Update on Asbestos and Lung Cancer Is There

Update on Asbestos and Lung Cancer Is There A Basis For A Claim?

Lung Cancer and Asbestos • Strong epidemiological evidence that asbestos causes all pathological types of lung cancer • Latency between exposure and increase in risk of lung cancer at least 10 years for non-small cell cancer, 5 years for more rapidly growing small cell cancer

Asbestos and Lung Cancer • Risk increases with dose • Much smaller relative risk than for mesothelioma: – Heavy exposure eg lagger, 1000 fold risk for mesothelioma but only 5 fold risk for lung cancer – Hence no significant increase in risk of lung cancer from light exposure which is more than enough to cause a substantial increase in risk of mesothelioma

Asbestos Carcinogenesis • Chromosomal/DNA damage results in mutations – Caused directly by asbestos – Caused by chemical mediators produced as a result of the presence of asbestos fibres – Caused by asbestos increasing the effects of tobacco carcinogens • Asbestos impedes DNA repair and reduces natural killer cell targeting of malignant cells • Some mutations promote cancerous behaviour of cells (oncogenes) • Others impede the effect of genes which suppress cancer (tumour suppressor genes)

Does Asbestos Induced Differ from Smoking Induced Lung Cancer? • Cancers from asbestos exposed and non-exposed subjects compared • Differences in DNA aberration profiles and gene expression identified • Implies that increasing the efficacy of tobacco carcinogens is not the only mechanism of asbestos lung carcinogenesis • Raises the possibility that identification of specific genetic abnormalities might eventually be useful in identifying which lung cancers were caused by asbestos

Mechanism of Asbestos Carcinogenesis • Proliferative model hypothesis (out-dated): – Asbestos damages epithelial cells lining airspaces causing proliferation of cells attempting to repair damage – Increased proliferation leads to increased opportunity for mutations leading to cancer – Increased proliferation is always accompanied by asbestos induced inflammation which leads to fibrosis • This hypothesis was the basis of the proposition that asbestosis must be present to attribute lung cancer to asbestos

Asbestos Lung Cancer: Is Asbestosis Necessary? • If asbestosis present lung cancer is attributable to asbestos; no dissent from this view • Increasingly accepted that asbestosis is not a necessary precursor of cancer but a marker of sufficient exposure to have more than doubled the risk of lung cancer • Risk increased by asbestos exposure but probably increased further if asbestosis also present Sluis-Cremer GK & Bezuidenhout BN Brit J Ind Med 1990; 47: 215 -216 Reid A et al Occup Environ Med 2005; 62: 885 -889

Risk of Lung Cancer from Asbestos and Smoking • All studies suggest more than additive, ie synergistic interaction • Most suggest multiplicative or near multiplicative Doll R, Peto J. Effects on Health of Exposure to Asbestos. HMSO 1985

Risk of Lung Cancer from Asbestos and Smoking Hammond EC et al Ann NY Acad Sci 1979; 330: 473

Lifetime % Risk Of Lung Cancer Multiplicative Interaction Means Proportion Of Risk Due To Asbestos Same In Smokers and Non-Smokers

Practical Implications of Multiplicative Interaction Between Asbestos and Smoking • Amount smoked not relevant to establishing causation of cancer by asbestos; this depends only on establishing a more than twofold risk from asbestos • While non-smoking status is a useful ‘jury point’ it is still necessary to establish a more than twofold risk from asbestos • Smoking history may be relevant to contributory negligence arguments • Warnings appeared on cigarette packets from 1971

Asbestos Induced Lung Cancer: How Many Cases? • Proportional mortality ratios for mesothelioma and lung cancer calculated for the period 1980 to 2000 • Smoking indicators derived from 3 General Household Surveys • Asbestos related lung cancer deaths estimated by calculating no of deaths expected in each occupational group if no asbestos exposure and subtracting from actual number • Estimated between 0. 7 and 1 lung cancer per mesothelioma, ie ~ around 2000 cases per year Darnton AJ et al Ann Occup Hyg 2005

Lung Cancer: 2, 000 Cases Annually Does Not Mean 2, 000 Viable Claims • For example, if 40, 000 smokers of whom 4, 000 would get lung cancer from smoking were subjected to enough asbestos exposure to increase their risk of lung cancer by 50% (1. 5 -fold) there would be 2, 000 extra cases caused by asbestos but in none would it be possible to establish causation by asbestos on the basis of the test being more than doubling of the risk • In reality there is a spectrum of exposures but many of the cases ‘caused by asbestos’ on the basis of epidemiology do not have viable claims

Attribution of Lung Cancer to Asbestos: The Helsinki Criteria • International expert meeting of 19 participants from 8 countries not producing asbestos • Report produced in 1998 • Now form the basis for the award of compensation in several countries • Any one clinical, pathological or occupational criterion sufficient for attribution of lung cancer to asbestos • All criteria imply sufficient exposure to have more than doubled the risk of lung cancer Consensus Report Scand J Work Environ Health 1997; 23: 311

Attribution of Lung Cancer to Asbestos: The Helsinki Criteria, Occupational – One year of heavy exposure, eg lagging, or 510 years of moderate exposure, eg shipbuilding, construction – Occupational history indicating cumulative exposure ≥ 25 fibre/ml years Consensus Report Scand J Work Environ Health 1997; 23: 311 -316

Asbestos Dose Estimation • Dose measured in fibre ml years • Represents product of mean airborne fibre concentration and duration of exposure in working years (one year taken as 2000 hours, or sometimes 1920) • Eg exposure to 5 fibres/ml for 5 years gives a dose of 25 fibre ml years

Attribution of Lung Cancer to Asbestos: The Helsinki Criteria: Clinical/ Pathological • Radiological or pathological diagnosis of asbestosis • Pathological diagnosis of asbestosis requires diffuse interstitial fibrosis in association with at least 2 asbestos bodies per cm 2 of routine (5 micron thick) lung tissue section, averaged over all sections examined • Fibre count in asbestosis range in same laboratory • (Specific fibre count numerical criteria quoted not applicable to data from laboratories other than Helsinki) Consensus Report Scand J Work Environ Health 1997; 23: 311 -316 Henderson DW Pathology 2004; 36: 517 -550 Roggli VL, et al. Arch Pathol Lab Med 2010; 134: 462 -480.

Attribution of Lung Cancer to Asbestos: The Helsinki Criteria • Some criteria more robust than others • Subsequently criticised for not taking account of fibre type • Reviewed and largely reaffirmed in 2004; account taken of fibre type Consensus Report Scand J Work Environ Health 1997; 23: 311

Modified Helsinki Criteria • Occupational history indicating cumulative exposure ≥ 25 fibre/ml years for exposure to mixed fibre types, ‘predominantly’ (in practice at least 80%) amphiboles (amosite and /or crocidolite) • For an equal mix of chrysotile and amphiboles around 40 fibre/ml years needed to double risk of cancer (although the risk is almost entirely due to the amphibole) • Dose for exposure to chrysotile only depends upon industry, eg textile manufacture 100, friction products 1000 fibre/ml years Consensus Report Scand J Work Environ Health 1997; 23: 311 Henderson DW et al, Pathology 2004; 36: 517 -550 Hodgson & Darnton Ann Occup Hyg 2000; 66: 565 -601

The Practical Medical Basis for an Asbestos Induced Lung Cancer Claim • At least one of: – Radiological evidence of asbestosis – Pathological evidence of asbestosis – Exposure history assessed by a consultant engineer/forensic scientist as comfortably fulfilling modified Helsinki criteria – A lung fibre count within the asbestosis range in the same laboratory

Assessing Cumulative Exposure • Often occupational histories are complex with different types of exposure in different employments • Need to estimate dose received from each activity in each period of employment • The more complex the exposure history the less likely that a dose estimate will be sufficiently reliable to substantiate a claim • Small changes in assumptions lead to large changes in estimated dose

Cumulative Dose Estimation • Requires detailed explanation and estimation by the Claimant concerning: – Circumstances of exposure – Proximity to source of asbestos dust – Frequency and duration of episodes of exposure – Protective measures, if any • Expert assessment requires knowledge of – Fibre levels generated by activities described – Fibre types associated with different activities

Approximate Asbestos Dust Levels Process Airborne Dust (f/ml) Mixing lagging 250 Stripping lagging 100 Cutting insulation board power saw 20 Cutting insulation board hand saw 5 Cutting cement sheet hand saw 1 Sanding asbestos plaster eg Artex 0. 1 Changing brake linings <0. 1 Health and Safety Executive Guidance Note EH 35, 1989 Harries PG Ann Occup Hyg 1971; 14: 241 -254

Fibre Types Usually Involved • Pipe lagging mostly amphiboles (amosite and crocidolite) • Insulation board (soft) amosite • Cement sheet (hard) chrysotile • Corrugated roof sheets chrysotile • Artex chrysotile • Brake and clutch linings chrysotile

Bystander Exposure • Frequently exposure was from being in the vicinity of asbestos use or disturbance • Airborne dust levels fall rapidly with distance • 20 feet away levels fall by about 90% • Estimation of distance from source therefore important

Common Exposures Which Are Unlikely To Be Important In Lung Cancer Causation • Brake and clutch linings • Artex mixing, applying and removing • Sanding soffits, gutters and downpipes before painting • Work with corrugated asbestos cement roofing sheets • Stripping asbestos with precautions from 1983 onwards • It is very uncommon for exposures which commenced after the early to mid 1970 s to have been sufficient to double the risk of lung cancer

Asbestos Exposure: Indirect Evidence • Unless employed in a recognised high risk trade, eg lagger, indirect evidence is seldom a sufficient basis for a meaningful dose estimate • Witnesses can describe the circumstances of exposure but unless they worked alongside the deceased all the time, or exposure was constant rather than intermittent, they cannot say what proportion of the deceased’s working time involved exposure • Hence, there is seldom a realistic basis for a claim in a deceased case without direct witness evidence unless there is lung tissue available from surgery or autopsy for fibre analysis

Basis For A Claim From Engineering Evidence • An estimate based on the Claimant’s evidence which is ‘just enough’, eg 25 fibre ml years of which 80% amphibole, is not a sound basis for a claim • Expert would have to concede in cross examination that there are wide confidence intervals around the estimates • Defendant will inevitably have an expert whose estimate on basis of Defendant’s evidence is lower, ie ‘not enough’ • A Judge who has no basis on which to prefer one expert is highly likely to find exposure was between the two estimates, ie ‘not enough’

Basis For A Claim From Engineering Evidence • If a claim is to be based solely on estimated exposure the estimate should be high enough for the expert to be able to acknowledge wide confidence intervals but still be confident that exposure was ‘enough’, – eg estimate total dose 80 fibre ml years +/- 40, – ie 40 – 120 fibre ml years – Estimate 70% amphibole, +/- 20%, ie 50% - 90% – So lower end of both ranges is 40 fibre ml years including at least 50% amphibole, ie ‘enough’

Pathological Quantification of Exposure • Counting asbestos bodies in lung sections uninvolved by cancer – Number of asbestos bodies per cm 2 of 5 micron thick section averaged over all sections examined • Quantitative analysis of fibre content of lung tissue; more statistically reliable – Light microscopy – Electron microscopy

Quantification of Asbestos Fibres in Lung Tissue • A piece of lung is weighed, usually around 0. 3 g • Ideally wet fresh lung used but usually lung from paraffin block used; because of dehydration count multiplied by 0. 7 to convert to wet lung count • Lung tissue is then digested with chemicals eg sodium hydroxide, or ashed in a furnace • Remaining material filtered to collect fibres for microscopy • Fibres counted • Multiplication factor applied to obtain count per gram of lung tissue

Type of Microscopy • Light microscopy (LM) can reliably count only coated fibres, ie asbestos bodies (AB) – LM cannot identify fibre types • Electron microscopy (EM) identifies uncoated fibres – Transmission EM can identify smaller fibres than scanning EM – EM can identify fibre types by looking at elemental composition of the fibre using energy dispersive xray micro-analysis (EDXA)

Fibre Counts: Methodological Issues • Different laboratories use variations of same techniques • Even when ostensibly using exactly the same technique different laboratories obtain different values on the samples • Therefore necessary to compare result in an individual case with reference range from same laboratory

EM Fibre Counts: Methodological Issues • Non-uniform distribution of fibres in lung tissue • Statistical error in counting • Together lead to variation between results from different samples of same lung • Up to 3 fold variation common, up to 10 fold occasionally

Clearance of Asbestos Fibres • Fibres cleared over time by natural mechanisms, eg engulfment by macrophages, expectoration in sputum, dissolution in situ • Clearance half time, ie time for count to fall by 50% varies with fibre type: – Chrysotile (white asbestos) a few months – Crocidolite (blue asbestos) 6 -7 years – Amosite (brown asbestos) 20 years

Clearance of Asbestos Fibres • Difficult to take into account because published data does not give time since exposure ceased • Clearance will have occurred in cases upon which asbestosis range is defined as well as in index case

Fibre Counts: Asbestosis Range • Total retained amphibole asbestos fibre count in cases of asbestosis, fulfilling current histological diagnostic criteria • Lower end of the range is the 5 th percentile, ie the level above which 95% of cases lie • Chrysotile count excluded because of rapid clearance and low potency

Fibre Count Criteria To Support Lung Cancer Causation • Asbestos bodies in lung sections – Average of 2 per cm 2 of 5 micron thick section – Or 12 per cm 2 of 30 micron thick section – ie the number needed for a diagnosis of asbestosis if diffuse interstitial fibrosis present • Fibre count – In the asbestosis range in the same laboratory – Light microscopy usually > 100, 000 per gm dried lung – Electron microscopy (Cardiff) > 3. 4 million amphiboles per gm dried lung (lower 5 th centile of 236 cases)

Conflicting Evidence • If conflict between estimated exposure and a fibre count usually more weight is accorded to the fibre count, but not always • Occupational history accorded more weight if: – Predominantly chrysotile exposure, because rapid fibre clearance makes fibre analysis useless for assessing chrysotile exposure – Fibre count clearly inconsistent with a simple occupational history, eg lagger for 20 years – Technical problem with analysis, eg lung contaminated by tumour tissue or insufficient tissue available to be representative

Lung Cancer Claims: Practicalities • Living Claimant – Obtain detailed statement specifying for each job • Dates, employer • Circumstances of exposure • Proximity to source of airborne fibres if indirect exposure • Frequency and duration of episodes of exposure • Precautions, if any – Warn Claimant and family post-mortem required if claim not concluded; doctors will not arrange if they are not thinking of disease as occupational

Lung Cancer Claims: Practicalities • Living Claimant – If solicitor is confident statement suggests sufficient exposure, ask medical opinion as to whether dose estimate required before medical report – If doubtful that sufficient exposure ask medical opinion, if doctor agrees insufficient, go no further – If obviously nowhere near sufficient exposure, go no further

Lung Cancer Claims: Practicalities • Deceased Claimant – If post-mortem done ask pathologist to preserve lung tissue uninvolved by tumour as well as tumour – Do not rely upon the post-mortem examination report conclusions; many are of abysmal standard – If PM not done find out if surgery performed; if so ask hospital to preserve tissues – Obtain preliminary medical opinion as to whether review of pathology and/or fibre count required

Lung Cancer Claims: Practicalities • Deceased Claimant, post-mortem not done and no surgical tissue available – Statement by deceased available? • If confident statement suggests sufficient exposure: ask medical opinion as to whether dose estimate required before medical report • If doubtful that there was sufficient exposure ask medical opinion; if doctor agrees, go no further • If obviously nowhere near sufficient exposure go no further – No statement by deceased • unless very obvious probability of heavy exposure, eg lagger, go no further

Asbestos and Lung Cancer Could the Test of Causation Change? • In an obiter dicta in the Supreme Court judgment in Sienckeiwicz v Grief and Knowsley MBC v Willmore 2011 concrning mesothelioma, Lord Phillips questioned the conclusion in Shortell v BICAL (2008) Construction Ltd in which Mackay J based his assessment of causation of lung cancer on a risk factor of greater than twofold from asbestos having been established: “I question whether ……. the ‘doubles the risk’ test is correct in cases where asbestos and tobacco smoke have combined to cause lung cancer”.

Shortell v BICAL (2008) • In Shortell v BICAL Ltd there was little discussion of the mechanisms of asbestos carcinogenesis • The Claimant’s case was based upon the dose of asbestos, estimated by Mr Deary at 99 fibre ml yrs involving mixed fibre types, having more than doubled the risk of lung cancer, hence satisfying the ‘but for’ test • The Defendant accepted that this was the appropriate test, but relied on Mr Walker who estimated the dose at only 9. 5 fibre ml years, so there was no need to explore mechanisms in evidence • This was why Mackay J, who preferred the evidence of Mr Deary, relied upon doubling of the risk as the test for establishing causation

Asbestos Carcinogenesis • It can be demonstrated that there is a synergy between asbestos and tobacco carcinogens in causing lung cancer, not only on the basis of the risk factors but also on the basis of molecular carcinogenesis • Asbestos fibres act cumulatively to increase delivery of tobacco carcinogens to lung epithelial cells, impair detoxification of some tobacco carcinogens, increase DNA damage, and impede DNA repair, thus increasing the frequency of genetic alterations which lead to cancer

Asbestos Carcinogenesis • It can thus be argued that in any person who has developed lung cancer after substantial exposure to asbestos it is more likely than not that asbestos fibres have physically contributed to the carcinogenic process, not just increased the risk that cancer would occur • It is still necessary to refer to risk factors as determined from epidemiological studies to quantify the contribution from asbestos

Phurnacite Litigation (2012) • The Hon Mrs Justice Swift – Accepted that coke plant fumes caused lung cancer (main carcinogen benzo[a]pyrene, also found in tobacco smoke) – Relied upon doubling of the risk test – Rejected an invitation to find that causation could be established on the basis that tobacco smoke and occupation involved exposure to the same carcinogen, even if the risk from the occupational contribution was less than twofold (Not appealed)

Asbestos and Lung Cancer Could the Test of Causation Change • Can the Court be persuaded to follow Lord Phillips to conclude that a risk of less than twofold from asbestos is sufficient? • If so, how much less than twofold? A less than 20% increase in risk as for mesothelioma in Sienkiewicz?

Asbestos Induced Lung Cancer Should Damages Be Apportioned?

Heneghan v Manchester Dry Docks et al (2014) • Lung cancer attributed to asbestos • Risk factor from asbestos estimated at 5 -fold, risk from smoking at 4 -fold • Agreed by both sides that, on balance, he would not have developed lung cancer without asbestos exposure, ie in legal terms asbestos caused the cancer • Available Defendants accounted for only 35. 2% of the total dose, one of them for only 2. 5% • Should damages be apportioned in accordance with Holtby (in asbestosis)?

Heneghan v Manchester Dry Docks et al 2014 • Claimant argued lung cancer is an indivisible injury, therefore no apportionment of damages • Also that, on balance, fibres from all exposures contributed to carcinogenesis • Defendants argued causation could be established only by analogy with Fairchild, ie each Defendant contributed to the risk since, on the balance of probabilities, the cancer would have occurred without any of the Defendants’ exposures, or even without all of them, since together they accounted for less than 50% of the risk due to asbestos

Heneghan Judgment • Mr Justice Jay concluded that the Claimant had to rely on an extension of Fairchild to establish causation against any of the Defendants, since the conventional ‘but for’ test could not be satisfied against any of them • Did not accept that consideration of mechanisms of carcinogenesis established that fibres from each probably contributed to causation of the disease (did not explain why not and dismissed evidence about carcinogenesis, which he referred to as ‘microbiological processes’ as irrelevant)

Heneghan Judgment • Damages awarded against the Defendants in proportion to their contribution to the total risk resulting from sued and non-sued exposures • Hence, the Claimant recovered 35. 2% of damages • Mr Justice Jay said if Claimant was right that damages should not be apportioned for an indivisible injury, ie cancer, and if the Defendant which contributed only 2. 5% had been the only one available to be sued that Defendant would have had to pay 100% of damages which the judge did not think would have been fair • The decision has been appealed

Lung Cancer Survival • 90% of patients inoperable at presentation • About half who undergo surgery die of the disease • Most with inoperable disease die within 1 year