blood-loss (usually by themethod of HALLBERG and NILSSON9) can testify tothe unreliability of reports of menorrhagia. Forexample, in a studylO of women presenting in afamily-planning clinic with no complaint of heavybleeding and requesting intrauterine contraception,14% had a measured mean menstrual loss, overtwo normal periods, of more than 80 ml (80 ml isregarded as the normal,11 12 and above it irori-defi-ciency anaemia becomes more common). The effectof contraception is another imponderable: contra-ceptive-pill users may dislike their normal periodswhen these return after sterilisation; and the typeof contraception used by a control group mayaffect the natural history of menstrual bleeding.The published investigations with one exceptionhave been uncontrolled, all have been retrospec-

1. Sacks, S., La Croix, G. Obstet. Gynec. 1962, 19, 22.2 Lu, T., Chun, D. J. Obstet. Gynœc Br. Commonw 1967, 74, 875.3. Lang, L. P., Richardson, K. D. ibid. 1968, 75, 972.4. Whitehouse, D. B. Br. med. J. 1971, ii, 707.5. Houseman, R. J. ibid. 1971, iii, 184.6 Muldoon, M. J. ibid. 1972, i, 84.7. Chamberlain, G., Foulkes, J. Lancet, 1975, ii, 878.8. Neil, J. R., Noble, A D., Hammond, G. T., Rushton, L., Letchworth, A. T.

ibid. 1975, ii, 699.9. Hallberg, L, Nilsson, L. Scand. J clin. Lab. Invest, 1964, 16, 244.

10. Guillebaud, J., Bonnar, J., Morehead, J., Matthews, A. Lancet, 1976, i, 387.11. Hallberg, L., Hogdahl, A. -M., Nilsson, L., Rybø, G. Acta obstet. gynœc.

scand 1966, 45, 320.12. Rybø, G. ibid. 1966, 45, suppl. 7.

tive, and menstrual loss was measured in none.NEIL et al.," in a study based on self-rating ques-tionnaires, compared the responses of patients upto 28 months after abdominal tubal ligation orlaparoscopic tubal diathermy with those of womenwhose husbands had been sterilised. Increasedmenstrual loss and menstrual pain were reportedby significantly more sterilised women than con-trols, and the women sterilised by laparoscopictubal diathermy seemed to suffer most. However,10% more of the control group had been on the pillbefore their husband’s sterilisation, 22-28% of thequestionnaires were not returned, and subjectivevariables may have affected responses. Vasectomyhas been socially acceptable for a far shorter timethan female sterilisation, so couples are likely to bedefensive and could well be less ready to admit toany problems after it—especially since "commonsense" dictates that there would be no effect onmenstruation. There has been one small objectivestudy: menstrual blood was collected and measuredin 25 women for three periods before operation andfor up to one year afterwards.13 No significant dif-ference was detected between blood-losses beforeand after the procedure (abdominal tubal ligationin all but one case). This investigation should

obviously be repeated with larger numbers andlonger follow-up. Ideally, such a prospective studyshould include a control group matched initiallyfor age, parity, and menstrual blood loss and simi-larly followed up with blood-loss measurements;but the logistics, and the difficulty of allowing forthe effects of continued contraception in the con-trol group, are daunting.

For the present, there exists a possibility that op-eration on the fallopian tubes may tend to cause in-creased or more painful menstruation, and a

number of mechanisms have been proposed.8 14Some observations suggest that prostaglandin-syn-thetase inhibitors may improve dysmenorrhoea andreduce measured menstrual blood-loss, and theprostaglandin status of the -uterus may possibly bealtered by damage to utero-ovarian blood-supply.But -elucidating the mechanism of any possibleeffect of tubal surgery on menstruation would be amajor undertaking; and the main hypothesis hasyet to be established.

There can, however, be little doubt that when awoman asks for sterilisation there -is a fairly highchance that she has early or established menstrualproblems. So couples requesting permanent contra-ception should invariably be interviewed together.A thorough menstrual history should be taken fromthe wife: she should be questioned about thenumber of pads and tampons used per period andabout "flooding", or clots, or very frequent chang-ing (more than once an hour) on her heavy days.

13. Kasonde, J. M., Bonnar, J. Unpublished.14. Darwish, D. H., Saafan, S. T. A. Lancet, 1975, ii, 975.