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.
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.
Chen et al [1] reported the positive association between
environmental tobacco smoke (ETS) and severe dementia syndromes. They
mentioned that Cox regression model was applied to detect statistical
significance.
I have two queries on their study. First, they conducted cross-
sectional study and Cox regression analysis was applied to detect relative
risk by adjusting several confounders. They described the methodol...
Chen et al [1] reported the positive association between
environmental tobacco smoke (ETS) and severe dementia syndromes. They
mentioned that Cox regression model was applied to detect statistical
significance.
I have two queries on their study. First, they conducted cross-
sectional study and Cox regression analysis was applied to detect relative
risk by adjusting several confounders. They described the methodological
explanation in the 4th paragraph of the discussion, mainly avoiding
overestimation of the association. Although they quoted one reference [2]
with their previous two papers to select Cox regression analysis,
estimation of odds ratio by logistic regression analysis seems appropriate
in their cross-sectional study, because statistical advantage of handling
censored cases and duration from baseline to event occurrence was not
considered for their analysis.
Second, in their Table 1, 791 current smokers were categorized as no
ETS exposure group. There is no difference of ETS exposure from others or
from himself/herself, and ETS can be applied to never smokers or former
smokers in general. This also related to the content in Table 3, which
presents risk assessment of ETS to all participants, including current
smokers, with severe dementia syndromes. As Table 3 contains results for
3769 never smokers, their conclusion that highest ETS exposure by
cumulative dose is a significant risk factor for severe dementia syndromes
is acceptable.
The mean age is over 70 years in their study, and the validation of
ETS exposure for long-term period should also be evaluated. As there is a
report that heavy smoking in midlife becomes a risk of Alzheimer disease
[3], cause-effect relationship between ETS and severe dementia syndromes
by longer follow-up study with adjustment of several confounders should be
conducted to validate their results.
REFERENCES
1. Chen R, Wilson K, Chen Y, et al. Association between environmental
tobacco smoke exposure and dementia syndromes. Occup Environ Med
2013;70:63-9.
2. Zhang J, Yu KF. What's the relative risk? A method of correcting
the odds ratio in cohort studies of common outcomes. JAMA 1998;280:1690-1.
3. Rusanen M, Kivipelto M, Quesenberry CP Jr, et al. Heavy smoking in
midlife and long-term risk of Alzheimer disease and vascular dementia.
Arch Intern Med 2011;171:333-9.
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.
Professor Kawada [1] commented on our use of Cox regression for the
analysis of cross-sectional data. [2] Although logistic regression is
often used to compute a prevalence odds ratio (POR) in cross-sectional
studies as an estimate of relative risk (RR), when the outcome is not rare
this overestimates the RR, sometimes changing the study conclusion. Cox
regression has been suggested instead to estima...
Professor Kawada [1] commented on our use of Cox regression for the
analysis of cross-sectional data. [2] Although logistic regression is
often used to compute a prevalence odds ratio (POR) in cross-sectional
studies as an estimate of relative risk (RR), when the outcome is not rare
this overestimates the RR, sometimes changing the study conclusion. Cox
regression has been suggested instead to estimate the prevalence rate
ratio (PRR).[3] We recently re-visited the relationship between POR and
PRR,[4] using the same dataset as the OEM article.[2] The logistic model
showed a POR of 1.22 (95%CI 1.10-1.35) in urban people (60.2%
hypertension) versus rural (55.3%), while a Cox model gave a PRR of 1.09
(1.02-1.16). The age-sex adjusted figures were 1.14 (1.03-1.27), and 1.06
(0.99-1.16) for the logistic and Cox models, respectively. In the case of
myocardial infarction (5.9% prevalence), however, we found similar RRs
between two models (age-sex adjusted POR 2.19, 1.75-2.74, and PRR 2.09,
1.68-2.59). [4] In our recent paper [2], the prevalence of severe
dementia syndromes was 10.6%, and if the a logistic model with the same
adjustments had been used, the POR would have been 1.43 (1.09-1.88). We
believe that the PRR of 1.29 (1.05-1.59) is more appropriate.
Professor Kawada made good comments on our data that smokers may
reduce the risk of severe dementia syndromes if avoiding exposure to
environmental tobacco smoke (ETS), although active smoking increased the
risk of dementia. The smokers must not smoke together (usually they do as
a culture), probably reducing both active and passive smoking in the
general population.
Since the situation of ETS in China remained little changed over the
last 3 decades, the ETS level to which the participants were exposed in
midlife may be similar to or even higher than that when they were older.
We will follow up the cohort to further examine the cause-effect
relationship between ETS and severe dementia syndromes.
Professor Ruoling Chen
Reference List
1 Kawada J. Environmental tobacco smoke and severe dementia
syndromes (comments). 2013.
2 Chen R, Wilson K, Chen Y, et al. Association between environmental
tobacco smoke exposure and dementia syndromes. Occup Environ Med 2013;70
(1):63-9.
3 Lee J. Odds ratio or relative risk for cross-sectional data? Int J
Epidemiol 1994;23 (1):201-3.
4 Wang J, Peng WJ, He Q, et al. Relationship between prevalence odds
ratio and prevalence rate ratio. Chinese J Health Statistics
2012;29:149-50.
The finding that nightshift work is linked to increased risk of
ovarian cancer1 is one of a long series of studies finding that nightshift
work is associated with increased risk of cancer [e.g., Ref. 2]. While
reduced production of melatonin is a possible explanation, a better
explanation is that since those on night shift sleep during daytime, they
spend less time in the sun when they could be making vitamin D. Solar
ul...
The finding that nightshift work is linked to increased risk of
ovarian cancer1 is one of a long series of studies finding that nightshift
work is associated with increased risk of cancer [e.g., Ref. 2]. While
reduced production of melatonin is a possible explanation, a better
explanation is that since those on night shift sleep during daytime, they
spend less time in the sun when they could be making vitamin D. Solar
ultraviolet-B (UVB) irradiance is the primary source of vitamin D for most
people.
Based on a study of night shift work and the risk of cancer in men,2
it was pointed out that a much better explanation than low melatonin was
low solar UVB and vitamin D [Grant, Am J Epi, in press]. Additional
support is found in the fact that night shift work is also associated with
reduced risk of skin cancer.3 Also, both solar UVB and vitamin D have been
found inversely correlated with risk of ovarian cancer.4,5
Thus, those working night shifts should consider taking vitamin D
supplements in amounts sufficient to raise serum 25-hydroxyvitamin D
concentrations to at least 75 nmol/l if not 100 nmol/l.4 To reach these
concentrations could take 1000 to 4000 IU/d vitamin D3.
References
1.Bhatti P, Cushing-Haugen KL, Kristine G, et al. Nightshift work and
risk of ovarian cancer. Occup Environ Med 2013 70:231-7.
2. Parent ME, El-Zein M, Rousseau MC, et al. Night work and the risk
of cancer among men. Am J Epidemiol. 2012;176:751-9.
3. Schernhammer ES, Razavi P, Li TY, et al. Rotating night shifts and
risk of skin cancer in the nurses' health study. J Natl Cancer Inst.
2011;103:602-6.
4. Grant WB. Update on evidence that support a role of solar
ultraviolet-B irradiance in reducing cancer risk. Anticancer Agents Med
Chem. 2013;13:140-6.
5. Toriola AT, Surcel HM, Calypse A, et al. Independent and joint
effects of serum 25-hydroxyvitamin D and calcium on ovarian cancer risk: A
prospective nested case-control study. Eur J Cancer. 2010;46:2799-805.
Conflict of Interest:
I receive funding from Bio-Tech Pharmacal (Fayetteville, AR), and the Sunlight Research Forum (Veldhoven) and have received funding from the UV Foundation (McLean, VA), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).
The authors want to thank Prof. Dr. Kawada for his interest in our
manuscript entitled 'Adverse effects of low occupational cadmium exposure
on renal and oxidative stress biomarkers in solderers' [1]. Prof. Kawada
recommends performing the multiple linear regression analysis without
adjusting for pack-years of smoking. It is known that smoking is a major
source of cadmium exposure [2, 3]. However, we want to underline th...
The authors want to thank Prof. Dr. Kawada for his interest in our
manuscript entitled 'Adverse effects of low occupational cadmium exposure
on renal and oxidative stress biomarkers in solderers' [1]. Prof. Kawada
recommends performing the multiple linear regression analysis without
adjusting for pack-years of smoking. It is known that smoking is a major
source of cadmium exposure [2, 3]. However, we want to underline that the
possibility of confounding through a non-cadmium-dependent effect of
smoking on the kidney must also be considered [2-6]. Therefore, we decided
also to adjust for pack-years of smoking. The renal markers NAG, micro-Alb
and RBP showed indeed negative regression coefficients. However, the
regression coefficients are very small and very imprecise. To comply with
space considerations, we did not show the regression coefficients and
standard errors for the intercept, age and pack-years of smoking in the
paper. Pack-years of smoking is statistically significantly associated
with the oxidative stress marker 8-isoprostane (model Cd-B: regression
coefficient, B = 0.05; 95% confidence interval, C.I. = 0.02 - 0.07; p
<0.001 and model Cd-U: B = 0.05; 95% C.I. = 0.02 - 0.07; p < 0.01).
The association between NAG and pack-years of smoking was borderline
statistically significant (model Cd-B: B = 0.03; 95% C.I. = -0.001 - 0.06;
p= 0.06 and model Cd-U: B = 0.03; 95% C.I. = -0.004 - 0.06; p = 0.08). No
statistically significant association was found between pack-years of
smoking and the other renal markers (i.e., IAP, micro-Alb and RBP) and
oxidative stress markers (i.e., d-ROM, GPX, SOD, 8-OHdG and AOPP).
References
1. Hambach R, Lison D, D'Haese P, Weyler J, Francois G, De Schryver
A, Manuel-Y-Keenoy B, Van Soom U, Caeyers T, van Sprundel M. Adverse
effects of low occupational cadmium exposure on renal and oxidative stress
biomarkers in solderers. Occup Environ Med 2013; 70: 108-13.
2. Jarup L, Berglund M, Elinder CG, Nordberg G, Vahter M. Health
effects of cadmium exposure - a review of the literature and a risk
estimate. Scand J Work Environ Health 1998; 24: 1-51.
3. Bernhard D, Rossmann A, Wick G. Metals in Cigarette Smoke. IUBMB
Life 2005; 57: 805-9.
4. McNamee R. Confounding and confounders. Occup Environ Med 2003;
60: 227-34.
5. Orth SR, Viedt C, Ritz E. Adverse effects of smoking in the renal
patient. Tohoku J Exp Med 2001; 194: 1-15.
6. Mercado C, Jaimes EA. Cigarette smoking as a risk factor for
atherosclerosis and renal disease: novel pathogenic insights. Curr
Hypertens Rep 2007; 9: 66-72.
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
We are grateful to Dr Jarvolm for his comments on our paper. The
specified aim of our study was to quantify the relationship between the
level of occupational isocyanate exposure and risk of developing asthma. The usual approach to this problem is a cohort study in an exposed work
force, possibly with a nested case referent analysis. A register based
case referent study of the type described by Dr Jarvol...
We are grateful to Dr Jarvolm for his comments on our paper. The
specified aim of our study was to quantify the relationship between the
level of occupational isocyanate exposure and risk of developing asthma. The usual approach to this problem is a cohort study in an exposed work
force, possibly with a nested case referent analysis. A register based
case referent study of the type described by Dr Jarvolm would be
unsuitable for this purpose because the source population would be ill defined, selection of a appropriate referents difficult, and reliable
assessment of their exposure almost impossible. We used the SWORD
reporting scheme, not as a register, but as a convenient means of
identifying workplaces from which clusters of asthma cases attributed to
isocyanates have been reported, and in which isocyanate exposure had been
assessed by an occupational hygienist; we then investigated those sites. In fact, a small number of additional cases were identified during the
course of the investigation and were included in the analysis. In company
A, where the majority of our cases worked, all employees were
subject to close respiratory supervision throughout their employment,
including pre-employment assessment; in company B, the occurrence of the
cluster of cases was recognised by the occupational health department and
the workers in the relevant areas investigated. We are therefore
reasonably confident that no cases were missed.
We were careful to select referents from workers who were exposed to
isocyanates and were under the same level of surveillance as the cases to
avoid some of the biases outlined by Dr Jarvolm. We agree that the close
matching of cases and referents probably reduced the sensitivity of the
study, but we felt that it was more important to do that than to risk
selection bias as described in his second hypothetical scenario. As we
also acknowledged in the article, we cannot exclude the theoretical
possibility that the cases of asthma were not caused by isocyanates, but
by other chemicals present in the plants. Confounding is a risk in any
observational study, although not necessarily a source of bias, but the
other agent would have to be closely correlated with the isocyanate
exposure to account for our findings.
The cases had work related asthma as diagnosed by an occupational
physician. Nearly all had a history of symptoms associated with work that
improved on days away from work and had had serial respiratory function
tests that supported the diagnosis. Challenge tests are rarely used in
the UK; very few centres undertake them, and without proper facilities are
considered dangerous. However, as explained in the article, in company A
persons with respiratory symptoms were removed from exposure to
isocyanates until they had recovered and then gradually returned to their
previous work under very close supervision with serial respiratory
function testing, which in practice was a form of challenge test.
The purpose of undertaking a case referent study was not to establish
that it is possible to develop isocyanate asthma at low exposures, but to
examine the exposure response relationship. We do not conclude from our
data that there is a threshold below which isocyanate exposure is safe. The level of 1.25 ppb was arbitrarily chosen because it was the median time weighted average exposure in the referent group in company A. Despite
the fact that all estimated eight hour TWA exposures were within the maximum
exposure limits, those subjects whose estimated eight hour TWA was greater
than 1.25 ppb appeared to be at increased risk of occupational asthma. However, the data were also compatible with a linear exposure response
relationship in which the odds of asthma increased by 1.08 for every
0.1ppb. A much larger study would be needed to test these two possible
exposure-response relationships fully.
The very interesting article by de Vocht et al (1) is a good
opportunity to discuss possible interpretations of results obtained in
ecological studies. The study included 165 nations as observations and
found an association between mobile/cellular telecommunications (per 100
people) and brain cancer (national age-adjusted incidence rates). Although
in this case authors were interested in the generation of individual-level...
The very interesting article by de Vocht et al (1) is a good
opportunity to discuss possible interpretations of results obtained in
ecological studies. The study included 165 nations as observations and
found an association between mobile/cellular telecommunications (per 100
people) and brain cancer (national age-adjusted incidence rates). Although
in this case authors were interested in the generation of individual-level
causal hypotheses, the same results can be interpreted in two more ways
based on multilevel causal approach,(2) promulgated by social
epidemiologists.
One first alternative interpretation can be called "full-population
approach". According to the classic article by Rose, determinants of
individual cases are not necessarily determinants of incidence rate.(3) In
this approach there is not interest in individual or other level
inferences, thus results of one ecological study could be valid in the
same aggregation level of observations analyzed. Until I know only one
study used national data from Nordic countries,(4) and its inconsistent
results can be explained per difficulties to explore latency periods. For
this, my conclusion is that de Vocht et al study is the most valid study
at national aggregation level.
The second alternative interpretation is interested in an ecological
approach but in different aggregation levels. For instance, it occurs when
ecological studies based on national data are evidence for national sub-
regions inferences. It can be possible but the presence of fallacy is a
threat. In this case is needed to explore cross-level fallacies similar to
ecological fallacy.(5) A discussion on this same topic is available in two
commentaries,(6,7) and inferences on different aggregation-levels can be
responsible of heterogeneity observed.
Explanations of these alternatives approaches should not to be based
on biomedical concepts. Macrodeterminants and population-level outcomes
act according to ecologic, social, cultural or economical processes. Thus
an initial explanation of results can be based on a previous study by
Milham, where "civilization" is the main determinant of some diseases with
high occurrence in recent years. (8)
In conclusion, I agree with the authors that in occupational and
environmental health ecological studies can be a useful source of
evidence. However their results can offer more evidence if they are
analyzed according to different aggregation-level approaches.
References
1. de Vocht F, Hannam K, Buchan I. Environmental risk factors for
cancers of the brain and nervous system: the use of ecological data to
generate hypotheses. Occup Environ Med 2013 (in press).
2. Diez-Roux AV. A glossary for multilevel analysis. J Epidemiol
Community Health 2002;56(8):588-94.
3. Rose G. Sick individuals and sick populations. Int J Epidemiol
1985;14(1):32-8.
4. Deltour I, Auvinen A, Feychting M, Johansen C, Klaeboe L, Sankila
R, Schuz J. Mobile phone use and incidence of glioma in the Nordic
countries 1979-2008: consistency check. Epidemiology 2012;23(2):301-7.
5. Idrovo AJ. Three criteria for ecological fallacy. Environ Health
Perspect 2011;119:A332.
6. Soderqvist F, Carlberg M, Hansson Mild K, Hardell L. Childhood
brain tumour risk and its association with wireless phones: a commentary.
Environ Health 2011;10:106.
7. Aydin D, Feychting M, Schuz J, Roosli M; CEFALO study team.
Childhood brain tumours and use of mobile phones: comparison of a case-
control study with incidence data. Environ Health 2012;11:35.
8. Milham S. Historical evidence that electrification caused the 20th
century epidemic of "diseases of civilization". Med Hypotheses
2010;74(2):337-45.
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,
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...
Chen et al [1] reported the positive association between environmental tobacco smoke (ETS) and severe dementia syndromes. They mentioned that Cox regression model was applied to detect statistical significance.
I have two queries on their study. First, they conducted cross- sectional study and Cox regression analysis was applied to detect relative risk by adjusting several confounders. They described the methodol...
(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...
In Reply,
Professor Kawada [1] commented on our use of Cox regression for the analysis of cross-sectional data. [2] Although logistic regression is often used to compute a prevalence odds ratio (POR) in cross-sectional studies as an estimate of relative risk (RR), when the outcome is not rare this overestimates the RR, sometimes changing the study conclusion. Cox regression has been suggested instead to estima...
The finding that nightshift work is linked to increased risk of ovarian cancer1 is one of a long series of studies finding that nightshift work is associated with increased risk of cancer [e.g., Ref. 2]. While reduced production of melatonin is a possible explanation, a better explanation is that since those on night shift sleep during daytime, they spend less time in the sun when they could be making vitamin D. Solar ul...
The authors want to thank Prof. Dr. Kawada for his interest in our manuscript entitled 'Adverse effects of low occupational cadmium exposure on renal and oxidative stress biomarkers in solderers' [1]. Prof. Kawada recommends performing the multiple linear regression analysis without adjusting for pack-years of smoking. It is known that smoking is a major source of cadmium exposure [2, 3]. However, we want to underline th...
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...
Editor-
We are grateful to Dr Jarvolm for his comments on our paper. The specified aim of our study was to quantify the relationship between the level of occupational isocyanate exposure and risk of developing asthma. The usual approach to this problem is a cohort study in an exposed work force, possibly with a nested case referent analysis. A register based case referent study of the type described by Dr Jarvol...
The very interesting article by de Vocht et al (1) is a good opportunity to discuss possible interpretations of results obtained in ecological studies. The study included 165 nations as observations and found an association between mobile/cellular telecommunications (per 100 people) and brain cancer (national age-adjusted incidence rates). Although in this case authors were interested in the generation of individual-level...
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