Mortality results in workers compensated for silicosis in Italy by
job and disability degree.
We wish to thank our German colleagues for giving us the opportunity
to clear some points of the mortality study of workers compensated for
silicosis in Italy [1]. The large number of silicotic compensated workers
investigated allowed us to perform specific analyses to reduce cohort
heterogeneity. Subcohort has been i...
Mortality results in workers compensated for silicosis in Italy by
job and disability degree.
We wish to thank our German colleagues for giving us the opportunity
to clear some points of the mortality study of workers compensated for
silicosis in Italy [1]. The large number of silicotic compensated workers
investigated allowed us to perform specific analyses to reduce cohort
heterogeneity. Subcohort has been investigated according to the year of
compensation assignment, to the level of disability (more or less than 31%
disability) and to the job. Among the overall cohort an increased
mortality from lung cancer in males has been observed as reported (SMR
1.10, 95% CI 1.03-1.18). In the subcohort of workers with a disability
degree more than 31% (2,717 subjects) cause specific SMRs are generally
higher (see table 1), e.g. for trachea, bronchus and lung cancer (SMR
1.16, 95% CI 0.99-1.35), esophagus cancer (SMR 1.39, 95% CI 0.83-2.32),
larynx cancer (SMR 1.77, 95% CI 1.17-2.68) and respiratory system cancer
(SMR 1.19, 95% CI 1.03-1.38). In the group of compensated subjects with a
disability degree more than 31% who worked in quarries/mines, SMR for
trachea, bronchus and lung cancer is 1.39 (95 % CI 0.96-2.01) and in the
group of compensated subjects who worked in glass industry is 1.17 (95 %
CI 0.94-1.47) (not reported in table). This last finding is consistent
with recent evidence from a previous study of art glass workers conducted
in Tuscany [2]. The analyses of these selected cohort, not presented in
the original article, strengthen, in our opinion, the internal consistency
and specificity of the observed increase for lung cancer among silicotics.
As far as the Healthy Worker Effect (HWE) is concerned, we are fully aware
of the complexity of the phenomenon which can be seen either as an example
of confounding or selection bias in occupational studies. In a cohort of
workers selected on the basis of compensation additional and peculiar
factors could be in place [3-4]. We assess an expected pattern of disease
in our study, with a significant increase for silica - associated causes
(lung cancer, silicosis and other pneumoconiosis): on this basis the role
of selection bias can be regarded as minor, if present [5].
Table 1. Selected cause specific mortality among male workers compensated for silicosis, Tuscany, Italy, between 1946 and 1979; standardised mortality ratios (SMRs), 95% confidence interval (95% CI) in the total cohort and in the selecetd cohort of male workers with more than 31% of disability degree.
Selected cause specific mortality
Overall cohort
(N = 14090)
Selected cohort of male workers with more than 31% of disability degree
(N = 2799)
SMR
95% CI
SMR
95% CI
All causes
0,93
0,91-0,95
1,02
0,97-1,07
Infectious diseases
1,79
1,43-2,25
2,91
1,95-4,37
Tuberculosis
2,91
2,21-3,82
5,18
3,26-8,22
All cancers
0,94
0,91-0,98
0,99
0,91-1,08
Lip oral cavity and pharynx
0,14
0,06-0,29
0,36
0,13-1,00
Digestive organs and peritoneum
0,91
0,85-0,97
0,93
0,80-1,07
Esophagus
1,01
0,78-1,32
1,39
0,83-2,32
Stomach
0,83
0,74-0,92
0,97
0,77-1,23
Colorectal
0,84
0,74-0,96
0,87
0,64-1,17
Liver
2,17
1,86-2,54
1,75
1,18-2,60
Gallbladder and extrahepatic bile ducts
0,81
0,53-1,22
0,64
0,23-1,79
Pancreatic
0,97
0,80-1,19
0,93
0,58-1,47
Peritoneum
0,37
0,15-0,91
0,00
0,00-0,00
Respiratory tract
1,09
1,02-1,16
1,19
1,03-1,38
Nose
1,06
0,31-3,67
0,00
0,00-0,00
Larynx
0,89
0,69-1,15
1,77
1,17-2,68
Trachea, bronchus and lungs
1,11
1,04-1,19
1,16
0,99-1,35
Respiratory system diseases
2,50
2,39-2,62
3,11
2,83-3,41
Chronic obstructive pulmonary disease
0,79
0,71-0,88
0,95
0,76-1,19
Bronchitis
0,84
0,75-0,94
0,97
0,76-1,23
Asthma
0,49
0,30-0,80
1,10
0,52-2,31
Anthracosilicosis
25,53
7,36-88,57
67,16
12,70-355,17
Asbestosis
8,62
2,49-29,91
46,32
13,43-159,76
Silicosis
21,82
20,67-23,04
26,78
23,95-29,94
Other pneumoconiosis
19,79
14,43-27,13
26,82
14,54-49,46
References
[1] Marinaccio A, Scarselli A, Gorini G, Chellini E, Mastrantonio M,
Uccelli R, Altavista P, Pirastu R, Merlo DF, Nesti M.Retrospective
mortality cohort study of Italian workers compensated for silicosis. Occup
Environ Med Nov;63(11):762-5
[2] Pirastu R, Bartoli D, Battista G, De Santis M, Iaia TE, Orsi D,
Tarchi M, Valiani M. A cohort mortality study of art glass workers in
Tuscany, Italy. Scandinavian Journal of Work Environment & Health
1998;24 (5):1-6
[3] Checkoway H, Pearce N, Kriebel D. Research Methods in
Occupational Epidemiology 2nd edition. Oxford, Oxford University Press,
2004
[4] Carpenter LM. Editorial. Some observations on the healthy worker
effect. British Journal of Industrial Medicine 1987; 44: 289-291
[5] Savitz DA. Interpreting Epidemiologic Evidence-Strategies for
study design and analysis. Oxford, Oxford University Press, 2003
Alessandro Marinaccio (1), Alberto Scarselli (1), Giuseppe Gorini
(2), Elisabetta Chellini (2), Marina Mastrantonio (3), Raffaella Uccelli
(3), Pierluigi Altavista (3), Roberta Pirastu (4) , Domenico Franco Merlo
(5) and Massimo Nesti (1) .
1 ISPESL - Italian Institute for Occupational Safety and Prevention,
Epidemiology Unit, Department of Occupational Medicine, Rome, Italy
2 CSPO - Center for Study and Prevention of Cancer, – Scientific
Institute of Tuscany – Tuscan Cancer Institute, Unit of Occupational and
Environmental Epidemiology, Florence, Italy
3 ENEA - Italian Agency for New Technologies, Energy and the
Environment, Unit of Toxicology and Environmental Sciences, Rome, Italy
4 University of Rome "La Sapienza", Department of Animal and Human
Biology, Rome Italy
5 IST - Italian Cancer Research Institute, Environmental Epidemiology
and Applied Biostatistics, Genoa, Italy
Corresponding author:
Alessandro Marinaccio, ISPESL (Italian institute for occupational safety
and prevention) – Department of Occupational Medicine – Epidemiology Unit
Via Alessandria 220/E; 00198 Rome – Italy , Tel.: +39-06-44280396; fax +39
-06-44250639
E-mail address: alessandro.marinaccio@ispesl.it
The absence of a significant nasal and ethmoid sinus cancer risk in
Finland may be due to the low concentrations of polyphenols in domestic
tree species as compared to imported wood from from more southern regions
(1). The determination of the polyphenol content could be a good chemical
surrogate for the detection of the species with carcinogenic properties
(2).
The absence of a significant nasal and ethmoid sinus cancer risk in
Finland may be due to the low concentrations of polyphenols in domestic
tree species as compared to imported wood from from more southern regions
(1). The determination of the polyphenol content could be a good chemical
surrogate for the detection of the species with carcinogenic properties
(2).
1 Mämmelä P, Phenolics in selected European harwood species by liquid
chromatography-electrospray ionisation mass spectromerty. Analyst, 2001;
126: 1535-1538.
I enjoyed reading the study of Huizink et al(1)about the Amsterdam
air disaster. As pointed out in their table 2, airway disease was one of
the symptoms found to be more prevalent in the exposed group. Reactive
airway disease can develop after a single large exposure to an irritant.
This type of injury has also been noted in the nasal airway. One of the
reasons the reactivity persists for many years or never goes awa...
I enjoyed reading the study of Huizink et al(1)about the Amsterdam
air disaster. As pointed out in their table 2, airway disease was one of
the symptoms found to be more prevalent in the exposed group. Reactive
airway disease can develop after a single large exposure to an irritant.
This type of injury has also been noted in the nasal airway. One of the
reasons the reactivity persists for many years or never goes away is the
fact that following the onset of the hyperreactive state even exposure to
very low levels of an irritant will trigger the reactivity. Each time
that occurs the inflammatory process that developed with the initial
exposure is perpetuated. If this can occur in the airways, why can’t one
experience reactive “stress” disease? Stress activates the hypothalamic-
pituitary-adrenal axis (HPA). More Recent studies demonstrate that
emotional stress is associated with inflammation (2,3). Huizink et al(1)
measured C-reactive protein, however, they didn’t control for age, body
mass index, total cholesterol etc. The serum ferritin is confounded since
it is an acute phase reactant.
If one postulates the development of a hyperreactive HPA axis then
lesser stressors, be they physiological, but especially emotional, will
trigger HPA reactivity. How frequently this may occur in any individual
would depend on many factors, including genetic, pre-exposure personality,
subsequent life events, etc. Depending on the frequency and duration of
this overstimulation it could lead to the development of all degrees of
HPA dysfunction, which in turn could effect the various systems
(endocrine, immune, emotional, etc.) leading to multiple health problems
and complaints. This would include chronic fatigue, fibromyalgia and
other non-explainable, as well as explainable diseases(4,5).
1. Huizink AC, Slottje P, Witteveen AB et al. Long term health
complaints following the Amsterdam Air Disaster in Police Officers and
Fire-Fighters. Occup and Environ Med 2006; 657-662.
2. Clays E, DeBacquer D, Delanghe J et al. Associations between
dimensions of job stress and biomarkers of inflammation and infection. J.
Occup Environ Med 2005; 47:878-883.
3. Ford DE, Erlinger TP. Depression and C-Reactive Protein in US
adults. Arch Intern Med 2004; 161:1010-1014.
4. McEwen B, Norton Lasley E, eds.: The End of Stress as we Know It.
Washington DC: Joseph Henry Press, 2002: 61-65.
5. Chrousos GP, Elenkov IJ. Interactions of the Endocrine and Immune
Systems In: De Groot LJ, Jameson JL, eds. Endocrinology, 4th Edition.
Philadelphia, USA, W.D. Saunders Company, 2001: 571-583.
I thank Andrews and Heller for showing an interest in nickel related
lung cancer in their electronic letter of 7 July 2006.[1] A large body of
evidence exists on the link between nickel exposure and lung cancer. Among
the most informative occupational cohorts were the one from Clydach, South
Wales (where the risk was first observed); several cohorts of Canadian
nickel workers; and the refinery cohort...
I thank Andrews and Heller for showing an interest in nickel related
lung cancer in their electronic letter of 7 July 2006.[1] A large body of
evidence exists on the link between nickel exposure and lung cancer. Among
the most informative occupational cohorts were the one from Clydach, South
Wales (where the risk was first observed); several cohorts of Canadian
nickel workers; and the refinery cohort from Kristiansand, Norway.[2] No
data on smoking was necessary to identify dose-related risks from nickel
exposure at these plants.
Andrews and Heller mainly focused on a nested case-control study
among the Norwegian refiners, published elsewhere.[3] For that study, we
calculated individual cumulative nickel exposures for 738 employees, of
whom 213 were diagnosed with lung cancer between 1952 and 1995. Exposure
estimates were derived from personnel files and a revised job-exposure
matrix.[4] Detailed smoking histories were collected from the participants
or their closest relatives. There was a participation rate of 94% of all
known cases and their matched controls.
The aim of our study was to sort out the effect of exposure to
different forms of nickel. The smoking data showed a strong, well-known
association with lung cancer, and when this effect was adjusted for, we
found a statistically significant effect from inhalation of nickel. The
risk of lung cancer in the highest exposure group was between three and
four times higher than that of the unexposed. The strongest dose-related
effect was seen for water-soluble nickel compounds. More than half the
number of lung cancers would have been avoided in the absence of nickel
exposure. There was low to moderate confounding from smoking.[3] The
effect of other potential confounders was negligible.[5]
Two tables from this study caught the attention of Andrews and
Heller, particularly the one intended to illustrate the joint effect of
nickel and tobacco.[1] In this subanalysis, the confidence intervals were
quite wide (omitted in Andrews’ and Heller’s letter) indicating that
further splitting of the data would be of limited interest.[3] We agree
with Andrews and Heller that some questions remain as regards the possible
pattern of interaction between smoking and nickel exposure, and we
conclude that the effect of nickel is seen most clearly in the group of
former smokers and light to moderate current smokers, comprising the
majority of the work-force.
Our case-control data were analysed with conditional logistic
regression, implying the use of multiplicative models. We explored our
final model for interaction, but the product terms were not statistically
significant.[3]
Tom K Grimsrud
Author’s affiliation
Cancer Registry of Norway, Oslo
Competing interests
None declared
References
1 Andrews DF, Heller JG. Smoking and lung cancer risk in Clydach
nickel refinery report (Electronic letter). Occup Environ Med 2006.
http://oem.bmjjournals.com/cgi/eletters/63/5/365
2 Doll R, Andersen A, Cooper WC et al. Report of the International
Committee on Nickel Carcinogenesis in Man. Scand J Work Environ Health
1990;16(1, special issue):1-82.
3 Grimsrud TK, Berge SR, Haldorsen T et al. Exposure to different
forms of nickel and risk of lung cancer. Am J Epidemiol 2002;156:1123-32.
4 Grimsrud TK, Berge SR, Resmann F et al. Assessment of historical
exposures in a nickel refinery in Norway. Scand J Work Environ Health
2000;26(4):338-45.
5 Grimsrud TK, Berge SR, Haldorsen T et al. Can lung cancer risk
among nickel refinery workers be explained by occupational exposures other
than nickel? Epidemiology 2005;16(2):146-54.
We appreciate the interest in our recent meta-analysis of
occupational trichloroethylene (TCE) exposure and non-Hodgkin’s Lymphoma
(NHL)(1). Three criticisms were mentioned as, “serious limitations”: 1)
that the alternative descriptions of the Group I occupational cohort
studies (multiple industry vs. aerospace, incidence vs. mortality and
Europe vs. U.S. studies) should have been characteri...
We appreciate the interest in our recent meta-analysis of
occupational trichloroethylene (TCE) exposure and non-Hodgkin’s Lymphoma
(NHL)(1). Three criticisms were mentioned as, “serious limitations”: 1)
that the alternative descriptions of the Group I occupational cohort
studies (multiple industry vs. aerospace, incidence vs. mortality and
Europe vs. U.S. studies) should have been characterized and discussed a
priori 2) that mortality and incidence data should not be combined in a
meta-analysis, and 3) our interpretation that the epidemiologic data are
not supportive of a causal relationship is wrong and it is suggested that
our analysis provides more evidence of a causal effect between TCE
exposure and NHL. These criticisms, however, are not serious limitations
and have little relevance in interpreting the meta-analysis findings. We
also disagree that our meta-analysis provides further support for a causal
association.
The author would have preferred that we consider interpretation of
potential sources of heterogeneity a priori. The evaluation of
heterogeneity across individual studies is a critical component of any
meta-analysis and has not been addressed in previous studies (2,3). We
did consider different approaches to stratification a priori, but
preferred to discuss the interpretation of this after we had analyzed
these (and other) potential sources of heterogeneity. Prior to conducting
a quantitative analysis of heterogeneity, interpretation of potential
findings would be mere speculation.
With respect to combining incidence and mortality data, we agree that
incidence data are generally preferable if available. In our meta-
analysis of subgroups of studies, we stratified studies on this
characteristic and, in fact, the analysis of mortality studies was more
homogeneous (Table 2). More importantly, if TCE exposure were causally
associated with NHL, we would expect both incidence and mortality rates to
reflect this.
Finally, with respect to causal interpretation of the available data,
it is our opinion that causal inference needs to be made based on a
comprehensive evaluation of the data. Such an evaluation is not limited
to the calculation of relative risk estimates and confidence intervals (or
p-values), but also includes evaluation of exposure-response, consistency,
and other factors, in addition to potential sources of bias (4,5).
Results were inconsistent across the different groups of studies (e.g.
considering Group I, Group II and the case-control studies), available
data in the Group I studies did not indicate exposure response trends,
there were significant limitations with respect to exposure classification
across all studies, and there was variation in findings across subgroups
within the Group I cohort studies. These observations considered together
led us to conclude that epidemiologic data of occupational TCE exposure
and NHL were not consistent with a causal association.
Jeffrey H. Mandel, MD, MPH
Michael Kelsh, Ph.D.
Pamela J. Mink, Ph.D.
Dominik D. Alexander, Ph.D.
Exponent Health Sciences
Conflict of interest: The authors have consulted for a number of
private and governmental clients on health issues related to occupational
and environmental TCE exposure.
References:
1. Wartenberg D. TCE exposure and NHL-supportive evidence.
OEM.bmjjournals.com/cgi/eletters/oem.2005.022418v1#349
2. Wartenberg D, Reyner D, Scott CS. Trichloroethylene and cancer: The
epidemiologic evidence. Environ Health Perspect 2000;108 (suppl 2):161-76.
3. Wartenberg D, Scott CS. Carcinogenicity of trichloroethylene (Letter).
Environ Health Perspect 2002;110:A13-A14.
4. Susser M. 1973. Causal Thinking in the Health Sciences: Concepts and
Strategies in Epidemiology. New York: Oxford University Press.
5. Bradford Hill A. 1965. The environment and disease: association or
causation? Proc R Soc Med 58:295-300.
Mortality results in a large cohort of workers compensated for
silicosis in Italy
–
Facts and possible artefacts
With interest we read the article by Marinaccio et al. [1]. Their retrospective mortality study of some 14.000 men compensated for silicosis in the Tuscany region would constitute a powerful addition to studies of cancer risks in compensated silicotics worldwide. In particular, some study results could c...
Mortality results in a large cohort of workers compensated for
silicosis in Italy
–
Facts and possible artefacts
With interest we read the article by Marinaccio et al. [1]. Their retrospective mortality study of some 14.000 men compensated for silicosis in the Tuscany region would constitute a powerful addition to studies of cancer risks in compensated silicotics worldwide. In particular, some study results could contribute to discussions as to under what circumstances crystalline silica, classified as Group 1 carcinogen since 1997 [2], acts as a lung carcinogen. Indeed, with cancers of the ‘trachea, bronchus and lungs’ observed/estimated in approximately 800 males, this study alone considered almost three times as many lung cancer deaths as the seven other SMR studies in compensated silicotics together which were included in a meta-analysis [3] which Marinaccio and colleagues cited.
And yet, before weighting the possible impact of the published information, we would kindly like to ask for clarification of uncertainties around some results. Examples include that (i) this study’s estimate of mortality for lung cancer [SMR=1.10;95%CI=1.03-1.18] is
discrepantly different from the individual and combined estimates of the aforementioned previous SMR studies [summary relative risk=2.40;95%CI=2.12-2.71], (ii) this study would point to a significant decrease of overall
mortality below 1, (iii) in view of some 30 SMRs for cancers and other diseases which are partly considerably below the 1, these study results need further discussion. In our view, the invocation of the Healthy Worker Effect without additional qualification does not suffice to interpret the findings in this heterogeneous cohort. Conceivably, details of silicosis compensation in the Tuscany region – but this had to be very different in
practice and effect from other regions in Italy [4-5] – may have led to significant selection biases. In any case, we disagree with what the authors state in their discussion: their finding of a marginally elevated
excess mortality for lung cancer among silicotics is not consistent with the results of previous studies but it is discrepant and needs to be explained – in detail and in context.
References
[1] Marinaccio A, Scarselli A, Gorini G, Chellini E, Mastrantonio M, Uccelli R, Altavista P, Pirastu R, Merlo DF, Nesti M. Retrospective mortality cohort study of Italian workers compensated for silicosis. Occup Environ Med 2006 [Epub ahead of print].
[2] International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 68. Silica, Some Silicates, Coal Dust and para-Aramid Fibrils. Lyon: International Agency for Research on Cancer, 1997.
[3] Smith AH, Lopipero PA, Barroga VR. Meta-analysis of studies of lung cancer among silicotics. Epidemiology 1995;6:617-624.
[4] Puntoni R, Goldsmith DF, Valerio F, Vercelli M, Bonassi S, Di Giorgio F, Ceppi M, Stagnaro E, Filiberti R, Santi L, Merlo F. A cohort study of workers employed in a refractory brick plant. Tumori 1988;74:27-33.
[5] Zambon P, Simonato L, Mastrangelo G, Winkelmann R, Saia B, Crepet M. A mortality study of workers compensated for silicosis during 1959 to 1963 in the Veneto region of Italy. In: Goldsmith DF, Winn DM, Shy CM, eds. Silica, Silicosis and Cancer: Controversy in Occupational Medicine. New York: Praeger, 1986;367-374.
Thomas C. Erren, Peter Morfeld, Christine B. Glende, Claus Piekarski
Institute and Policlinic for Occupational and Social Medicine, School
of Medicine and Dentistry, University of Cologne, Germany
Corresponding author:
Thomas C. Erren
MD, MPH
Institute and Policlinic for Occupational and Social Medicine
School of Medicine and Dentistry
University of Cologne, Germany
Tel.: +49-221-4785819; fax: +49-221-4785119
E-mail address: tim.erren@uni-koeln.de
This carefully conducted investigation confirms the idea that
paternally mediated reproductive effects are possible in the painting
trades (1,2).
Perhaps, a better indicator of exposure than toluene and its
metabolites would be the use of urinary alkoxyacetic acids which stem from
aliphatic ethylene glycol ethers typically used in modern water miscible
paints (3) and which are confirmed t...
This carefully conducted investigation confirms the idea that
paternally mediated reproductive effects are possible in the painting
trades (1,2).
Perhaps, a better indicator of exposure than toluene and its
metabolites would be the use of urinary alkoxyacetic acids which stem from
aliphatic ethylene glycol ethers typically used in modern water miscible
paints (3) and which are confirmed testicular toxins.
The critical toxic mechanism may be the inhibition of succinate
dehydrogenase activity (4) which links the mitochondrial respiratory chain
with the tricarboxylic acid cycle. The accumulating succinate has
important metabolic effects as it impedes the degradation of the hypoxia
inducible factor 1 (HIF-1) in proteasomes thereby allowing upregulation of
several growth factors relevant in apoptosis and cell growth (5).
References
1 Welch LS, Schrader SM, Turner TW, Cullen MR. Effects of exposure to
ethylene glycol ethers on shipyard painters: II. Male reproduction. Am J
Ind Med, 1988; 14: 509-528.
2 Lähdetie J. Occupational- and exposure-related studies on human
sperm. J Occup Environ Med, 1995; 37: 922-930.
3 Laitinen J, Liesivuori J, Savolainen H. Urinary alkoxyacetic acids
and renal effects of exposure to ethylene glycol ethers. Occup Environ
Med, 1996; 53: 595-600.
4 Laitinen J, Liesivuori J, Turunen T, Savolainen H. Urinary
biochemistry in occupational exposure to glycol ethers. Chemosphere, 1994;
29: 781-787.
5. Brière JJ, Favier J, Benit P. Mitochondrial succinate is
instrumental for HIF 1 alpha nucler translocation in SDHA-mutant
fibroblasts under normoxic conditions. Hum Mol Genet, 2005; 14: 3263-3269.
Mandel and colleagues' article on trichloroethylene (TCE) exposure
and non-Hodgkin's lymphoma (NHL) provides an interesting review of
relevant studies although it has serious limitations (1).
First, there are three alternative descriptions of their
stratification of Group 1 studies: population source (multiple industries
vs. only aerospace), outcome (incidence vs. mortality) and location
(...
Mandel and colleagues' article on trichloroethylene (TCE) exposure
and non-Hodgkin's lymphoma (NHL) provides an interesting review of
relevant studies although it has serious limitations (1).
First, there are three alternative descriptions of their
stratification of Group 1 studies: population source (multiple industries
vs. only aerospace), outcome (incidence vs. mortality) and location
(European vs. US). It would have been helpful to specify a priori the
interpretive advantages and disadvantages of each rather than focusing on
population source.
Second, in their cohort analyses, they combine incidence and
mortality data. Implicit are several unjustified assumptions including:
(1) TCE exposure confers quantitatively similar risks for incidence and
mortality; (2) temporal changes in risk occur equally in incidence and
mortality; (3) because mortality lags incidence, TCE exposure must have
been relatively constant in each study longitudinally, (even though
technological improvements likely decreased exposure); and, (4) although
they state, “The increases for NHL in the general population over the
past several decades have been for both morbidity and mortality, (p.20)�
SEER data show incidence increased more than mortality (Figure 1),
especially in white males (Figure 2), resulting in a nearly two-thirds
increase in percent surviving at least 5 years from 1960 to 1995 (from 31%
to 51% in white males)(2).
Third, although the authors conclude that, "there is
insufficient evidence to suggest a causal link between TCE and NHL"� (abstract) all 8 Group I studies showed elevated risks, with 2
statistically significant, and all 4 summary risk estimates were elevated
with 3 statistically significant. Group I comparisons of highest and
lowest, cumulative, and duration of, exposures show similar patterns.
Group II data are less compelling, although the case control data show
some support.
In summary, contrary to Mandel et al.'s conclusions, the results,
which extend our work (3,4) provide increasing support for a causal
relationship between TCE and NHL.
Daniel Wartenberg, PhD, Professor
Department of Environmental and Occupational Medicine
Robert Wood Johnson Medical School
170 Hoes Lane
Piscataway, NJ 08854
Tel: 732-445-0197
Fax: 732-445-0784
dew@eohsi.rutgers.edu
Competing interests: Dr. Wartenberg has provided testimony on behalf
of plaintiffs in TCE litigation.
References
1. Mandel JH, Kelsh M, Mink PJ, Alexander DD , Kalmes R, eingart M et
al. Occupational trichloroethylene exposure and non Hodgkin's lymphoma: A
review and meta-analysis. Occup Environ Med 2006;doi:10.1136:1-35.
2. Ries, L. A. G., Harkins, D., Krapcho, M., Mariotto, A., Miller, B.
A., Feuer, E. J., Clegg, L., Eisner, M. P., Horner, M. J., Howlader, N.,
Hayat, M., Hankey, B. F., and Edwards, B. K. SEER Cancer Statistics
Review, 1975-2003. 2006. Bethesda, MD, National Cancer Institute
(http://seer.cancer.gov/csr/1975_2003).
3. Wartenberg D, Reyner D, Scott CS. Trichloroethylene and cancer:
The epidemiologic evidence. Environ Health Perspect 2000;108 (suppl 2):161-76.
4. Wartenberg D, Scott CS. Carcinogenicity of trichloroethylene
(Letter). Environ Health Perspect 2002;110:A13-A14.
Figure 1: SEER annual incidence and mortality data
Figure 2: SEER annual incidence and mortality Data for white males only
The authors conclude that 'there was evidence of a persisting risk
among process workers first employed since 1953' in the Clydach, South
Wales, refinery. Unfortunately, they were unable to incorporate the
confounding influence of such well-known predictors of health as attained
education, income level and smoking status. An analysis of their data,
stratified finely by smoking status, would yield use...
The authors conclude that 'there was evidence of a persisting risk
among process workers first employed since 1953' in the Clydach, South
Wales, refinery. Unfortunately, they were unable to incorporate the
confounding influence of such well-known predictors of health as attained
education, income level and smoking status. An analysis of their data,
stratified finely by smoking status, would yield useful information on the
independent effect of exposure. The confounding role of smoking behaviour
on inferences concerning nickel exposure can be demonstrated by examining
a recently published case-control study by one of the authors of lung
cancer risk in Norwegian nickel refinery workers.[1]
Table 1, abridged from a corresponding table in Grimsrud et al.
(2002)1, shows clearly that lung cancer risk increases with amount smoked,
reaching a 30-fold higher level for the Norwegian study's heaviest
smokers.
Table 2 shows that total nickel exposure risk decreases with
increasing smoking level, clearly illustrating the complex interaction of
disease, exposure and smoking behaviour. The highest exposure risk appears
for the Never/Former smokers. However, for this group, the counts of cases
in Table 2 (3,23) are almost the same as the counts (4,22) of the cases in
Table 1. The significant odds ratios (ORs) for lung cancer were 3.8 for
smoking and 5.0 for exposure. Without adjusting for smoking in this group,
it is not possible to assess the separate contribution of either exposure
or smoking. However, as will be seen, most of the risk associated with
exposure comes from this small subset.
This confounding of smoking and exposure effects is not surprising
since there was a higher proportion of non-smokers among the controls in
the Never/Former smoker group (93 of 234 controls or 40%) than among the
cases (4 of 26 cases or 15%) (Table 1). The Light/Medium smoker group also
shows relatively more light smokers among its controls (106 of 253
controls or 42%) than among its cases (49 of 146 cases or 34%). The OR for
total nickel exposure in this group rises from 12.3 to 22.1 or 1.8 (Table
2). This estimate can be compared with the smoking OR for this group,
which rises from 11.7 in Light smokers to 17.7 in Medium smokers or 1.5
(Table 1). These OR values are also not significantly different. The lung
cancer risk in the Light/Medium smokers of the study could be attributed
to smoking behaviour. Finally, the odds ratio of 0.9 in the heavy smoking
group (Table 2) also provides no evidence of risk associated with nickel
exposure.
The complete Norwegian case/control dataset would have been required
to duplicate exactly the odds ratios estimated using conditional logistic
regression models to analyze lung cancer risk as a function of smoking
status and total nickel exposure in Table 7 of Grimsrud et al. (2002).
However, a simple logistic analysis (Table 3) closely approximates those
ORs and their confidence intervals. This good agreement allows us to use
our logistic models to examine the relationships between smoking and
exposure in the Norwegian study.
These odds ratios by smoking status lead to a conclusion very
different from Grimsrud et al.'s. Significantly elevated lung cancer risks
are seen for the Never/Former and Light/Medium smoker groups and, for the
reasons discussed above, the attribution of this risk to smoking and/or
exposure is unknown. These findings could be due to differences in the
smoking histories of cases and controls.
A comparison of two logistic models, each containing additive terms
for total nickel exposure (2 levels) and smoking (3 levels) as explanatory
factors, but one of which also includes a linear interaction term for
exposure and smoking, shows that the interaction term is significant (p=0.016).[3] The significance of the interaction term indicates that an
analysis that omits it will yield measures of exposure risk that include
interaction effects.
Smoking and exposure are strongly related in the Norwegian study. Its
authors used a simple model in which the effects of smoking and exposure
on lung cancer risk were presumed additive. Our analysis has shown the
exposure/smoking interaction effect is significant. When one factor
(smoking) has a large effect relative to that of the factor of interest
(nickel exposure), the analysis is more informative if done separately for
each level of the influential factor.[4] The failure to include this step in
the analysis makes it impossible to assess the risk of nickel exposure.
This calculation, which could be simply done with available Norwegian
data, would inform our understanding of exposure risk in this and other
studies, including the current Clydach study.
D.K. Andrews and J.G. Heller
Authors' affiliations
D.K. Andrews, Dept. of Statistics, University of Toronto
J.G. Heller, James G. Heller Consulting Inc., Toronto, Canada, and
Dept. of Public Health Sciences, University of Toronto
Competing interests
Inco Ltd financially supported preparation of this letter by the authors. Falconbridge Ltd financially supported research2 by the authors
underlying this letter.
References
1 Grimsrud TK, Berge SR, Haldorsen T, et al. Exposure to different
forms of nickel and risk of lung cancer. Am J Epidemiol 2002; 156: 1123-
1132.
2 James G. Heller Consulting Inc. Report for Falconbridge Limited
on Occupational Exposure Limits for Nickel. Falconbridge Ltd., Toronto,
Canada. April 8, 2005. [unpublished]
3 The SAS code yields output for two logistic models with and
without an interaction term. The first model without the term has a chi
squared likelihood ratio of 99.1857 with 4 degrees of freedom (df). The
second with the term has a likelihood ratio of 93.4049 with 3 df.
Consequently, the addition of the interaction term accounts for a decrease
of (99.1857 - 93.4049) = 5.5808 with 1 df. The probability that a chi-
square with 1 df exceeds this value is 0.016202, rounded to 0.016 in the
text. Alternatively, SAS code yields a p-value of 0.0211 for the test of
significance of the interaction term, based on an asymptotic approximation
of normality for the distribution.
4 Cox DR, Planning of Experiments. John Wiley and Sons, New Jersey.
April 1992. ISBN: 0-471-57429-5.
The paper by Laakkonen et al., (1) reported a lower than expected
rate of lung cancer in textile workers for men and women. The data in
this study, as has been previously reported (2), suggest that a dose-
response relationship exists for increasing cotton textile dust and
lowered lung cancer rates. I would like to make several comments
regarding this excellent report on dust exposure and respirator...
The paper by Laakkonen et al., (1) reported a lower than expected
rate of lung cancer in textile workers for men and women. The data in
this study, as has been previously reported (2), suggest that a dose-
response relationship exists for increasing cotton textile dust and
lowered lung cancer rates. I would like to make several comments
regarding this excellent report on dust exposure and respiratory cancer.
Numerous studies (3-7) have shown that exposure to organic dust,
especially that having endotoxin, results in lower rates of lung cancer.
These studies (2,3) have evaluated cotton textile and agricultural workers
in regard to beneficial effects. Automobile workers exposed to
contaminated machinery oils that contain high levels of endotoxin have
also been reported to exhibit lower than expected rates of lung cancer
(8). This concept has been termed the occupational hygiene hypothesis (9).
When studies are adjusted for the major confounder of lung cancer,
smoking, the benefits of exposure remained (3,6,7). Recently, a study (7)
of women Chinese textile workers, whom few smoked, reported similar
findings of reduced lung cancer. In this population, it was determined
that the influence of the small number of smokers was negligible on cancer
rates and that this population could be considered non-smokers (10).
Historically, the reason given for lower rates in these occupational
groups was a lower smoking rate, which was also suggested by Laakkonen.
If the current studies of workers exposed to endotoxin-containing dust are
analyzed in total, there appears to be a dose-response relationship (2),
as indicated in Laakkonen’s study, and the confounder smoking is not
responsible for these lower rates. A review of smoking rates indicates
that cotton textile workers have a similar or higher rate than controls or
the general population (11). Similar smoking rates in textile and
control populations was initially shown by Henderson and Enterline (12),
where rates of 51.9 and 51.2 percent for textile workers in 1967 and the
US population (control) in 1970 were observed, respectively. It should
also be noted that the epidemiological studies have been supported by
animal investigations (13), which suggest a benefit against tumor
metastasis. However, there have been epidemiological investigations that
suggest exposure to cotton textile dust result in an increased risk of
cancer (e.g. brain tumors) (14).
Recently, studies (10,15-17) of women Chinese textile workers have
reported reduced rates of cancer in other organ systems beside the lung
(e.g. liver, rectum, stomach and esophageal) . This indicates that the
benefits of occupational exposure to endotoxin may not be limited to the
respiratory system.
It has also been suggested that other occupational groups (e.g.
sewage treatment workers) (18) that are exposed to endotoxin may be having
reduced cancer rates from exposure. However, for the most part, few
investigations on the beneficial effects of occupational exposure have
been conducted. It should be noted, that one study (19) of smelter
workers that were exposed to selenium also observed a lower than expected
rate of lung cancer. This study along with those of agricultural and
textile workers indicate that benefits from exposure may be more common
than previously thought.
Based on the study by Laakkonen (1) and others (2), additional
investigation on the benefits of occupational exposure is warranted. Few
would have suggested years ago that exposure to dust in the occupational
environment would have a benefit against cancer. However, evidence for
such benefits existing is strong and the historical explanation of smoking
being the responsible effect of lowered cancer rates in these occupational
groups no longer appears applicable. Thus, benefits of organic dust
exposure in reducing cancer should be considered a real effect and
warrants intense investigation.
Some have suggested that exposure to endotoxin early in life, and
possible in the occupational environment, also provides protection against
allergy and/or asthma, which has been commonly called the hygiene
hypothesis (20). It can be suggested that the mechanisms associated with
the hygiene hypothesis and reduced cancer (occupational hygiene
hypothesis) are the same or similar. Both appear to involve toll-like
receptors and involvement of cytokines (6,11,20). For cancer, it has been
suggested that this mechanisms involves pathways that results in apoptosis
of the target cell, which is a cancer cell (6,11,21). There is likely an
interrelationship between this anti-cancer activity and inflammation.
There are, however, risks of occupational disease (20) from exposure
to endotoxin (22) and organic dust (23) and these risks are suggested to
outweigh any benefits associated with reduced cancer rates.
References
1. Laakkonen A, Kyyronen P, Kauppinen T, Pukkala E. (2006).
Occupational exposure to eight organic dusts and respiratory cancer.
Occupational and Environmental Medicine.
2. Mastrangelo G, Fedeli U, Fadda E, Lange JH. 2002. Epidemiologic
evidence of cancer risk in textile industry workers: a review and update.
Toxicol Ind Health 18: 171-181.
3. Mastrangelo G, Marzia V, Milan G, Fadda E, Fedeli U, Lange JH (2004) An
exposure-dependent reduction of lung cancer in dairy farmers. Indoor and
Built Environment 13: 35-44.
4. Lange JH, Mastrangelo G, Fedeli U, Rylander R, Lee E. (2003). Endotoxin
exposure and lung cancer mortality by type of farming: is there a hidden
dose-response relationship? Annals of Agriculture and Environmental
Medicine 10: 229-32.
6. Mastrangelo G, Grange JM, Fadda E, Fedeli U, Buja A, Lange JH.
(2005). Lung cancer risk: effect of dairy farming and the consequence of
removing that occupational exposure. American Journal of Epidemiology.
161: 1037-1046.
7. Astrakianakis G, Seixas N, Camp J, Ray R, Gao DL, Wernli K, Thomas
DB, Checkoway H. (2005) Reduced lung cancer risk associated with cotton
dust exposure in women textile workers in Shanghai, China. American
Journal of Epidemiology 161:S39 (abstract).
8. Schroeder JC, Tolbert PE, Eisen EA, Monson RR, Hallock MF, Smith
TJ, Woskie SR, Hammond SK, Milton DK. (1997). Mortality studies of
machinery fluid exposure in the automobile industry IV: a case-control
study of lung cancer. Am J Ind Med 31: 525-33.
9. Lange JH, Rylander R, Fedeli U, Mastrangelo G. (2003). Extension
of the hygiene hypothesis to the association of occupational endotoxin
exposure with lower lung cancer risk. Journal of Allergy and Clinical
Immunology 112: 219-20.
10. De Roos AJ, Ray RM, Gao DL, Wernli KJ, Fitzgibbons ED, Ziding F,
Astrakianakis G, Thomas DB, Checkoway H. (2005). Colorectal cancer
incidence among female textile workers in Shanghai, China: a case-control
analysis of occupational exposures. Cancer Causes and Control 16:1177-
1188.
11. Lange JH (2006). Reduced lung cancer in workers exposed to
organic dust: epidemiological and experimental evidence. Current Topics in
Toxicology. (in press)
12. Henderson V, Enterline PE. (1973). An unusual mortality
experience in cotton textile workers. Journal of Occupational
Medicine.15:717-719.
13. Lange JH. (1992). Anticancer properties of inhaled cotton dust: a
pilot experimental investigation. Journal of Environmental Science and
Health (Part A). A27: 505-514.
14. Gold LS, De Roos AJ, Ray RM, Wernli K, Fitzgibbons ED, Gao DL,
Astrakianakis G, Feng Z, Thomas D, Checkoway H. (2006). Brain tumors and
occupational exposures in a cohort of female textile workers in Shanghai,
China. Scand J Work Environ Health. 32:178-84.
15. Chang C-K, Astrakianakis G, Thomas DB, Seixas NS, Ray RM, Gao DL,
Wernli KJ, Fitxgibbons ED, Vaughan TL, Checkoway H. Occupational exposures
and risks of liver cancer among Shanghai female textile workers – a case-
cohort study. International Journal of Epidemiology 2006;35: 361-9.
16. Fitzgibbins ED, Ray RM, Gao DL, LI W, Seixas NS, Camp JE,
Astrakianakis G, Feng Z, Thomas DB, Checkoway H. (2006) Occupational risk
factors for esophageal cancers among female textile workers in Shanghai,
China. 163:717-25.
17. Wernli KJ, Fitzgibbins ED, Ray RM, Gao DL, LI W, Seixas NS, Camp
JE, Astrakianakis G, Feng Z, Thomas DB, Checkoway H. (2006) Occupational
risk factors for esophageal cancers among female textile workers in
Shanghai, China. Am J Epidemiol 163:717-25.
18. Lange JH, Mastrangelo G and Thomulka KW (2003) Will sewage workers
with endotoxin-related symptoms have benefit of reduced lung cancer?
(Letter), Occupational and Environmental Medicine, 60:142-149.
19. Gerhardsson L, Brune D, Norberg IGF, Webster PO. (1985).
Protective effect of selenium on lung cancer in smelter workers. Brit J
Ind Med 42:617-26.
21. Lange JH, Mastrangelo G, Fadda E, Priolo G, Montemurro D, Grange
JM,. (2005). Elevated lung cancer risk shortly after smoking cessation: is
it due to reduction of endotoxin exposure? Medical Hypotheses. 65:534-541.
22. Thorn J, Rylander R. Inflammatory response after inhalation of
bacterial endotoxin assessed by induced sputum techniques. Thorax
1998:53:1047-52.
23. Christiani DC, Wang XR. Respiratory effects of long-term exposure
to cotton dust. Curr Opin Pulm Med 2003:9:151-5.
Mortality results in workers compensated for silicosis in Italy by job and disability degree.
We wish to thank our German colleagues for giving us the opportunity to clear some points of the mortality study of workers compensated for silicosis in Italy [1]. The large number of silicotic compensated workers investigated allowed us to perform specific analyses to reduce cohort heterogeneity. Subcohort has been i...
Dear Editor,
The absence of a significant nasal and ethmoid sinus cancer risk in Finland may be due to the low concentrations of polyphenols in domestic tree species as compared to imported wood from from more southern regions (1). The determination of the polyphenol content could be a good chemical surrogate for the detection of the species with carcinogenic properties (2).
1 Mämmelä P, Phenolics in...
I enjoyed reading the study of Huizink et al(1)about the Amsterdam air disaster. As pointed out in their table 2, airway disease was one of the symptoms found to be more prevalent in the exposed group. Reactive airway disease can develop after a single large exposure to an irritant. This type of injury has also been noted in the nasal airway. One of the reasons the reactivity persists for many years or never goes awa...
Dear Editor,
I thank Andrews and Heller for showing an interest in nickel related lung cancer in their electronic letter of 7 July 2006.[1] A large body of evidence exists on the link between nickel exposure and lung cancer. Among the most informative occupational cohorts were the one from Clydach, South Wales (where the risk was first observed); several cohorts of Canadian nickel workers; and the refinery cohort...
(author response)
We appreciate the interest in our recent meta-analysis of occupational trichloroethylene (TCE) exposure and non-Hodgkin’s Lymphoma (NHL)(1). Three criticisms were mentioned as, “serious limitations”: 1) that the alternative descriptions of the Group I occupational cohort studies (multiple industry vs. aerospace, incidence vs. mortality and Europe vs. U.S. studies) should have been characteri...
Mortality results in a large cohort of workers compensated for silicosis in Italy – Facts and possible artefacts
With interest we read the article by Marinaccio et al. [1]. Their retrospective mortality study of some 14.000 men compensated for silicosis in the Tuscany region would constitute a powerful addition to studies of cancer risks in compensated silicotics worldwide. In particular, some study results could c...
Dear Editor,
This carefully conducted investigation confirms the idea that paternally mediated reproductive effects are possible in the painting trades (1,2).
Perhaps, a better indicator of exposure than toluene and its metabolites would be the use of urinary alkoxyacetic acids which stem from aliphatic ethylene glycol ethers typically used in modern water miscible paints (3) and which are confirmed t...
Dear Editor,
Mandel and colleagues' article on trichloroethylene (TCE) exposure and non-Hodgkin's lymphoma (NHL) provides an interesting review of relevant studies although it has serious limitations (1).
First, there are three alternative descriptions of their stratification of Group 1 studies: population source (multiple industries vs. only aerospace), outcome (incidence vs. mortality) and location (...
Dear Editor,
The authors conclude that 'there was evidence of a persisting risk among process workers first employed since 1953' in the Clydach, South Wales, refinery. Unfortunately, they were unable to incorporate the confounding influence of such well-known predictors of health as attained education, income level and smoking status. An analysis of their data, stratified finely by smoking status, would yield use...
Dear Editor,
The paper by Laakkonen et al., (1) reported a lower than expected rate of lung cancer in textile workers for men and women. The data in this study, as has been previously reported (2), suggest that a dose- response relationship exists for increasing cotton textile dust and lowered lung cancer rates. I would like to make several comments regarding this excellent report on dust exposure and respirator...
Pages