Asbestos, Smoking and Lung Cancer: An Update

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DOI: 10.3390/ijerph17010258
Cite this publication
Abstract
This review updates the scientific literature concerning asbestos and lung cancer, emphasizing cumulative exposure and synergism between asbestos exposure and tobacco smoke, and proposes an evidence-based and equitable approach to compensation for asbestos-related lung cancer cases. This update is based on several earlier reviews written by the second and third authors on asbestos and lung cancer since 1995. We reevaluated the peer-reviewed epidemiologic studies. In addition, selected in vivo and in vitro animal studies and molecular and cellular studies in humans were included. We conclude that the mechanism of lung cancer causation induced by the interdependent coaction of asbestos fibers and tobacco smoke at a biological level is a multistage stochastic process with both agents acting conjointly at all times. The new knowledge gained through this review provides the evidence for synergism between asbestos exposure and tobacco smoke in lung cancer causation at a biological level. The evaluated statistical data conform best to a multiplicative model for the interaction effects of asbestos and smoking on the lung cancer risk, with no requirement for asbestosis. Any asbestos exposure, even in a heavy smoker, contributes to causation. Based on this information, we propose criteria for the attribution of lung cancer to asbestos in smokers and non-smokers. Keywords:asbestosis; carcinoma; cumulative exposure; mesothelioma; multiplicative model;pathogenesis; smoking; synergism
International Journal of
Environmental Research
and Public Health
Review
Asbestos, Smoking and Lung Cancer: An Update
Sonja Klebe 1, * , James Leigh 2, Douglas W. Henderson 1,and Markku Nurminen 3,4
1Department of Anatomical Pathology, SA Pathology and Flinders University, Adelaide, SA 5042, Australia
2Asbestos Diseases Research Institute, University of Sydney, Concord, NSW 2139, Australia;
jleigh@bigpond.com
3Department of Public Health, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
markstat.consultancy@elisanet.fi
4MarkStat Consultancy, 00250 Helsinki, Finland
*Correspondence: sonja.klebe@sa.gov.au; Tel.: +61-08-820-439-36
Professor Henderson is deceased while writing the paper.
Received: 18 November 2019; Accepted: 24 December 2019; Published: 30 December 2019


Abstract:
This review updates the scientific literature concerning asbestos and lung cancer,
emphasizing cumulative exposure and synergism between asbestos exposure and tobacco smoke,
and proposes an evidence-based and equitable approach to compensation for asbestos-related lung
cancer cases. This update is based on several earlier reviews written by the second and third
authors on asbestos and lung cancer since 1995. We reevaluated the peer-reviewed epidemiologic
studies. In addition, selected
in vivo
and
in vitro
animal studies and molecular and cellular studies
in humans were included. We conclude that the mechanism of lung cancer causation induced by the
interdependent coaction of asbestos fibers and tobacco smoke at a biological level is a multistage
stochastic process with both agents acting conjointly at all times. The new knowledge gained through
this review provides the evidence for synergism between asbestos exposure and tobacco smoke in lung
cancer causation at a biological level. The evaluated statistical data conform best to a multiplicative
model for the interaction eects of asbestos and smoking on the lung cancer risk, with no requirement
for asbestosis. Any asbestos exposure, even in a heavy smoker, contributes to causation. Based
on this information, we propose criteria for the attribution of lung cancer to asbestos in smokers
and non-smokers.
Keywords:
asbestosis; carcinoma; cumulative exposure; mesothelioma; multiplicative model;
pathogenesis; smoking; synergism
1. Introduction
Asbestos exposure has been related to lung cancer causation since the 1930s, and much research
has been published since then on epidemiological, clinical, biological, and medico-legal aspects of
this relationship. Asbestos-related lung cancer is quantitatively more important than mesothelioma
but is underrecognized because of the dominating eect of tobacco smoking in the causation of most
lung cancers.
Four of the most important outstanding research questions in this area are: (i) How do
tobacco smoking and asbestos fibers combine at a biological level to produce the well-known
supra-additive interaction in causing lung cancer? (ii) How much asbestos exposure is needed to
make a legally-significant contribution to lung cancer causation in the presence or absence of tobacco
exposure? (iii) Is the presence of asbestosis necessary for any attribution of lung cancer to asbestos?
(iv) How should lung cancer be compensated and how should tobacco smoking be allowed for in
common law proceedings and in statutory compensation schemes?
Int. J. Environ. Res. Public Health 2020,17, 258; doi:10.3390/ijerph17010258 www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2020,17, 258 2 of 23
This review considers the recent literature on causation and compensation of asbestos-related
lung cancer and, in answering the above-mentioned medico-legal questions, proposes a rational,
scientifically-based and equitable approach to compensation for asbestos-related lung cancer. The
original Helsinki Criteria and updates did not consider smoking, and the exposure criteria were
intended to apply irrespective of smoking, but here we have added a special consideration for life-long
nonsmokers and ex-smokers with >30 yr since quitting.
Preliminary Remarks
As reviewed by Henderson and Leigh [
1
], anecdotal autopsy reports of lung cancer in workers
with asbestosis were reported in the mid-1930s [
2
5
], and in 1938, three German papers and a review
from Austria reported evidence of a link between asbestosis and lung cancer [
6
]. Nordmann and
Sorge referred to this occurrence as the occupational cancer of asbestos workers, and they thought that
approximately 12% of asbestosis patients might develop lung cancer [
7
]. Nordmann and Sorge induced
lung tumors in mice by the inhalation of chrysotile asbestos; the apparatus used for this experiment is
illustrated in Proctor’s book The Nazi War on Cancer, and in 1943, the German government designated
lung cancer in association with any degree of asbestosis as a compensable disease [
6
,
8
]. This nexus
was rediscovered by Doll, who found that: One hundred and thirteen men who had worked for
at least 20 years in places where they were liable to be exposed to asbestos were followed up, and
the mortality among them compared with that which would have been expected on the basis of the
mortality experience of the whole male population [9].
Thirty-nine deaths occurred in the group, whereas 15.4 were expected. The excess was due to
excess deaths from lung cancer (11 against 0.8 expected) and respiratory and cardiovascular diseases
with asbestosis. All the cases of lung cancer were confirmed histologically, and all were associated
with the presence of asbestosis; the average risk among men employed for 20 or more years was of the
order of 10 times that experienced by the general population. The risk became progressively less as the
duration of employment under the old dusty conditions decreased.
In his paper, Doll, also placed emphasis on Merewether’s 1949 observation that at autopsy, lung
cancer was found in 31 of 235 cases of asbestosis (13.2%), but in only 91 out of 6884 cases of silicosis
(1.3%), and on Gloyne’s analogous observation of lung cancer in 17 of 121 autopsy cases of asbestosis
(14.1%), in comparison to 55 out of 796 cases of silicosis (6.9%) [9,10].
The literature on asbestos and lung cancer has been reviewed extensively by Henderson, Leigh and
coauthors [
11
21
]. From that literature, there is general agreement on a number of issues concerning
asbestos and lung cancer, namely:
All commercial asbestos fiber types can be implicated in the causation of lung cancer, e.g.
amphibole anthophyllite and including the noncommercial amphibole, tremolite. In this context,
commercial amphiboles crocidolite and amosite appear to be about equipotent on a fiber-for-fiber
basis for lung cancer induction, and chrysotile is also implicated, especially in the chrysotile textile
industry [
22
,
23
]. (There remains an unexplained 30-fold to 50-fold dierential in the risk of lung
cancer among the Charleston textile workers who used commercial Canadian chrysotile almost
exclusively, in comparison to a much smaller risk for the Quebec chrysotile miners and millers).
Whilst histological criteria have been established, the dierential diagnosis of malignant
mesothelioma, primary lung carcinomas, and pleural metastases can cause problems, especially
in the case of sarcomatoid tumors [
24
,
25
]. A comparison of the frequency of DNA copy number
changes between mesothelioma and lung carcinoma using discriminant analysis suggests that
they are genetically-dierent tumors [
26
]. In the case of malignant mesothelioma, asbestos is
overwhelmingly the singular identifiable causal factor, with only rare cases related to other factors
such as erionite or fluoro-edenite fiber inhalation, ionizing radiation (sometimes in association
with asbestos exposure), and innate susceptibility factors such as germline mutations aecting the
BAP1 gene. Tobacco is not implicated in the causation of mesothelioma.
Int. J. Environ. Res. Public Health 2020,17, 258 3 of 23
Lung carcinoma, on the other hand, is a multifactorial cancer for which tobacco (especially
cigarette smoke) represents the most potent causal factor on a worldwide basis. There are other
known causes such as ionizing radiation (including radon gas daughters); certain metals such
as hexavalent chromium, nickel, cadmium, arsenic and beryllium; silica, diesel particulate, and
heated cooking [27].
There are no clinical, radiographic or pathologic features of the tumor that discriminate clearly
between lung cancers for which asbestos exposure can be implicated versus those for which
it cannot; that is, there are no dierences in the anatomical distribution of lung cancers in
asbestos-exposed individuals (such as the upper vs. lower lobe or a central vs. peripheral
localization), and all major histological types of lung carcinoma occur in asbestos-exposed
individuals in comparison to nonexposed subjects, with no significant dierences in the
immunophenotypes, and no clear or diagnostic dierences in the molecular-genetic profiles
(see later discussion).
The relationship between asbestos and lung cancer in general is governed by a near-linear
dose-response relationship, with no clearly delineated threshold, but the gradient of the
dose-response line is less steep than the analogous dose-response line between asbestos and pleural
malignant mesothelioma. From Gustavsson’s meticulous case-referent studies in Stockholm
County [
28
,
29
], there appears to be some evidence that the dose-response gradient for lung cancer
is steeper at low cumulative exposures than at higher exposure [
29
] (see also [
17
,
30
], and later
discussion in this review). In their 2000 review of 17 cohort studies, Hodgson and Darnton
commented that if a threshold does apply to lung cancer induction by amphibole asbestos, ‘it must
be very low’, where as a threshold for chrysotile—a ‘zero or at least very low risk’—is ‘strongly
arguable’ (but they commented that the asbestos-related dose-response eect for lung cancer
in the Charleston textile cohort is ‘untypically high’ [
31
]). In contrast, some other studies have
also found a higher dose-response eect for asbestos textile workers than for other chrysotile
exposures [32,33].
However, several longstanding issues on which dissenting conclusions have been drawn are
the exact nature of interaction between tobacco smoke and asbestos, and whether asbestosis is a
requirement for the attribution of lung cancer to asbestos in an asbestos-exposed smoker:
It is accepted that tobacco (especially cigarette) smoke and asbestos functionally interact in the
causation of lung cancer; however, the type and strength of this interaction have occasionally been
the issue if debate [
34
]. It is our opinion that the eect is synergistic, i.e., the combined eect is
greater than the sum of the individual eects. By definition and in biological terms, the dierence
(the synergistic eect) cannot be apportioned back to each of these individual carcinogens; this
issue is explored further in a later section of this review.
It is our opinion on the balance of probabilities that asbestosis is not a necessary prerequisite for
the attribution of lung cancer to asbestos in an asbestos-exposed smoker.
The following section of this review highlights a few publications on this issue.
2. Materials and Methods
The authors reviewed key epidemiological, pathological, and basic biology papers that had been
published since the previous review by two of the authors on the subject [
17
]. A formal meta-analysis
was not performed.
3. Discussion
3.1. Lung Cancer and Cumulative Asbestos Exposure, with or without Asbestosis-Source Epidemiological Data
A 2005 review limited to nine key epidemiological papers found that seven of the nine papers
supported the case that asbestosis was not a necessary prerequisite for attribution of lung cancer to
Int. J. Environ. Res. Public Health 2020,17, 258 4 of 23
asbestos exposure; it found weaknesses in all the studies reviewed, and concluded that a consideration
of fiber type would be critical in putting the issue beyond doubt, and that epidemiology alone could
not resolve this medico-legal issue [
35
]. This review was limited to all the studies above and many
others are analyzed in greater detail in the reviews mentioned above [17,30,35,36].
A study bearing on lung cancer mortality among insulation workers was reported by Markowitz
and colleagues [
37
]; this investigation focused on 2377 male North American insulators for whom
chest x-ray, spirometric, occupational, and smoking data were collected in 1981–1983, and for 54,243
nonasbestos-exposed blue collar male workers for whom occupational and smoking data were collected
in 1982. Lung cancer caused 339 (19%) insulator deaths. The authors found that lung cancer mortality
was increased by asbestos exposure alone among nonsmokers (rate (risk) ratio [RR] =3.6; 95%
confidence interval [CI] =1.7–7.6) i.e., among those without evidence of asbestosis on chest x-ray at the
beginning of the study, although 1.3% of this group died from asbestosis during the period 1981–2008),
in comparison to asbestosis among nonsmokers (RR =7.40; 95% CI =4.0–3.7), and by smoking without
asbestos exposure (RR =10.3; 95% CI =8.8–2.2). In this study, the joint eect of smoking and asbestos
alone was additive (RR =14.4; 95% CI =10.7–19.4), and for asbestosis, the joint eect with smoking
was supra-additive (RR =36.8; 95% CI =30.1–45.0). Insulator lung cancer mortality halved within
10 years of smoking cessation, and it approached that of never-smokers at 30 years after cessation.
Unsurprisingly, the Markowitz et al. study has attracted criticism [
38
,
39
], to which Markowitz et al.
responded [
40
]. In an editorial on the Markowitz et al. paper, Balmes commented that we ‘know’ that
(i) ‘asbestos exposure alone is capable of causing lung cancer’; (ii) asbestos and smoking together are
associated with at least an additive increased risk of lung cancer; (iii) the presence of asbestosis further
increases the risk in both smokers and nonsmokers; and (iv) smoking cessation substantially decreases
the lung cancer risk associated with asbestos exposure [italicized text in the original editorial]) [41].
A comprehensive study of lung cancer mortality in UK asbestos workers based on 1878 deaths
in the period 1971–2005 confirmed a multiplicative interaction of tobacco and asbestos exposure,
an increased dose-related risk of lung cancer in never-smoking asbestos workers compared to the
never-smoking general population, based on 32 never smoker male lung cancer deaths (SMR 95%
CI 93–192) (i.e., P ~ 0.06 one- sided), and a substantial reduction in lung cancer risk with smoking
cessation [42].
A very large pooled analysis of 14 case—referent studies in Europe and Canada conducted
in 1985–2010 (17,705 cases, 21,813 referents, 6958 exposed males, 482 exposed females)—showed
no departure from a multiplicative model in males and a more than additive eect in females [
43
].
In all males, the mean coecient was 0.061 per fiber-year, and for blue collar worker males, 0.033
per fiber-year. Females showed no significant increase in risk (p>0.05), but exposures were much
lower [43].
We also assign significance to the 1994 case-referent study reported by Karjalainen and colleagues
on the association the between lung asbestos fiber burden and the risk of lung cancer—based on 113
lung cancer patients treated by surgery, vs. 297 autopsy referents in the Finnish population. Lung
tissue fiber assays were carried out for fibers longer than 1
µ
m by SEM (mainly amphibole fibers). The
odds ratio for lung cancer (OR
LCA
) increased to 1.7 for concentrations in the range 1.0–5.0 million
fibers/g dry lung and to 5.3 for concentrations of
5.0 million fibers/g dry lung, in comparison to a
reference group with a fiber concentration of <1.0 million [
44
]. The authors stated that when two cases
of asbestosis and seven cases of minor ‘histological fibrosis compatible with asbestosis’ were excluded,
an elevated OR
LCA
was still associated with asbestos fiber concentrations of
5.0 million fibers/g dry
lung (the age-adjusted OR
LCA
was 2.8; 95% confidence interval, CI =0.9–8.7; p-value =0.07) and for
fiber counts in the range 1.0-5.0 million, the OR
LCA
was 1.5 (95% CI =0.8–2.9; p=0.19). This study
has been criticized because the results failed to achieve ‘significance’ in terms of pvalues, thereby
proving that ‘significance’ lay only with the cases of fibrosis [
45
]. However, this criticism is weakened
by two factors: (i) the limit p
0.05 is an arbitrary statistical convention, and reality often lacks sharp
boundaries of this type; and (ii) what is important in this study is the trend from a low to a higher
Int. J. Environ. Res. Public Health 2020,17, 258 5 of 23
OR
LCA
with transition from an intermediate fiber count (1.0–5.0); the clinical asbestosis cases were
in the heaviest exposure group and that the mild histological fibrosis cases were in the intermediate
exposure group—the OR
LCA
s then become 2.85 and 1.8 respectively, as consistent as possible with the
age-adjusted OR
LCA
s of 2.8 and 1.5 in the original paper and trend testing then yields X
2
(1 d.f.) =7.2
(p<0.01). In addition, one can recalculate the OR
LCA
for adenocarcinoma only, after the exclusion of
all cases with any fibrosis; assuming that all were in the high fiber group, the OR
LCA
(2.65; 95% CI =
1.11–6.26; p<0.001) is still significantly elevated, for a count >1.0 million compared to <1.0 million.
The study by Karjalainen and colleges [
44
] study formed the basis in part for the uncoated amphibole
asbestos fiber counts specified originally in The Helsinki Criteria [46].
An earlier review or meta-analysis of epidemiologic studies concluded that persons without
asbestos-related pleural plaques do not have an increased risk of lung cancer in the absence of
parenchymal asbestosis [
47
]. The reviewer inferred that this conclusion provided indirect supportive
evidence for the proposition that asbestosis is a necessary precursor of asbestos-related lung cancer.
Nurminen and Tossavainen showed that such a proposition lacked any logic [48,49].
In this context, it is our assessment that the weight of scientific evidence indicates that the risk
(and occurrence) of lung cancer is related to cumulative asbestos exposure per se, with no requirement
for asbestosis [
1
,
17
,
28
,
29
,
31
]. We draw this conclusion, although dissenting opinion this issue has
persisted [
50
52
] for years after the Hughes and Weill study [
53
]. That study favored a requirement
for asbestosis in order to attribute lung cancer to asbestos. But if asbestosis is present, the risk of
lung cancer is further enhanced (for additional references on this issue and our responses to the
‘dissenting’ opinion, see Henderson and Leigh [
1
,
17
,
30
]. In this setting, we consider that asbestosis
appears primarily to be a marker for substantial to heavy cumulative asbestos exposure.
3.2. A Peer Opinion Regarding the Requirement for Asbestosis for Attribution of Lung Cancer
The cumulative exposure model with no requirement for asbestosis was further strengthened
by the results of an international ‘Delphi’ study on asbestos-related disorders, published in 2009 [
54
].
The database PUBMED was searched for all persons in the world with three or more first-author
publications on asbestos-related disease for the period 1991–2002: 95 were found. The respondents to
computer questionnaire (34/95) replied to a series of questions, one of which was ‘Pulmonary fibrosis
is a prerequisite to attribute the development of lung cancer to asbestos’; there was strong consensus
that this was not the case (median score 1 out of 10 on a scale of strongly disagree (0) to strongly agree
(10). A second question was ‘Workers with asbestos exposure and pleural plaques or diuse pleural
thickening without (fibrosis) are at increased risk of lung cancer’; there was strong consensus that
this was the case, with a median score 9 on the same scale. A third question was ‘Workers who have
significant asbestos exposure (but who do not have asbestosis) are at increased risk of bronchogenic
carcinoma’; there was strong consensus that this was the case (median score of 9 on the same scale). A
fourth question was ‘A history of asbestos exposure of sucient duration, dose and latency is likely to
be the cause of interstitial fibrosis in the absence of other explanations’; a consensus was reached with
a median score 9 on the same scale.
3.3. The Pathogenesis of, and Some Molecular Alterations in, Asbestos-Related Lung Cancer
The cellular and molecular pathogenesis of fiber-induced lung cancer has been extensively studied
over the last 20–30 years, and although knowledge is incomplete, much is known about it. The current
consensus view is that asbestos participates in both the initiation and the proliferation phases of tumor
development. The monograph on human carcinogenesis by arsenic, metals, fibers, and dust [
55
]
reviews the evidence and the Consensus Report states as much.
Carcinogenesis by fibers appears to be a multistage process which may arise by the ability of
fibers to cause (i) altered expression or function of key genes arising from genetic or epigenetic
alterations; (ii) altered cell proliferation; (iii) altered regulation of apoptosis; or (iv) chronic, persistent
inflammation [55].
Int. J. Environ. Res. Public Health 2020,17, 258 6 of 23
Our opinion, based on current scientific literature, is that in view of the capacity of asbestos fibers
to be involved at all stages of tumor development, all cumulative exposure to asbestos in an individual
plays some contributory part in causation of the tumor, and consequently, that this cannot be separated
from the concurrent eects of tobacco smoke; the evidence suggests that asbestos fibers increase the
uptake and metabolism of polycyclic aromatic hydrocarbons (which are amongst the best characterized
carcinogens in cigarette smoke) by lung epithelial cells [
56
59
]. In addition, cigarette smoke increases
the binding of asbestos fibers to lung epithelial cells [
60
,
61
]. The lung epithelial cells are genetically
damaged, some damaged cells become malignant, and malignant cells proliferate at dierent times.
DNA repair processes are occurring (or may be impaired), and oncogenes and suppressor genes are
activated and inactivated.
Altered cells are being removed by apoptosis, necrosis, and immunological means. Fibers are
being cleared at diering rates and, if exposure continues, they continue to be deposited in the lung.
Components of cigarette smoke have been shown to impair the clearance of particulates, including
asbestos fibers, form the upper airways [
62
,
63
]. All these processes at a cellular level are stochastic,
in that probabilities of fiber-cell interaction depend on the number of fibers and the numbers of cells
present at any point in time and space. Hence, simplistically, the more fibers, the more there are
free radicals, and the greater the probability of genetically-damaged and proliferating cells at any
given time point. This is shown diagrammatically in Figure 1. See also the Interational Agencyf
(or Research on Cancer (IARC) Monograph 100C [
55
] for a detailed review of lung cancer causation
by asbestos. Recently, a putative new mechanism has been proposed whereby asbestosis, lung
cancer, and mesothelioma pathogenesis has a common ground based on asbestos-induced epithelial
to mesenchymal transition (EMT), mediated through a transforming growth factor (TGF)
β
pathway.
New direct evidence for this mechanism in bronchial epithelial cells exposed
in vitro
to chrysotile has
recently been published [64].
To the best of our knowledge, the molecular profiles of the carcinomas (such as epidermal growth
factor or anaplastic lymphoma kinase mutation expression) do not distinguish definitively between
those lung carcinomas for which asbestos causation can be implicated, in comparison to those for
which it cannot. Although a few recent studies have found an association between the type of mutation
and asbestos causation, in our opinion, it is still not possible from genetic studies to clearly identify an
asbestos-caused carcinoma in comparison to equivalent lung carcinomas in the general population.
Nelson et al. found k-ras mutations more frequently in asbestos-exposed lung adenocarcinomas than
carcinomas in nonexposed lung [
65
]; Kettunen et al. found a statistically significant greater frequency
of chromosome position 2p16 loss in lung cancers (all cell types) from asbestos exposure compared to
nonexposure carcinomas [
66
]. The 2014 update of the Helsinki criteria recommends no changes to the
1997 criteria in relation to lung cancer. The report stated that the only means to evaluate the potential
usefulness of a molecular assay is by comparison with the present criteria of attribution, preferably in
prospective international multicenter studies. It also noted that further studies are required before
genetic biomarkers can be applied to support attribution in individual cases [67].
3.4. The Synergy between Asbestos Fibers and Tobacco Smoke for Lung Cancer Causation Epidemiological Data
A current consensus view is that asbestos exposure and tobacco smoking interact synergistically
for the causation of lung cancer, described by a multiplicative model, recognized since 1968 [
68
], although
a more than additive (submultiplicative) eect has also been invoked [
69
]. Furthermore, an additive
model has been applied for the Quebec chrysotile cohort in particular, and Markowitz and colleagues
recorded an additive and supra-additive eect for asbestos alone and asbestosis respectively in their
mortality analysis of North American insulators [37] (see Appendix Afor definition of the models).
In the very large 1979 cohort mortality study of US insulation workers (276 lung cancer deaths)
by Hammond et al. [
70
], smoking increased the risk of lung cancer by about 10-fold, and asbestos
increased the risk by about 5-fold; the two together increased the risk by about 50-fold (not 15-fold),
compared with that of the nonsmokers who were unexposed to asbestos; an almost pure multiplicative
Int. J. Environ. Res. Public Health 2020,17, 258 7 of 23
eect. If all factors contributing to lung cancer were summarized in a figure of 53 to quantify the
actual average risk in a smoker with asbestos exposure, its components are 1 for the base risk, 10
(10.85–1) for the smoking risk, 4 (5.17–1) for the asbestos risk, and 38 (53–1–10–4) for the risk that
depends on the interaction between smoking and asbestos. It is readily evident that the interaction is
of major importance.
However, from a pathobiological perspective and as matter of definition, the interactive eect
cannot be partitioned into the individual eects of smoking and asbestos. Nurminen and Karjalainen
have also emphasized the multiplicative proportion of fatalities related to occupational factors
(including lung cancer with smoking and asbestos) in Finland [
71
]. The Australasian Faculty of
Occupational Medicine of the Royal Australasian College of Physicians has reiterated the consensus
view that the relationship is generally multiplicative, although recognizing that lighter smokers may
have a greater dose-related risk of lung cancer from asbestos [72].
An authoritative review on possible biologic mechanisms for this synergistic eect and the forms
of statistical interaction has been made by the International Agency for Research on Cancer [
73
]. After
reviewing various studies, the authors concluded that the multiplicative model generally gives the
best fit. Liddell argues that the Quebec miner and miller cohort studies indicate an additive eect
of smoking and asbestos rather than a multiplicative one, although he concedes than an ‘additive
hypothesis is not generally applicable’ [
74
,
75
]; he mentions the review of Lee [
76
] on the nature of
the interaction between smoking and asbestos in causing lung cancer, but does not deal with Lee’s
finding that in 30/31 datasets analyzed, the eect was greater than additive, with no overall departure
from the multiplicative model. Lee analyzed the Quebec cohort data by two dierent methods, and
found that the data did not show true departure from the multiplicative model; he concluded that the
multiplicative model is the best overall fit. A large case-referent study (1004 cases and 1004 matched
controls) found no statistical evidence to support departure from a multiplicative model [
77
]. Vainio
and Boetta concluded that the interaction approximates the multiplicative model, and that tobacco
smoke and asbestos may have independent eects on the multistage process of carcinogenesis [
73
]. A
recent meta-analysis including some more recent studies showed a supra additive synergy implying
biological level interaction [
69
]. This is also supported by the recent large study by Olsson et al., where
14 case-control studies conducted in 1985–2010 in Europe and Canada were pooled. These included
more than 17,000 lung cancer cases and 21,813 controls with detailed information on tobacco habits
and lifetime occupations. An increasing lung cancer (all major histological types) risk for men was
seen with increasing asbestos exposure in all smoking categories, whereas in women, lung cancer risk
was increased in current smokers (ORs ~ two-fold), regardless of histological type. The data again
supported a multiplicative eect of eect of combined asbestos exposure and smoking in males, and
the eect was more than additive in females [43].
3.4.1. The Synergy between Asbestos Fibers and Tobacco Smoke for Lung Cancer Causation:
Biological Data
Tobacco smoke can act at early stages, inducing genetic alterations, DNA adducts, and mutations
in genes critical to cancer formation. Tobacco smoke can also influence the uptake of particulates by
bronchial epithelial cells [
78
]. It is likely that the chemical basis of tobacco-induced mutations is the
oxidation of DNA groups by free radicals. Epidemiological evidence suggests that tobacco may also
act at later stages of the cancer process. Tobacco smoke has both gaseous and particulate components;
the latter can stimulate macrophages to release cytokines and free radicals [
79
]. Macrophages
associated with tumors are critical to both the initiation and maintenance of lung cancers, as well as to
metastases [
80
]. Asbestos can be cytotoxic (killing cells) and genotoxic (damaging genes), and may
cause proliferative lesions in the lungs. Asbestos fibers can generate free radicals either directly or
after attempted phagocytosis by macrophages. It is likely that the chemical basis of asbestos-induced
mutations is the oxidation of DNA groups by free radicals. Asbestos is genotoxic to bronchial epithelial
cells [45,65,8183].
Int. J. Environ. Res. Public Health 2020,17, 258 8 of 23
Asbestos may cause chronic inflammatory changes, which release cytokines (including growth
factors), providing a selective advantage for cells which have undergone cancerous mutation due
to carcinogens in the tobacco smoke or due to asbestos itself [
73
]. These cytokines and chemokines
produced during the inflammatory process are critical to tumor development [
84
]. Recent studies have
directly shown interaction between tobacco smoke and known lung carcinogens of the type found in
tobacco smoke and asbestos in causing lung cancer [
2
,
85
88
]. The exact mechanisms that underpin the
synergism between tobacco smoke and asbestos for lung cancer induction are not fully understood. It
should be emphasized that the interaction happens at a biological level, and is not just a statistical
interaction [89].
Several mechanisms have been proposed as potential explanations, of which the most likely
appear to be the following:
(1)
asbestos contributes to improved uptake of chemical carcinogens in cigarette smoke and their
metabolism to carcinogenic metabolites in lung epithelial cells
(2)
inhibition of clearance and retention of carcinogens
(3)
chronic inflammation that drives development and metastases of lung tumors
(4)
Direct synergistic eects on proliferation
For example, carcinogens in cigarette smoke such as benzo[a]pyrene (B[a]P) may be adsorbed
onto asbestos fibers (e.g., crocidolite or chrysotile), with subsequent delivery of the carcinogens into
cells at high concentrations [
56
]. Tobacco smoke may interfere with the clearance of asbestos from the
lungs; Churg and Stevens found elevated concentrations of asbestos fibers in the airway tissues of
smokers in comparison to nonsmokers, for both amosite (~6-fold) and chrysotile (~50-fold), especially
for short fibers (in comparison, parenchymal amosite fiber concentrations were comparable in the
smoker and nonsmoker groups) [
90
]. The importance of the inflammatory responses is reviewed
in [
84
]. Direct supra-additive eects on mutations in bronchial epithelial cells of free radicals are
generated by tobacco constituents and asbestos fibers. In this context, some carcinogens in tobacco
smoke have the capacity to induce showers of free radicals (such as hydroxyl radical spin adducts [
91
].
This is the same eect induced by ionizing radiation [92] and asbestos fibers [20,93].
3.4.2. The Synergy between Asbestos Fibers and Tobacco Smoke for Lung Cancer Causation–Animal
Studies
Kimizuka et al. investigated the cocarcinogenic eects of chrysotile and amosite asbestos plus
the tobacco smoke carcinogen benzo[a] pyrene (B[a]P) in hamster lungs [
94
]. Between 18–24 months
after the last intratracheal instillation, the number of tumors was examined. In the chrysotile +B[a]P
group, there were 37 tumors that included 16 carcinomas in 12 animals, and 30 tumors including
11 carcinomas in 12 animals were found in the amosite +B[a]P group. In the chrysotile +B[a]P
group, all animals developed tumors, as did 92% in the amosite +B[a]P group; the carcinomas were
found in 83% and 67%, respectively. The numbers of tumors and carcinomas and the frequency of the
tumor-bearing or carcinoma-bearing hamsters in the chrysotile +B[a]P and the amosite +B[a]P groups
were significantly higher than those of the groups instilled independently. Although the number
of tumors or the frequency of tumor-bearing animals was higher in the chrysotile +B[a]P than the
amosite +B[a]P group, the dierences were not significant. The results were considered to indicate
that both chrysotile and amosite play an important role in the genesis of bronchogenic carcinoma.
Harrison et al. investigated the combined eect in the lungs of rats of simultaneous exposure to
chrysotile asbestos and N-nitrosoheptamethyleneimine (NHMI) for the development of metaplastic,
hyperplastic, and neoplastic lesions [
85
]. The eects were more pronounced in males than females, and
NHMI administration increased the frequency of hyperplastic lesions with augmentation by chrysotile
(although this was not statistically significant), but a ‘promoting’ eect of chrysotile was observed
for the induction of lung tumors (all but two out of 11 primary tumors were in rats treated with both
NHMI and chrysotile), although this finding was not confirmable statistically because of the small
Int. J. Environ. Res. Public Health 2020,17, 258 9 of 23
number of tumors observed. A sex dierence in inflammatory responses involving higher expression
of Cox-2, VEGF-A, and VEGF-R2 in males compared with females has recently been observed in other
models [95], and consequently, research bodies now recommend use of sex-matched cohorts [96].
Kamp et al. [
82
] found evidence that cigarette smoke extracts (CSE) augmented amosite
asbestos-induced alveolar epithelial cell (AEC) injury by generating iron-induced free radicals that
damage DNA. In this study, amosite or CSE each resulted in dose-dependent toxicity to AECs (WI-26
and rat alveolar type I-like cells), and the eects of CSE +amosite in combination were synergistic in
A549 cells and additive in WI-26 cells. The authors concluded that the data adduced further support for
genotoxicity of asbestos and cigarette smoke in relevant target cells in the lung, and that iron-induced
free radicals may, in part, cause these eects.
Loli et al. investigated the mutagenic eects of amosite asbestos and B[a]P in the lungs of
λ
-lacI
rats. In the first experiment, intratracheal instillation of both amosite and B[a]P in combination resulted
in a supra-additive increase in mutation frequency, in comparison to rats treated only with amosite or
with B[a]P [
86
]. In the second experiment, the intraperitoneal administration of B[a]P did not alter
significantly the mutation frequency induced by amosite after either four or 16 weeks of treatment, and
B[a]P-DNA adduct levels were unaected by amosite cotreatment in both experiments. The authors
concluded that the ‘striking enhancement eect of B[a]P may provide a basis for understanding the
suspected [sic] synergism of smoking on asbestos carcinogenesis.’ This group also reported in 2006
that DNA adducts induced by simultaneous B[a]P and man-made mineral fibers (MMMF) indicated a
strong increase in the mutation frequency [97].
A very recent study in a mouse inhalation model shows that exposure to combined tobacco smoke
and chrysotile asbestos suppressed the innate immune response (NLRP3 inflammasome) to asbestos
fibers, resulting in reduced fiber clearance and more chronic inflammation, leading to carcinogenesis.
Confirmatory
in vitro
studies in human monocytes produced a similar eect with combined tobacco
smoke and asbestos exposure [98].
3.4.3. The Synergy between Asbestos Fibers and Tobacco Smoke for Lung Cancer Causation—Studies
in Humans
In addition, a recent genome wide methylation study (using Illumina HumanMethylation450K
Bead Chip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or nonexposed
patients revealed that dierential methylation profiles could be identified, depending on the etiology;
the authors suggested that the methylation changes in tumors may be specific for risk factors [
99
]. At
this stage, this is early and preliminary work, but it is conceivable that in future, mutation signatures
associated with dierent etiologies of lung tumors may be able to verify the mutagenic eect of smoking
and/or asbestos exposure in the in causal pathways in the tumor tissue.
In addition, molecular studies in humans ‘further suggest that asbestos enhances the mutagenicity
of tobacco carcinogens and that it acts, at least in part, independent of the tissue damage responsible
for fibrosis.’ [
87
] Nelson et al. [
65
] investigated k-ras codon 12 mutations among 84 male patients with
adenocarcinoma of lung for whom a work history was available, as well as a chest radiograph for all
those who had a history of occupational exposure to asbestos. K-ras mutations were more prevalent
in patients with a history of occupational asbestos exposure (crude OR =4.8; 95% CI =1.5
15.4)
in comparison to those without asbestos exposure. The association remained after adjustment for
age and pack-years smoked (adjusted OR =6.9; 95% CI =1.7
28.6). An index score that weighted
for both the dates of exposure and estimated exposure intensity indicated that subjects with k-ras
mutations had significantly greater asbestos exposures than those without such mutations (p<0.01).
A supra-additive eect of smoking and asbestos exposure on the percentage of k-ras mutations was
shown (Figure 2in the original). The duration of exposure was not associated with k-ras mutations, but
time after initial exposure was significantly associated with mutation status. ‘The association between
k-ras mutation and reported asbestos exposure was not dependent on the presence of radiographic
evidence of asbestos-related disease.’ The findings were considered to suggest ‘that asbestos exposure
Int. J. Environ. Res. Public Health 2020,17, 258 10 of 23
increases the likelihood of mutation at k-ras codon 12 and that this process occurs independently of
the induction of interstitial fibrosis.’ In an earlier study, the same group of researchers also found
that asbestos exposure (p<0.01) and a duration of more than 50 years of smoking (p<0.01) were
significantly associated with exon deletion from the fragile histidine triad (FHIT) gene [100].
3.4.4. The Synergy between Asbestos Fibers and Tobacco Smoke for Lung Cancer Causation: Summary
While the precise mechanism of interaction between asbestos exposure and tobacco smoke in
causing lung cancer is not fully understood, a great deal of research has been done in this area over the
last 20–30 years. It is not possible in our view to analyze their causal interdependence in the individual
case when both have acted, as they must do to some extent, from a purely physico-chemical point
of view, and it is thus more probable than not that in this situation, the lung cancer was the singular
result of the two factors acting together.
Exposure to either factor alone without the presence of the other is capable of causing lung
cancer, but when both are present, in our opinion, on the basis of the above biological evidence of
interdependence, both must have been acting to some extent in the process of carcinogenesis. To
assume otherwise would be to reject the existence of physical and chemical laws governing biological
behavior. All medical science depends on the transfer of knowledge gained from cellular, molecular,
and animal experiments to man, without requiring the replication of the chemistry and physics in
the human by direct invasive human experimentation. A corollary of the above is that any asbestos
exposure, even in a heavy smoker, could be considered to legitimate causation.
Our current understanding of the biological mechanism of lung carcinogenesis induced by asbestos
and tobacco is shown in Figure 1.
Int. J. Environ. Res. Public Health 2020, 17, x 10 of 22
the last 20–30 years. It is not possible in our view to analyze their causal interdependence in the
individual case when both have acted, as they must do to some extent, from a purely physico-
chemical point of view, and it is thus more probable than not that in this situation, the lung cancer
was the singular result of the two factors acting together.
Exposure to either factor alone without the presence of the other is capable of causing lung
cancer, but when both are present, in our opinion, on the basis of the above biological evidence of
interdependence, both must have been acting to some extent in the process of carcinogenesis. To
assume otherwise would be to reject the existence of physical and chemical laws governing biological
behavior. All medical science depends on the transfer of knowledge gained from cellular, molecular,
and animal experiments to man, without requiring the replication of the chemistry and physics in the
human by direct invasive human experimentation. A corollary of the above is that any asbestos
exposure, even in a heavy smoker, could be considered to legitimate causation.
Our current understanding of the biological mechanism of lung carcinogenesis induced by
asbestos and tobacco is shown in Figure 1.
Figure 1. Mechanism of lung cancer causation by asbestos and tobacco smoke. ROS = reactive oxygen
species; RNS = reactive nitrogen species.
3.5. Relevance of Estimates of Cumulative Asbestos Exposure to Causal Attribution and Lung Cancer Risk
A cumulative exposure of 25 fibers/mL-years (fiber-yrs) can be associated with the first signs of
clinical asbestosis [9], although histological asbestosis can occur at lower exposures [22]. As discussed
by Henderson et al. [17,101], others have claimed that the dose necessary for the development of
asbestosis is 25–100 fiber-yrs [101]. The estimated cumulative dose of asbestos required for induction
of asbestosis has diminished over the years, and reference [102] refers to a lifetime risk of asbestosis
of 2/1000 at 4.5 fiber-yrs, drawing attention to ‘a few’ asbestosis deaths at less than five fiber-yrs in
the study reported by Dement et al. [103]. In their stepwise decision-tree approach to assessing
asbestosis, Burdorf and Swuste [102] suggested that for any probability of exposure defined by
Figure 1.
Mechanism of lung cancer causation by asbestos and tobacco smoke. ROS =reactive oxygen
species; RNS =reactive nitrogen species.
Int. J. Environ. Res. Public Health 2020,17, 258 11 of 23
3.5. Relevance of Estimates of Cumulative Asbestos Exposure to Causal Attribution and Lung Cancer Risk
A cumulative exposure of 25 fibers/mL-years (fiber-yrs) can be associated with the first signs of
clinical asbestosis [
9
], although histological asbestosis can occur at lower exposures [
22
]. As discussed
by Henderson et al. [
17
,
101
], others have claimed that the dose necessary for the development of
asbestosis is 25–100 fiber-yrs [
101
]. The estimated cumulative dose of asbestos required for induction
of asbestosis has diminished over the years, and reference [
102
] refers to a lifetime risk of asbestosis of
2/1000 at 4.5 fiber-yrs, drawing attention to ‘a few’ asbestosis deaths at less than five fiber-yrs in the
study reported by Dement et al. [
103
]. In their stepwise decision-tree approach to assessing asbestosis,
Burdorf and Swuste [
102
] suggested that for any probability of exposure defined by industry, evidence
of direct exposure at a level of
5.0 fibers/mL for more than one year is sucient for ‘ascertainment’ of
asbestosis (i.e., >5.0 fiber-yrs). When assessing asbestosis related to low-’dose’ exposures, it is important
for two factors to be taken into account: (i) a low mean/median ‘dose’, as calculated across a population
from average airborne fiber concentrations, may not reflect large variations in exposure for some
individuals comprising the relevant population; and (ii) the nonrecognition of other exposures [17].
A cumulative asbestos exposure of 25 fiber-yrs is also the level accepted as being associated with
an approximate doubling of lung cancer risk relative to a nonexposed person i.e., additive increase in
rate (risk) ratio (RR) from 1 to 2 for mixed fiber type exposures according to De Vuyst [
104
]. This was
the basis of its selection by the German authorities [
105
] and the original Helsinki expert group [
46
].
Other studies would put the additive increase in rate ratio for 25 fiber-yrs at 0.06, with meta-analysis
of all fiber types included [
106
], 0.25, UK chrysotile textile work [
101
], or 0.5, USA chrysotile textile
work [107,108].
A rate ratio of RR =2 has been commonly equated by some with an attributable fraction in the
exposed (AF
E
), corresponding to ‘probability of causation’) of 0.5 (50%). Thus, if RR =(incidence rate
exposed)
÷
(incidence rate unexposed) =I
E
/I
0
=2, then AF
E
is given by (I
E
I
0
)/I
E
=(RR
1)/RR =(2
1)/2=0.5. The ratio (I
E
I
0
)/I
E
represents the proportion of diseased cases in the exposed group in
which disease is caused by exposure (some cases would appear in the absence of exposure). If AF
E
=
0.5, the proportion of exposed cases in whom the exposure caused the disease would be 0.5 (50%).
Translated into a probability in the individual, one could thus argue that given an exposed case,
the probability that the exposure caused the disease is 0.5 (50%). This could be conveniently equated
with the civil standard of proof. However, there has been persistent, strong criticism of this approach.
It is thought that the attributable fraction in the exposed may often underestimate the probability
of causation. This is because the probability of causation applies to an individual, and depends on
biological, epidemiological, and other evidence, whereas AF
E
is an epidemiological measure and
applies to populations. Sampling error, variation in background risk, individual susceptibility, and
biological mechanisms can all aect the probability of causation. Furthermore, there is a distinction
between cases solely caused by exposure and those whose causation is accelerated by exposure; for
expositions of these concepts in mathematical, semilay and legally-directed terms, see [72,109112]
Greenland, for example, pointed out two misconceptions, which are common in the literature
relating epidemiology to compensation decisions. First, “the probability of causation cannot be
computed solely from the relative risk.” Second, “the exposure dose at which the probability of
causation exceeds 50% (the point at which exposure causation is more likely than not) may fall well
below the “doubling dose” (the dose at which the incidence of disease is doubled).” Greenland
concluded: “In particular, and contrary to common perceptions, a rate fraction of 50% (or equivalently,
a rate ratio of 2) does not correspond to a 50% probability of causation.” [110].
In the case of some occupational lung cancers, a RR =1.1 (rather than 2), equating to an attributable
fraction of 9%, has been accepted as indication of a material liability to causation rather than ‘the cause
of’ by civil courts [113,114].
The IARC classifies carcinogens as category 1 (human carcinogen) when the typical rate ratios
from human cohort studies are 1.3–1.6, for example silica [
115
], and diesel exhaust fumes [
116
]. The
caveats on the well-known Bradford Hill guidelines [
117
] on causality are laid out in Rothman and
Int. J. Environ. Res. Public Health 2020,17, 258 12 of 23
Greenland [
118
], where the relation of magnitude of association (e.g., magnitude of rate ratio) to
reliability of causal inference is discussed, giving examples of low rate ratios where causation is
accepted (e.g., smoking and cardiovascular disease; passive smoking and lung cancer). There is nothing
particularly magical about a RR =2 as compared to, say, RR =1.1. A value of RR =2 represents a
doubling, whereas a RR =1.1 represents an increase in rate ratio by 10% [110].
Whether a RR =1.1 is clinically-significant or not depends on the size of the exposed group and the
background (nonexposed) incidence rate. For example, if 100,000 persons are exposed to an agent at an
exposure level creating a rate ratio of 3, when the background incidence rate is 1 per 100,000 per year,
then 3
1=2 extra cases per year are produced in this population by the exposure. If 100,000 persons
are exposed to an agent at an exposure level creating a rate ratio of 1.1 when the background incidence
rate is 70/100,000 per year (as for lung cancer), then 77
70 =7 extra cases per year are produced in
this population. It is important to be sure that a rate ratio of 1.1 obtained from an epidemiological
study is statistically significant (i.e., not due to sampling error or chance), and that it is not the result of
uncontrolled confounding factors. This is ensured by good epidemiological study design. It is now
generally thought that those wishing to challenge increased rate ratios of low magnitude on the basis
of unknown confounders should bear the onus of demonstrating this confounding eect. It remains
generally true, however, that higher rate ratios are less likely to be distorted by unknown confounders.
The clinical or public health significance of an increased rate ratio also depends on the proportion
of the population exposed. If many in a population are exposed at a low RR, this can result in a larger
number of exposure-attributable cases in the total population compared to a situation where there is a
high RR but only a small number of exposed.
The lung cancer RR for 25 fiber-yrs of exposure has been estimated at 2.5 for amosite factory
workers [
119
] and 1.8 for the Wittenoom crocidolite miners/millers in Western Australia [
17
].
Rödelsperger and Woitowitz also found that an analysis of South African amosite and crocidolite miner
data indicated rate ratios of 2 at less than 25 fiber-yrs of cumulative exposure [120].
From the year 2000, three important new studies relating to the risk-dose relationship for
asbestos-related lung cancer have been published. These studies are of mixed exposures, and are well
designed case referent studies. In a very large, very well designed case-referent study in Sweden
(1042 cases 2364 referents), the coecient for increase in lung cancer risk was 0.14 per fiber-yr, giving a
RR =4.5 for 25 fiber-yrs [
28
]. In a further study [
29
] exploring risk at lower ‘doses’, the lung cancer
risk was 1.9 at a ‘dose’ of 4 fiber-yrs. A natural spline model applied to 19 studies estimated RR for
exposure of 4 and 40 fiber years between 1.013 1and 1.027 and 1.13 and 1.3, respectively, but was heavily
influenced by three-to-four-fold dierences in RR between chysotile and amphibole at doses below 40
fiber years [
121
]. The eect of smoking was between additive and multiplicative. In June 2002, in a
large population-based matched, case-referent study (839 cases 839 referents), Pohlabeln et al. [
122
]
found in a validation subsample of 164 male cases and their 164 referents a smoking adjusted odds
ratio (OR) of 1.71 (95% CI =1.18–2.46) for an asbestos exposure of 25 fiber-yrs and a smoking-adjusted
risk (OR) of 1.94 (95% CI =1.10–3.43) for the category >10 fiber-yrs. The authors claimed that these
results were consistent with a doubling of lung cancer risk at 25 fiber-yrs of exposure.
The Olsson [
43
] pooled case referent study would give a doubling of risk at of 16.4 fiber-yrs (all
men) and 30.3 fiber-yrs (blue collar workers)
Case-referent studies, if well designed, give the same information as cohort studies, and should
be included in any meta-analyses along with all relevant studies, published or unpublished [118].
A meta-analysis of 17 selected published cohort studies by Hodgson and Darnton [
31
] set forth
a lung cancer rate ratio of 0.05 per fiber-yr for amphibole asbestos (RR =2.25 at 25 fiber-yrs) and
0.001 per fiber-yr for commercial chrysotile (RR =1.025 at 25 fiber-yrs) as reasonable overall best
estimates. The highest estimate for the chrysotile rate ratio was 0.005 (RR =1.125 at 25 fiber-yrs).
Mixed exposures would have intermediate values. However, Hodgson and Darnton [
31
] omitted the
chrysotile cohort study with the highest risk/dose coecient (South Carolina textile workers) from
their analysis, and they also excluded case-referent studies. Inclusion of those studies would have
Int. J. Environ. Res. Public Health 2020,17, 258 13 of 23
resulted in higher overall chrysotile textile and mixed exposure coecients. More recent analyses
of relative lung cancer potency of dierent fiber types using a similar selection of cohorts (but with
some significant exclusions) by Berman and Crump [
123
] give similar results. The US EPA has now
decided not to use the Berman and Crump modeling in risk assessment. Recent reevaluations of the
relative lung cancer carcinogenicity of chrysotile and the amphiboles, taking data quality into account,
concluded that there is little dierence between chrysotile and amphibole in this respect [
124
]. A recent
nested case-referent study within a major Chinese cohort study of workers exposed only to chrysotile
gave an OR =3.7 in the high exposure group, and more than additive synergism with smoking [125].
There is no threshold for asbestos related lung cancer [
55
,
126
]. Some studies appear to indicate
that adenocarcinoma risk tends to have a steeper dose-response gradient with quantified asbestos
exposure than other lung cancer cell types [
126
]. A recent, very large general population cohort study
(58,279 men followed for 17.3 years) of cancer risks, especially at lower levels of occupational asbestos
exposure, appeared to show that lung adenocarcinoma is only a significant risk at the highest level of
exposure studied [
127
]. (This finding contrasts with the preceding statement that adenocarcinoma has
a steeper dose response relationship with asbestos.) However, in their discussion (p. 17), the authors
explain that this may be due to the study design and the fact that smoking is only weakly associated
with adenocarcinoma. When stratified for smoking, the asbestos association for adenocarcinoma
is indeed higher than for all cell types pooled. It should also be noted that the highest cumulative
exposure category in this study is only 6.7 fiber-yrs (median).
The deficiencies and uncertainties of the meta-analyses of the published data with large
heterogeneity have been pointed out [128].
Further discussion of more recent literature on asbestos and lung cancer in relation to the Helsinki
and AWARD Criteria has been provided [
1
,
30
,
129
]. Those reviews defend the epidemiological bases
of the Helsinki Criteria and strengthen them in the light of new data since 1997. They defend the
position that asbestosis is not a prerequisite for attribution, and that for mixed fiber type exposure,
where the precise composition is not known, the 25 fiber-yr level (or equivalent exposure history or
lung fiber content) is a reasonable level for attributing lung cancer to asbestos exposure, irrespective
of smoking history. They accept that for certain cohorts, for lifelong nonsmokers or where the
actual type of exposure is known with certainty, then a higher or lower criterion may apply. For
lifelong nonsmokers or smokers who have quit for more than 30 years before diagnosis, a cumulative
exposure of 5 fiber-yrs has been recommended as sucient to assign a causal liability by asbestos
to lung cancer [
30
,
37
]. Lifelong nonsmokers have about three times the dose-related risk of lung
cancer from asbestos as smokers [
130
]. Guidotti [
89
] considers that because of the rarity of lung
cancer in nonsmokers, an association of lung cancer with asbestos can be assumed if any asbestos
exposure has occurred. This could be in addition to a coaction from other occupational lung carcinogen
exposure [
131
]. Asbestosis—not asbestos exposure—has been invoked as the ‘primary risk factor for
lung cancer’ as recently as 2014 [
38
], and Cagle [
51
] commented that ‘Unless and until a better marker
comes along, the only consistently reliable marker for an asbestos-related lung cancer is asbestosis,
especially in asbestos workers who are also tobacco smokers.’ We consider that in some instances, a
clinical-radiologic diagnosis of early/mild asbestosis cannot be made with consistency or reliability, and
may be the subject of dispute among respiratory physicians and radiologists, because of the following
disagreements:
Dispute as to whether there is genuine interstitial fibrosis, even in high-resolution CT scans [
132
],
or whether any changes are related to associated pleural fibrosis.
Dispute as to whether interstitial fibrosis represents asbestosis or idiopathic pulmonary fibrosis
(usual interstitial pneumonia [UIP]) or nonspecific interstitial pneumonia [NSIP] unrelated to
asbestos, especially when pleural plaques are not demonstrable [133].
Even on histologic examination, disagreement between pathologists as to whether there is genuine
interstitial fibrosis in a distribution appropriate for asbestosis, i.e., a UIP pattern or the fibrotic
Int. J. Environ. Res. Public Health 2020,17, 258 14 of 23
variant of NSIP, or diuse interstitial fibrosis which is not readily classifiable as either [
133
], or
whether there are sucient asbestos bodies for that diagnosis [134].
We consider that the prevailing evidence conforms to the cumulative exposure model for the
risk of lung cancer with no requirement for asbestosis (although asbestosis remains one criterion for
asbestos exposure). In addition, a recent systematic literature analysis of 5864 citations on asbestos and
lung cancer in PubMed and Embase generally confirms the principles of the Helsinki Criteria [36].
3.6. Problems with Numerical Assessments of Asbestos Exposure
Systematic measurements of airborne asbestos fiber concentrations in various workplaces have
been carried out in nations such as Germany [
105
] and Sweden [
28
,
29
], and in special industries
elsewhere, thereby allowing estimates to be made of cumulative exposure expressed as fibers/mL-years.
However, no such measurements have been carried out in many workplaces in various nations
—especially for the end-uses of asbestos-containing materials (e.g., building construction; shipyards,
and power stations in Australia). In these latter circumstances, estimates of exposure are often assessed
by the use of data from other workplaces and nations. In adversarial court proceedings, we have often
encountered widely-divergent estimates of exposure (sometimes more than 100-fold) on the same
case, from occupational hygienists, some incompatible with the diseases present (e.g., in one case of a
pleural mesothelioma patient with asbestosis and a 10-year history of ship construction in Scotland
and Australia, his estimated cumulative exposure was about 1.0 fiber-yr). In such circumstances, we
prefer to use expressions such as ‘light’, ‘moderate’, or ‘heavy’ exposure, while acknowledging the
imprecision of those terms; at least they are not predicated upon the specious pseudo-precision of a
numerical estimate.
The background levels of asbestos bodies in the lungs of patients with no specific asbestos
exposure seem to be higher in Finland than in other countries. Karjalainen et al. [
44
] analyzed the
relation between pulmonary concentrations of asbestos bodies (AB) and asbestos fibers (AF) from
lung cancer patients in Helsinki as indicators of asbestos exposure. The regression equation log (AF)
=
0.429 +0.600 log (AB) was found to predict the concentration of asbestos fibers (10
6
fibers
·
g
1
)
corresponding to a given number of asbestos bodies in a section of lung tissue. In medico-legal cases,
the methodological variation involved in asbestos fiber and asbestos body counting must be recognized,
and all available exposure data should be used to produce the best possible estimate of exposure.
In terms of the lung tissue concentration of uncoated asbestos fiber concentrations for mixed-fiber
exposures, the Helsinki Criteria set forth counts of
2.0 million amphibole fibers (>5
µ
m in length)/g dry
lung or
5.0 million amphibole fibers >1
µ
m in length. However, because of dierent methodologies,
dierent laboratories can find dierent fiber concentrations [
36
]. Therefore, we would now modify
this criterion and specify an amphibole fiber count above the fifth percentile concentration for cases of
asbestosis, as assessed by the same laboratory.
3.7. Proposed Criteria for Attribution of Lung Cancers to Exposure to Asbestos
A set of criteria for attribution with respect to asbestos from the original Helsinki Criteria as been
set forth by Henderson and Leigh [
30
], which can be presented in slightly modified and abbreviated
form for the smoking categories as follows
Asbestos exposure with a minimum latency interval of 10 years
AND
For current smokers:
A nondisputed or majority clinical-radiologic or histologic diagnosis of asbestosis.
OR
The occurrence of asbestosis among other workers in the same workforce carrying out similar
work for similar durations of time and at similar times.
OR
Int. J. Environ. Res. Public Health 2020,17, 258 15 of 23
A nondisputed/majority estimate of cumulative exposure to asbestos of 25 fiber-years or more for
mixed-fiber, end-use exposure to asbestos (e.g., in the building construction industry and for insulation
work). For amphibole-only (amosite or crocidolite) exposures, a nondisputed estimated cumulative
exposure of 20 or 25 fiber-years, and 25 fiber-years for asbestos textile workers. For chrysotile-only
exposures, most notably the Canadian chrysotile miners and millers, and exposure to friction products,
200 fiber-years, and for other chrysotile-only exposure, 100 fiber years. This is based on the estimated
relative potency of 1:4 amphibole:chrysotile [121].
OR
At least 5 years of asbestos exposure before 1975, or 5–10 years after 1975, for asbestos textile
workers, asbestos insulation workers including work in shipbuilding, power stations, railways
workshops, and others in close proximity to such work, especially when it was carried out in confined
and poorly ventilated workplaces, or a duration of one year for work that involved consistent or
frequent spraying of asbestos insulation. Henderson and Leigh [
30
] excluded Canadian chrysotile
miners/millers and friction products workers from this assessment.
OR
For never-smokers or those who had ceased smoking 30 years or more before the diagnosis of
lung cancer; cumulative exposure amounting to 5 fiber-years, or exposure amounting to one-third of
the durations for work set forth in the preceding paragraph.
OR
A concentration of asbestos bodies or uncoated amphibole fibers at or in excess of the fifth
percentile count in cases of asbestosis for the same laboratory (for fibers of the same length) for
mixed-fiber end-use exposures. Because chrysotile fibers are cleared from lung more rapidly than
amphibole, fiber assays should not be used for chrysotile-only exposures; instead, the occupational
history should be substituted.
These criteria are summarized in a simplified flow chart in Figure 2.
Int. J. Environ. Res. Public Health 2020, 17, x 15 of 22
workshops, and others in close proximity to such work, especially when it was carried out in confined
and poorly ventilated workplaces, or a duration of one year for work that involved consistent or
frequent spraying of asbestos insulation. Henderson and Leigh [30] excluded Canadian chrysotile
miners/millers and friction products workers from this assessment.
OR
For never-smokers or those who had ceased smoking 30 years or more before the diagnosis of
lung cancer; cumulative exposure amounting to 5 fiber-years, or exposure amounting to one-third of
the durations for work set forth in the preceding paragraph.
OR
A concentration of asbestos bodies or uncoated amphibole fibers at or in excess of the fifth
percentile count in cases of asbestosis for the same laboratory (for fibers of the same length) for mixed-
fiber end-use exposures. Because chrysotile fibers are cleared from lung more rapidly than
amphibole, fiber assays should not be used for chrysotile-only exposures; instead, the occupational
history should be substituted.
These criteria are summarized in a simplified flow chart in Figure 2.
Figure 2. Simplified flow chart for attribution of lung cancer to exposure to asbestos, taking into
account tobacco smoke.
The proposed Criteria are designed primarily for statutory compensation where smoking is not
to be considered. In a litigation situation where tobacco smoking can be considered, either as joint
tortfeasor or as an example of contributory negligence, different approaches may be needed, and
apportionment methods applied. A simplified flowchart is presented in Figure 2. Since asbestos and
smoking are inseparable agents at the biological level in the individual case, there will always be
some joint contribution to causation by the asbestos, even at exposures below 25 fiber/mL-yr; this
should be proportionally compensated, taking smoking history and any possible genetic
susceptibility into account. This has also been recognized in a recent critique of the 2014 update of
the Helsinki criteria.[135]. A range of possible models for taking smoking into account is available
[12,89].
However, it should be emphasized that all such apportionment schemes are contrived
mathematical models, even if based on both biometric theory and empirical data, and cannot reflect
perfectly the complex biological reality. The possibility of taking genetic susceptibility into account
in individual lung cancer cases may become more feasible with the application of genome-wide gene-
environment interaction analyses for asbestos exposure [136].
4. Conclusions
Figure 2.
Simplified flow chart for attribution of lung cancer to exposure to asbestos, taking into
account tobacco smoke.
The proposed Criteria are designed primarily for statutory compensation where smoking is not
to be considered. In a litigation situation where tobacco smoking can be considered, either as joint
tortfeasor or as an example of contributory negligence, dierent approaches may be needed, and
apportionment methods applied. A simplified flowchart is presented in Figure 2. Since asbestos and
smoking are inseparable agents at the biological level in the individual case, there will always be
Int. J. Environ. Res. Public Health 2020,17, 258 16 of 23
some joint contribution to causation by the asbestos, even at exposures below 25 fiber/mL-yr; this
should be proportionally compensated, taking smoking history and any possible genetic susceptibility
into account. This has also been recognized in a recent critique of the 2014 update of the Helsinki
criteria [135]. A range of possible models for taking smoking into account is available [12,89].
However, it should be emphasized that all such apportionment schemes are contrived mathematical
models, even if based on both biometric theory and empirical data, and cannot reflect perfectly the
complex biological reality. The possibility of taking genetic susceptibility into account in individual
lung cancer cases may become more feasible with the application of genome-wide gene-environment
interaction analyses for asbestos exposure [136].
4. Conclusions
The new knowledge gained through this predominantly didactic review takes the form of evidence
for the synergism between asbestos and tobacco smoke in lung cancer causation at a biological level, and
the proposed science-based and equitable approach to compensation implications for asbestos-related
lung cancer. The evaluated statistical data conform to a multiplicative model for lung cancer risk, with
no requirement for the presence of asbestosis.
Author Contributions:
All authors contributed to the intellectual content, writing and preparation for publication
of this paper. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest:
The first three authors have prepared reports on asbestos exposure and lung cancer for
courts and tribunals in Australia and the United Kingdom and have given testimony on the issue for plaintis and
defendants. None of the authors have any aliation with the asbestos industry or any nonprofessional group that
lobbies for or against industry.
Appendix A
Definitions of Additive and Multiplicative Models
Additive model (1) A model used in epidemiology, the structural form of which implies that the
disease rate (R) is a linear function of an intercept term (
α
), an exposure eect (
β
E), and covariate
eects (
δ
C): R =
α
+
β
E+
δ
C. Expressed equivalently, the rate dierence (RD) for the eect of a unit
increase in exposure is constant across covariate levels and equal to the exposure coecient
β
: RD =
β
.
For example, the joint eect of two dichotomous exposures E
1
and E
2
(coded 1 =exposure present, 0 =
exposure absent) on the rate dierence is the sum of their singular eects:
RD =[α+β1(E1=1) +β2(E2=1) +δC] - [α+β1(E1=0) +β2(E2=0) +δC] =β1+β2=RD1+RD2(A1)
Hence the term additive model.
Multiplicative model (2) A model used in epidemiology, the structural form of which implies that
the disease rate (R) is an exponential function of an intercept term (
α
), an exposure eect (
β
E), and
covariate eects (
δ
C): R =exp(
α
+
β
E+
δ
C). Expressed equivalently, the rate ratio (RR) for the eect of
a unit increase in exposure is constant across covariate levels and equal to the antilog of the exposure
coecient
β
: RR =exp(
β
). For example, the joint eect of two dichotomous exposures E
1
and E
2
(coded 1 =exposure present, 0 =exposure absent) on the rate ratio is the product of their singular
eects:
RR =exp[α+β1(E1=1) +β2(E2=1) +δC]/exp[α+β1(E1=0) +β2(E2=0) +δC] =exp(β1+β2)=exp(β1)×exp(β2)=RR1×RR2(A2)
Hence the term multiplicative model.
Int. J. Environ. Res. Public Health 2020,17, 258 17 of 23
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  • ... In an attempt to answer the difficult questions of whether asbestos was the actual cause of lung cancer and if a patient might be eligible for compensation, criteria for the causation of asbestos-induced lung cancer were established by a group of experts in Helsinki in 1997 [9,10]. However, considering the fact that asbestos and smoking are parts of a synergistic carcinogenic process [11], it is extremely difficult to accurately calculate the contribution of asbestos to lung cancers occurring in asbestos-exposed smokers. The Helsinki criteria rely on occupational history and the presence of asbestosis and fiber counts in lung tissue. ...
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