Ann. occup. Hyg., Vol. 45, No. 4, pp. 327–338, 2001 2001 British Occupational Hygiene Society

Published by Elsevier Science Ltd. All rights reservedPrinted in Great Britain.

0003-4878/01/$20.00

Letters to the Editor

The Quantitative Risks of Mesothelioma and Lung Cancer in Relation toAsbestos Exposure

PII: S0003-4878(01)00029-1

Drs. Hodgson and Darnton (2000) are to be congratu-lated on their convincing demonstration of the greatdifference in hazard between chrysotile and theamphiboles. There have been many attempts over thepast two decades to produce quantitative risk assess-ments of asbestos, but theirs is the most convincingevidence to date of the great gap between the twofibre types. They have also provided a good analysisof the problems and difficulties to be faced in anyundertaking of this kind owing to the unsatisfactorynature of so much of the historical dose-responsedata. Their discussion is often enlightening and twotopics, the high lung cancer rates in the Carolinacohort and the comparative incidence of pleural andperitoneal mesotheliomas, merit short papers in theirown right.

But there are two aspects of their paper whichinvite major criticism. The first is the treatment ofchrysotile and mesothelioma. The authors classify theCarolina cohort as chrysotile only, and find that thetwo cases of mesothelioma there—one of which is aperitoneal case, the type often said not to be associa-ted with chrysotile exposure (Doll and Peto, 1985)—produce a risk estimate an order of magnitude higherthan the two mining cohorts. They acknowledge thata small amount of crocidolite was used, but dismissthis as insignificant when averaged over the wholecohort. To do this is to ignore industrial realities; theprobability is that higher exposures would have beenexperienced by a very small number of employeesengaged in processing the crocidolite yarn. The factthat their 3 other chrysotile-only manufacturingcohorts, along with the 5 other available cohorts lack-ing data on cumulative dose (Weiss, 1977; Achesonet al., 1982; Gardner and Powell, 1986) all were with-out any attributable cases of mesothelioma, greatlyincreases the probability that the two Carolina caseswere due to amphibole exposure.

Received 5 October 2000.

327

Two mining cohorts were included, Balangero with2 cases and Quebec with 33. But it is now knownthat some crocidolite was processed at Balangero,where there is no amphibole contamination (Prof. U.Gruber, Zurich, personal communication), and therelationship between the presence of tremolite orcommercial amphibole and mesothelioma incidencehas been well established for the Quebec miners(McDonald et al., 1997; Dufresne et al., 1995, 1996).In Southern Africa, on the other hand, where tremo-lite is minimal, no mesotheliomas have been ident-ified in chrysotile-only miners despite large numbersemployed (Rees et al., 1999).

This issue should not be dismissed as unimportantfor several reasons: tremolite can now be readilyidentified in bulk samples and heavily contaminatedseams avoided; much chrysotile is being mined inparts of the world, including Russia and Brazil, wheretremolite is low or absent; chrysotile is widely distrib-uted over the world’s surface, and a panic overenvironmental chrysotile is currently affecting pro-perty values in parts of California. And, lastly, it isimportant to establish whether fibres which can beeffectively cleared from the lungs at low levels ofinhalation are as free from causing mesothelioma inhumans as they are in experimental animals, sincemuch risk assessment of man-made and organic fibresdepends on it. If this paper is to be a scientificappraisal and not a regulatory play-safe, all thesepoints should be acknowledged. Ingenuity of statisti-cal calculations can not justify neglect of other veryrelevant data if the results are used to draw general-ised conclusions.

But the greatest criticism must be reserved for thesecond half of the paper, which is concerned withdose-response at lower doses. As the authors pointout, the main interest in risk assessment in currentconditions is for exposure levels two or three ordersof magnitude lower than the old occupational levels.In the first half of the paper dose-response relation-ships are obtained by plotting mortality against point

328 Letters to the editors

estimates of the average cumulative exposure in f/mlyears for each cohort. These whole-cohort averagesassume a linear dose-response over the range experi-enced, and for lung cancer have the major problemthat smoking habits and other socio-economic factorsmay cause excess mortality for the cohort to differsignificantly from the reference population even atzero dosage (an extreme example is the Patersoncohort for which Nicholson (1985) calculated theSMR zero dose intercept at 325!). The problems havebeen discussed by Liddell and Hanley (1985).

But what these whole-cohort point estimates cannot do is provide any information on dose-responseat doses much lower than the whole cohort averagesused, and the failure of the authors to use the con-siderable amount of information on the shape of thedose-response curve within some of the individualcohorts is both puzzling and, in this context, inexcus-able. The use of measurements of individual dose cat-egories within single cohorts is not without its prob-lems, as the authors point out. But the disadvantagesof inaccuracies in individual does-assignments andflattening of the slope estimate are comprehensivelyoutweighed by the removal of the need for particle-to-fibre counts between different types of industry,the dose-response in many cohorts over a greaterrange, and the reduction of the need for external stan-dard populations.

The authors’ failure to use this vital source of infor-mation is particularly evident when they come to dis-cuss thresholds. In the realm of asbestos-related dis-ease the word threshold has become politicallyincorrect recently, perhaps as a result of pressuregroups and legal action. But the lungs, like other sys-tems in the body, have their defences. We were alltaught that everything or nothing can be poison—itis the dose that matters. It would be sad if, in theAnnals of all places, this were forgotten. Modernresearch into malignancies caused by external agentssuggests that this old principle may apply here justas much as to direct toxins. Any discussion of fibreeffects at low-doses is incomplete unless it takes intoaccount what is known of the biology of lungdefences.

It is stated in the paper that “The attempt to deducea threshold by identifying the lowest estimated dosereceived by any observed case is a logical nonsense”.Perhaps we should be told how else thresholds areestimated in human toxicology. I think the authors areindulging in misleading wordplay, perhaps under theimpact of the regular cry by pressure groups that“there is no proven threshold”. Of course there isn’t.We are dealing here with inductive, not deductivescience, and must proceed by amassing observationsand improving their accuracy, so that we obtainincreasing probability but never proof. It is true thata strict definition of threshold in asbestos-related dis-ease requires to be qualified, for example as anexposure below which disease will not be epidemiol-

ogically detectable. But the range of uncertaintyattached to any numerical estimates is so large thatthis would be assumed in any less contentious con-text.

The justification given for not including a thresholdfor lung cancer is illuminating. The authors acknowl-edge that the recent HSE Review (Meldrum, 1996),presented as the HSE stance on the subject, concludesthat the risk of lung cancer from asbestos only beginsin the presence of asbestosis. But they then dismissthis by suggesting that if there is a threshold forasbestosis it is so low as to be insignificant, quotingSluis-Cremer in justification and ignoring otherhigher estimates, including that of >25 f/ml.yr, admit-tedly for clinical rather than pathological asbestosis,accepted in the HSE report by Doll and Peto. To usethe data for South African miners from Sluis-Cremeret al. (1990) in this way is to commit a statisticalerror. No individual exposures were available, andSluis-Cremer et al. were very frank about the imper-fections of what data they had, including probablematerial underestimation in 1965–75. For individualdoses, calculated mean fibre concentrations for wholemines were multiplied by conversion factors rep-resenting means for particular jobs. This proceduremay give acceptable figures for average exposures butmay be wildly inaccurate for lowest exposures asso-ciated with disease. For any individual, the mineexposure may not be exactly x, but x±a where a rep-resents the deviation from the average for that parti-cular mine at that particular time. (Individuals withlow cumulative exposures will mostly have beenemployed for relatively short periods, so that long-term averaging would be precluded). Similarly, theindividual’s actual job exposure will deviate from theaverage y by an amount ± b, so that some of thecumulative exposures represented by xy will actuallyhave been (x + a)(y + b), and, for occasional individ-uals, may depart very substantially from xy. Whenthe lowest exposures are being sought in evidence fora threshold, these cases, together with a substantialaddition from environmental exposure discussed inthe text, may introduce a gross underestimate evenbefore the probable underestimation discussed in thepaper is taken into account. I remember making thispoint to the late Dr. Sluis-Cremer soon after the paperwas published. He merely shrugged his shoulders andsaid, referring to the figures: “They were all we had”.He felt the pattern was important but didn’t expectspecific figures to be taken too seriously.

After summarily dismissing the threshold problem,the authors discuss the uncertainty about whether therelationship between exposure and outcome seen inthe observed range continues to hold outside thatrange. Then without using the within-cohort infor-mation available to them, or that from cohorts inwhich the dose has not been quantified, they producea series of rabbits out of the hat in the shape of risksummaries for cumulative exposures ranging from

329Letters to the editor

100 down to 0.005 f/ml years. But the proof of thepudding is in the eating, and nowhere do they subjecttheir calculations and guesses to the test of reality.They neither acknowledge those who have done so,e.g. Liddell (1991) and Camus et al. (1998), and havefound the earlier estimates, based on the linear dose-response found at higher exposures, to be inappli-cable, nor those who have adopted the alternativeapproach based on intensity rather than simple cumu-lative exposure (Liddell et al., 1998; Vacek andMcDonald, 1990), which provides other correctiveinformation on the lower ranges of the dose-response curve.

The first half of the paper contains many goodpoints and one or two gems, but the second half,sadly, adds nothing to our understanding of the risksof low level asbestos exposure, providing risk esti-mates that have no sound basis and that do not matchup with reality.

KEVIN BROWNE2 Burnham Road, North Creake, Norfolk NR21 9JP,

UK

REFERENCES

Acheson ED, Gardner MJ, Pippard EC, Grime LP. Mortalityof two groups of women who manufactured gas masks fromchrysotile and crocidolite asbestos: a 40 year follow-up. BrJ Ind Med 1982;39:344–8.

Camus M, Siemiatycki J, Meek B. Nonoccupational exposureto chrysotile asbestos and the risk of lung cancer. N Engl JMed 1998;338:1565–71.

Doll R, Peto J. Effects on health of exposure to asbestos. Lon-don: HMSO, 1985.

Dufresne A, Harrigan M, Masse S, Begin R. Fibers in lungtissues of mesothelioma cases among miners and millers of

Asbestos and Cancer

PII: S0003-4878(01)00030-8

Hodgson and Darnton (2000)—referred to below asH&D—have done a great service, if only forpresenting mortality rates for cohorts of asbestosworkers in a way that facilitates close examinationof what has been called ‘the fibre gradient’ or the‘amphibole hypothesis’.

FIBRE TYPES

The three principal types of asbestos (bearing thesame generic name but alike only in being fibroussilicates) are chrysotile, which has always accountedfor at least 90% of commercial usage, and two amphi-boles, crocidolite, the more commonly used, andamosite, the amphiboles having chemical consti-

the township of Asbestos. Quebec. Am J Ind Med1995;27:581–92.

Dufresne A, Begin R, Churg A, Masse S. Mineral fibre contentof lungs in patients with mesothelioma seeking compen-sation in Quebec. Am J Respir Crit Care Med1996;153:711–8.

Gardner MJ, Powell CA. Mortality of asbestos-cement workersusing almost exclusively chrysotile fibre. J Soc Occup Med1986;36:124–6.

Hodgson JT, Darnton A. The quantitative risks of mesotheli-oma and lung cancer in relation to asbestos exposure. AnnOccup Hyg 2000;44(8):565–601.

Liddell F. Exposure-response: asbestos and mesothelioma. EurRespir Rev 1991&3(12&03):18&11.

Liddell FDK, Hanley JA. Relations between asbestos exposureand lung cancer SMRs in occupational cohort studies. Br JInd Med 1985;42:389–96.

Liddell F, McDonald A, McDonald J. Dust exposure and lungcancer in Quebec miners and millers. Ann Occup Hyg1998;42:7–20.

McDonald A, Case B, Churg A, Dufresne A, Gibbs G, Sebas-tien P. et al. Mesothelioma in Quebec miners and millers:epidemiology and aetiology. Ann Occup Hyg1997;41:707–19.

Meldrum M. Review of Fibre Toxicology. Sudbury: HSEBooks, 1996.

Nicholson W. Airborne asbestos health assessment update.EPA, 1985.

Rees D, Myers J, Goodman E, Blignaut C, Chapman R, Bach-mann M. Case-control study of mesothelioma in SouthAfrica. Am J Ind Med 1999;35:213–22.

Sluis-Cremer GK, Hnizdo E, DuToit RSJ. Evidence for anamphibole asbestos threshold exposure to asbestosis assessedby autopsy in South African asbestos miners. Ann OccupHyg 1990;34:443–51.

Vacek PM, McDonald JC. Effect of intensity in asbestos cohortexposure-response analyses, In: Sakurai H, editor. Occu-pational epidemiology. Elsevier Science Publishers; 1990. p.189–93.

Weiss W. Mortality of a cohort exposed to chrysotile asbestos.J Occup Med 1977;19:737–40.

tutions quite disparate from that of chrysotile. The(microscopic) respirable forms of the three types alsodiffer greatly not only in shapes and sizes, so affect-ing penetration, but also in their durability in lung andother tissue. Markedly different health effects weretherefore only to be expected.

Largely because of differences in their(macroscopic) physical characteristics, the three typesof fibre have had varied commercial uses, but in mostindustrial practices workers exposed to amphiboleasbestos have also been exposed to chrysotile. Suchexposures are said to be to mixtures, or to mixed

Received 2 November 2000; in final form 27 February 2001.