Mobile phone use and risk of glioma in adults: case-control study
BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.38720.687975.55 (Published 13 April 2006) Cite this as: BMJ 2006;332:883
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Several rapid responses contend that since cell phone use actually
appeared
protective against glioma, that there are only two choices--either they
are
actually protective, or the study is flawed.
There is in fact another completely rationale explanation, which is
that cell
phone use is correlated with some other behavior or factor which is
protective
against glioma, and that the study was simply not designed to detect this
external influence. That such a basic premise of epidemiological and
correlative research was overlooked in the critical letters is
astonishing.
Beyond this fact, is it so outlandish to believe that cell phones
might actually
mitigate the risk of glioma? It seems to me the responses to the study
tend to
assume that radio waves must be dangerous, despite very limited if any
proof
of causation (though correlation has been shown in some research and
denied in others) of cancer and several other conditions. Anyhow, if radio
waves and related energies have biological effects, must they be
inherently
negative? I do not know but I think there is a lot of jumping to
conclusions
and bias in this discussion clouding people's reason.
Competing interests:
I own and use a cell phone
regularly.
Competing interests: No competing interests
It appears inconsistent for Hepworth and colleagues to implicate
recall bias as an explanation for the significant association between
glioma risk and the laterality of mobile phone use found by their study.
If the subjects with glioma (the cases in this case-control study) were
truly affected by recall bias, wouldn't we also expect that the cases’
reporting of overall mobile phone use to be similarly biased? But this is
not what was found--the study’s results indicate no association between
overall mobile phone use and glioma. How do the authors explain this
apparent ‘selective recall bias’ with the reporting of laterality of
mobile phone use apparently affected by recall bias, but the reporting of
overall mobile phone use being unaffected?
Competing interests:
None declared
Competing interests: No competing interests
We have read this recently published paper, UK part of the so-called
Interphone study, with interest.1 However, the results are difficult to
interpret due to several limitations in the study design and analysis.
The participation rate was extremely low, for cases 51 % and for
controls only 45 %. Furthermore “non-participating controls were replaced”
thus with potential for selection bias for the controls. In fact
participating controls were more affluent than both non-participating
controls and participating cases. There is a clear gradient of mobile
phone use as to social class. In our case-control study encompassing
answers from 1 254 (88 %) cases with a benign brain tumour, 905 (90 %)
cases with a malignant brain tumours and 2 162 (89 %) controls use of
cellular telephones was reported by 48 % of the most affluent cases and 36
% in the least affluent group. 2,3
Use of cordless telephones was not assessed in contrast to our
studies. The “unexposed” group was thus not truly unexposed to microwaves.
The analysis of laterality is doubtful since the “unexposed” group
contained subjects with exposure to microwaves on the opposite side of the
head than analysed; analysis of ipsilateral exposure with contralateral
exposure classified as “unexposed” and analysis of contralateral exposure
with ipsilateral exposure classified as “unexposed”.
We note that the numbers of interviewed cases are not constant. In
the abstract 966 cases are reported but in Table 2 numbers of tumour grade
and side of phone use are given for 972 cases, see footnotes. In Table 3
of 14 odds ratios 13 are < 1.0 and one > 1.0 indicating non-random
variation and methodological problems in the study. Brain tumour cases may
not be ideally interviewed face to face shortly after their operation due
to serious cognitive behavioural defects such as memory loss and aphasia.
In the Danish Interphone study cases with glioma scored significantly
lower than controls due to problems in recalling words (aphasia) and
symptoms due to paralysis. 4 These aspects are not at all discussed in the
paper.1 In contrast to our studies the interviewers knew if it was a case
or a control that was interviewed.
As to urban and rural living the investigators seam just to have
asked about the study subjects own ideas on that without relying on
official statistics. Thus these data are less informative compared with
our data where we used the Swedish Population Registry for municipality
for all cases and controls and Statistics Sweden for further
classification into 6 categories of population density.5
Our latest publication on malignant brain tumours and use of cellular
and cordless telephones is not cited although available at internet since
July 14, 2005.6 Now results of the pooled analysis of our studies are
published.2,3 Clearly we found an increased risk for high-grade
astrocytoma using >10 years latency period. It is unfortunate that the
current publication does not give results for high-grade and low-grade
glioma separately.
It is interesting to note that the article cites critics of our
studies published even before our results appeared in scientific
literature. Two of the cited reports have never been published in a pre-
review journal and are thus not possible to rebut. The third cited report
was published in 2000, thus even when our first large case-control study
was on going and no data had been reported. Furthermore, there seems to be
a link to the mobile phone industry among some of the cited authors.7
We note that some of the participating universities and authors have
received grants from the telecom industry. Also this study was heavily
telecom industry funded. Besides local industry grants in UK the
Interphone study according to IARC is funded from industry with 3.5
million Euros, and from the European Union, 3.85 million Euros (E Cardis,
personal communication). The contract stipulated that the industry has the
right to be informed about the results a maximum of seven days before the
publication.8 Receiving grants from industry is by the International
Committee of Medical Journal Editor regarded as “the most important
conflicts of interest”. In a review of health studies on environmental
tobacco smoke the rate ratio of a paper with at least one author with
industry associations reaching an industry-favourable conclusion was 3.2,
95 % CI 1.4-7.5.9 It should be noted that one of the authors (Dr Swerdlow)
is a member of ICNIRP, a German foundation on this issue that does not
recognize any cancerogenesis from microwave exposure. ICNIRP seems to be a
closed organisation that elects its own members and without full
disclosure how it is financed. Membership might be a conflict of interest.
Finally, we do not agree with the statement in the accompanied
editorial that “any risk to the individual mobile phone user of developing
brain pathology is fleetingly small” and that there is “no need to apply
the precautionary principle” for mobile use.10 This is a too premature
statement since studies on long term health effects, especially for
children, are lacking.
Lennart Hardell, MD, PhD, Professor
Department of Oncology, University Hospital, SE-701 85 Orebro and
Department of Natural Sciences, Orebro University, SE-701 82 Orebro,
Sweden
Kjell Hansson Mild, PhD, Professor
National Institute for Working Life, SE-907 13 Umeå and Department of
Natural Sciences, Orebro University, SE-701 82 Orebro, Sweden
Correspondence: Dr Lennart Hardell, Department of Oncology,
University Hospital, SE-701 85 Orebro, Sweden
phone + 46 19 602 15 46, fax + 46 19 10 17 68, e-mail:
lennart.hardell@orebroll.se
References
1. Hepworth SJ, Schoemaker MJ, Muir KR, Swerdlow AJ, van Tongeren
MJA, McKinney PA. Mobile phone use and risk of glioma in adults: case-
control study. BMJ 2006;332:883-6.
2. Hardell L, Carlberg M, Hansson Mild K. Pooled analysis of two case
-control studies on the use of cellular and cordless telephones and the
risk of benign brain tumours diagnosed during 1997-2003. Int J Oncol
2006;28:509-18.
3. Hardell L, Carlberg M, Hansson Mild K. Pooled analysis of two case
-control studies on use of cellular and cordless telephones and the risk
of malignant brain tumours diagnosed during 1997-2003. Int Arch Occup Env
Health 2006; DOI 10.1007/s00420-006-0088-5.
4. Christensen HC, Schüz J, Kosteljanetz M, Poulsen HS, Boice JD,
McLaughlin JK, Johansen C. Cellular telephones and risk for brain tumors.
A population-based, incident case-control study. Neurology 2005;64:1189-
95.
5. Hardell L, Carlberg M, Hansson Mild K. Use of cellular telephones
and brain tumour risk in urban and rural areas. Occup Environ Med
2005;62:390-4.
6. Hardell L, Carlberg M, Hansson Mild K. Case-control study on the
association between the use of cellular and cordless telephones and
malignant brain tumors diagnosed during 2000-2003. Env Res 2005; DOI:
10.1016/j.envres.2005.04.006
7. Hardell L. From phenoxyacetic acids to cellular telephones: Is
there historic evidence of the precautionary principle in cancer
prevention? Int J Health Services 2004;4:25-37.
8. IARC (2005) http://www.iarc.fr/ENG/Units/RCAd.html (Assessed April
19, 2006).
9. Garne D, Watson M, Chapman S, Byrne F. Environmental tobacco smoke
research published in the journal Indoor and Built Environment and
associations with the tobacco industry. Lancet 2005;365:804-9
10. Maier M. Brains and mobile phones. The biggest risk to health
from mobile phones is using them while driving. BMJ 2006;332:864-5.
Competing interests:
None declared
Competing interests: No competing interests
Hepworth et al (1) have conducted a case-control study to assess the
risk of glioma in relationship to mobile phone use in 966 cases and 1716
controls selected from general practitioners lists. They found no
relation for risk of glioma and time since first use, lifetime years of
use, and cumulative number of calls and hours of use. However they found
an increased risk for tumour ipsilateral to the side most used, and a
parallel reduction in the contralateral side.
The study has several problems which limit the confidence that can be
placed on the results. 50% of the controls did not participate. In the
case of 21% of controls this was due to “non-response”. This failure to
contact the subject could have been due to the subject not having a mobile
phone and so would bias the control group to include mainly users. In
addition the control group who were eventually recruited were more
affluent than cases and so better able to afford a mobile phone and to use
it more leading to systemic bias in the control data which would mask any
effect of phones.
47% of cases did not participate. 37% of the cases were too ill or
mentally impaired due to the effects of the tumor or treatments. However
the clarity of thought of the remainder was not assessed yet this is
critical for accurate recall of data over 10 years. The quality of data
collection is entirely dependent on the accuracy of recall by subjects for
upto and over 10 years previously, regarding average amount of time use,
number of calls, use of hands-free kits and side of head on which the
mobile phone was used. The accuracy of the recall of this data is crucial
but not substantiated in the paper. There is no reference to cross-
checking the recall data with billing data to determine the margins of
error regarding phone usage. Recall has been shown to be highly inaccurate
compared to billing data.
Parslow et al (2) obtained recall data about mobile phone use from 93
volunteers and compared this to their outgoing phone bills over a six-
month period. They found only modest correlations and concluded "self
reported mobile phone use may not fully represent patterns of mobile phone
use". Similar findings have been made by Samkange-Zeeb (3) and colleagues
who compared self reported cell phone use with billing data over a three
month period. Shum et al (4) surveyed 61 volunteers over a three-year
period regarding reported mobile phone use compared to billing data and
similarly found the majority were not able to report their duration of use
to within +/- 25% of the minutes obtained from billing data. These
studies have found problems in recall data over relatively short periods
of time, yet Hepworth etal place reliance on accurate recall for upto and
over 10 years, even though such recall is likely to be even more
unreliable and lead to substantial non-differential misclassification and
a null finding.
30% of cases were not interviewed because they were too ill or dead.
These subjects are likely to have included the highest grade tumors.
Removal of this large number of cases will alter the number of cases
available for analysis and so lessen the likelihood of finding a
relationship between severity of tumor and use of phone.
The study contains serious flaws which lessen the confidence that can
be placed on the conclusion of no association of glioma and mobile phone
use.
Dr Bruce Hocking
Specialist in Occupational Medicine
9 Tyrone St,
Camberwell,
Victoria 3124,
Australia
References.
1. Hepworth SJ, Schoemaker MJ, Muir KR, Swerdlow AJ, van Tongeren MJ,
McKinney PA. Mobile phone use and risk of glioma in adults: case-control
study.
BMJ. 2006 Jan 20;
2. Parslow RC, Hepworth SJ, McKinney PA (2003) Recall of past use of
mobile phone handsets. Radiat Prot Dosimetry.106(3):233-40.
3. Samkange-Zeeb F, Berg G, Blettner M. (2004) Validation of self-
reported cellular phone use.J Expo Anal Environ Epidemiol. 14(3):245-8.
4. Shum M, Kelsh M, Zhao K, Erdreich L. Comparison of recall of
mobile phone use with billing record data. Proceedings.
Bioelectromagnetics Society conference. Dublin. 2005.
Competing interests:
None declared
Competing interests: No competing interests
L. Lloyd Morgan's calculation is not valid since it assumes that the
odds ratios are stochastically independent, which they are presumably not.
But further support for the type of selection bias suggested by
Samuel Milham and L. Lloyd Morgan comes from other parts of the Interphone
study:
According to Lahkola et al. [1], participation proportions in the
Finnish part were 46% among controls and 84% among cases. Cellular phone
usage was more prevalent in participants than in incomplete participants
(those not willing to give a full personal but a brief telephone
interview). When incomplete participants were included, the odds ratio for
brain tumors and regular mobile phone use rose from 0.55 (CI: 0.39 - 0.77)
to 0.73 (CI: 0.56 - 0.96). Also mobile phone numbers were less likely
available for totally refusing controls (who even declined a telephone
interview) than for participating controls.
Similarly, results of a nonresponder questionnaire indicated a lower
proportion of cell phone users among nonresponders (but responders to the
nonresponder questionnaire) than among responders in the German Interphone
part [2].
1. Lahkola A, Salminen T, Auvinen A. Selection bias due to
differential participation in a case-control study of mobile phone use and
brain tumors. Ann Epidemiol. 2005 May;15(5):321-5.
http://www.annalsofepidemiology.org/article/PIIS1047279705000116/abstract
2. Schüz J, Böhler E, Berg G, Schlehofer B, Hettinger I, Schlaefer K,
Wahrendorf J, Kunna-Grass K, Blettner M. Cellular Phones, Cordless Phones,
and the Risks of Glioma and Meningioma (Interphone Study Group, Germany).
Am J Epidemiol. 2006 Jan 27; [Epub ahead of print]
http://aje.oxfordjournals.org/cgi/content/abstract/kwj068v1
Competing interests:
None declared
Competing interests: No competing interests
Sir
Sheldon L. Epstein perhaps accurately reflects the current scientific
position as regards ionising radiation as a causative agent in brain
cancers - although I think the study has numerous possible flaws some of
which have been highlighted by other responders.
However, I note that Sheldon was careful to mention only ionising
radiation, yet radios and radio telephones carry another probable risk
form non-ionising radaition and, having measured the continuous bursts of
high level (>100 milligauss - the limit of the measuring equipment I
was using - a Trifield Meter) electromagnetic radiation emitted by such
equipments when transmitting and receiving I suggest that this radiation
carries hazards which are, as yet, not properly described in well-quoted
research into mobile phone use by scientists or engineers who have
confined the discussion so often to ionising radiation.
The same arguments take place over mobile phone mast sites. For some
I have witnessed, and one in particular I advised on some years ago,
persons who believed they had developed adverse reactions to adjacent
mobile phone masts (eg. medically confirmed neurological for which the
specialist could offer no explanation as to cause) were informed by
engineers and scientists comissioned to investigate that ionising
radiation could not be the cause as hotspots, though identified as being
present in the building in question, were not impacting directly on the
complainant's location and originated from another mobile phone mast
located in another part of town! The mast present adjacent to the
complainant, on a roof 8 feet above head height, would however be emitting
high levels of electromagnetic radiation when in use which could impact on
the location in question and might be the cause of the neurological
problems that developed soon after the mast was installed.
Regards
John H.
Competing interests:
None declared
Competing interests: No competing interests
In years past, this paper would never have been published because
such a low participation rate of cases and controls would have, by itself,
been a cause for rejection. With only 51% of glioma victims (30% had died
by the time they were contacted) and 45% of the controls (29% refused to
participate) participating, combined with more affluent controls than
cases, there is little reason to believe any of the reported results.
Affluent participating controls are more likely to use cellphones
than the non-participating controls. Such a “selection bias” would result
in an underestimation of the risk of glioma from cellphone use. The sheer
proportion of non-participating controls makes such selection bias highly
probable.
The study would seem to suggest that using a cellphone would protect
the cellphone use from the risk of glioma. If there is no risk of glioma
from cellphone use, then there would be about the same number of odds
ratios greater than one (increased risk) as there would be odds ratios
less than one (reduced risk). Overall this study reports 34 odds ratios
greater than one to 8 odds ratios less than one. This is equivalent to
saying if I flip a coin 42 times, what is the chance that I will get 34
heads and 8 tails. Such a probability can be calculated. The probability
that cellphone use protects the user from glioma is 99.997%.
There are only two possible conclusions. Either cellphone use
protects the user from glioma, or the study is flawed. You, the reader,
must choose between these two possibilities. There is no other choice
possible.
In spite of these incredible flaws, the study did report a 60%
increased risk of glioma for regular cellphone use of 10 years or more on
the same side of the head as the location of the tumor. Hardell et al.
(Environmental Research 12 July 2005) reported for wireless phone use on
the same side of the head, the risk of high-grade astrocytoma was 4.2, 3.2
and 4.0 for analog and digital cellphone and cordless phone use,
respectively. The Hepworth et al. paper did not reference this study
(even though it was published some 4 months prior to acceptance of the
Hepworth paper.) has found similar results, though with much higher risk
of glioma.
The reference group for this study’s findings is “Never/non-regular”
cellphone users. Because this reference group did not exclude the users
of cordless (DECT) phones the reference group cannot be described as
unexposed. Hardell et al.(July 2005)reported that cordless phone users
who did not use cellphone are at risk of high-grade astrocytoma (OR=1.9,
CI; 1.01-3.5).
Finally, it is important to understand that this study, as is true
with every Interphone study, has received substantial funding from the
cellphone industry. Though the study reports that this funding “ensures
complete independence for the scientific investigators,” this is
inherently not possible. Researchers careers are dependent on receiving
research grants. Even with isolation of funding for a specific study from
the researchers themselves, the conflict-of-interest in such funding is
not resolved. Because the researchers know where the funding has come
from, the old adage, “Don’t bite the hand that feeds you” becomes the
effective psychological reality (whether conscious or unconscious).
This same conflict-of-interest issue can be seen within the United
States Government's Federal Drug Administration (FDA) where pharmaceutical
companies pay fees for drug approval isolated from specific research
projects. It is quite apparent that the FDA has come to see the
pharmaceutical industry as their customer, not the American public.
Also to note: just like the pharmaceutical industry-funded studies,
industry-funded cellphone studies will not release their protocols--so
that there is limited assurance both as to the validity of their study
procedures and the steps take to shield research from economic interests.
For example, the Interphone study protocol, a common protocol used by
13 participating countries, is kept “strictly confidential.” While there
is a process to maintain the independence of researchers from direct
cellphone industry involvement, it is unclear as to what and how the
cellphone industry was involved in the Interphone study protocol design.
Certainly, the Interphone definition of “regular” cellphone use is set to
such a minimal standard that few could imagine a finding of risk. Regular
cellphone use is defined as cellphone use for at least once a week for six
months or more, a year prior to the study cutoff date.
The important question to ask is, if this were a study of the risk of
lung cancer from smoking would there be a likelihood of finding a risk of
lung cancer from smokers who had smoked at least once a week for 6 months
or more, a year prior to the study cutoff date? And, would there be a
finding of risk, if as is the case in this study for cellphone use, the
lifetime years of smoking for 10 years or more included only 3.9% of the
smokers in the study?
Competing interests:
None declared
Competing interests: No competing interests
The study by Hepworth et al. (1) is a thoroughly planned
investigation of the potential association between glioma and mobile phone
use. It has an interesting methodological aspect in that it utilized
records of general practitioners for the selection of control subjects.
However, there are severe shortcomings of conduction, analysis and report
including faulty interpretations and unfounded conclusions. Do authors
really think that there is any occupational or environmental factor on
earth capable of inducing glioma within a period of 3 to 4 years (the
average duration of use of a mobile phone in this study)? Not even after
high doses of therapeutic x-rays (2,3) such short latencies have been
observed. There are only 5% of cases with a duration of mobile phone use
that reaches or exceeds 10 years. Therefore, it is completely out of
question that induction of glioma can be studied. Only an effect on tumour
development and growth can possibly be detected. As pointed out earlier
(4,5) the case-control design is inefficient to study such effects if
duration of exposure is short. Furthermore, if an effect on an already pre
-malignant lesion is studied only exposures to that region are exposures
at all. Therefore the only relevant analysis is that of laterality. And,
surprisingly, this analysis resulted in a significantly increased risk
that increased further if longer exposure durations were considered. Hence
the only analysis compatible with the natural history of the disease and
exposure conditions showed a significantly increased risk. But still the
authors conclude: “This…study found no increased risk of developing a
glioma associated with mobile phone use…” Authors point to the fact that
the odds-ratio for contralateral exposure is below one and seem to
interpret this as an indication for recall bias. However, they seem not to
be aware that this is simply a consequence of their method of analysis and
of the significant effect on the ipsilateral side.
1 Hepworth SJ, Schoemaker MK, Muir KR, Swerdlow AJ, van Tongeren
MJA, McKinney PA. Mobile phone use and risk of glioma in adults: case-
control study. BMJ, doi:10.1136/bmj.38720.667975.55 (published 20 January
2006)
2 Simmons NE, Laws ER Jr. Glioma occurrence after sellar
irradiation: case report and review. Neurosurgery 1998, 42:172-178.
3 Kranzinger M, Jones N, Rittinger O, Pilz P, Piotrowski WP, Manzl M
et al. Malignant glioma as a secondary malignant neoplasm after radiation
therapy for craniopharyngioma – Report of a case and review of reported
cases. Onkologie 2001; 24:66-72.
4 Kundi M. Mobile phone use and cancer. Occup Environ Med 2004;
61:560-570.
5 Kundi M, Hanson Mild K, Hardell L, Mattsson M-O. Mobile
telephones and cancer – A review of epidemiological evidence. J Toxicol
Environ Health B 2004; 7:351-384.
Competing interests:
None declared
Competing interests: No competing interests
1: Am J Epidemiol. 1988 Jan;127(1):50-4. Related Articles, Links
Increased mortality in amateur radio operators due to lymphatic and
hematopoietic malignancies.
Milham S Jr.
Epidemiology Section, Washington State Department of Social and
Health Services, Olympia 98504.
To search for potentially carcinogenic effects of electromagnetic
field exposures, the author conducted a population-based study of
mortality in US amateur radio operators. Ascertainment of Washington State
and California amateur radio operators (67,829 persons) was done through
the 1984 US Federal Communications Commission Amateur Radio Station and/or
Operator License file. A total of 2,485 deaths were located for the period
from January 1, 1979 through December 31, 1984, in a population of amateur
radio operators which accumulated 232,499 person-years at risk. The all-
cause standardized mortality ratio (SMR) was 71, but a statistically
significant increased mortality was seen for cancers of the other
lymphatic tissues (SMR = 162), a rubric which includes multiple myeloma
and non-Hodgkin's lymphomas. The all-leukemia standardized mortality ratio
was slightly, but nonsignificantly, elevated (SMR = 124). However,
mortality due to acute myeloid leukemia was significantly elevated (SMR =
176).
PMID: 3422125 [PubMed - indexed for MEDLINE]
Competing interests:
None declared
Competing interests: No competing interests
Mobile Phone use and oliodendroglioma
I read your article with interest but it has not convinced me that my
husband's tumour was not due, in some part, to his high mobile phone use.
He was 38 years old when the grade II oliodendroglioma was discovered in
his right frontal lobe, about the size of a tangerine. The tumour was on
his right side, he is right-handed. He has always put his mobile to his
right ear - he has used a mobile for about 10 years. The last five of
those years were very heavy use as he is self-employed and not fixed to a
desk. I feel that there is a real correlation in his case with mobile
phone usage but I have no way of proving this. We have no family history
of cancer - both his parents are well and his grandparents died of old
age. I am particularly concerned about the risk factors for our children
who are now at an age where mobile phones are de rigour.
Competing interests:
None declared
Competing interests: No competing interests