Occup Environ Med 2004; 61:560–570. doi: 10.1136/oem.2003.007724
users amounting to hundreds of millions of people worldwide has raised concerns aboutpossible consequences on public health if mobile phones turn out to be less safe than
previously assumed. In fact, never before in history has a device been used that exposes such agreat proportion of the population to microwaves in the near-field and at comparatively highlevels. The advantages of this technology with respect to health protection are undeniable,considering the many lives that have been saved by mobile phone calls in cases of emergency. Onthe other hand, telephoning while driving has become an important cause of accidents. However,the issue of possible long term effects such as the development of cancer is controversial. Whilethere are still not enough data to present a final risk assessment, there is evidence fromepidemiological and experimental studies that long term exposure to emissions from mobilephones may lead to a small to moderate increased risk of developing certain types of cancer. If ahigh proportion of the population is exposed, even a small additional risk could be of greatimportance to public health protection; hence measures reducing exposure may be indicated.
However, because of the undeniable scientific uncertainties, industry lobbying has beensuccessful in avoiding too strict prevention strategies.
After not more than 20 years of mobile telecommunication, the third generation of mobile phonesis already awaiting introduction onto the market (some test areas are now in operation). InEurope mobile telephony started in 1981, and in the USA in 1983. The first generation mobilephones were the so called analogue types. The signal was transmitted by frequency modulation infrequency bands around 450 MHz and 900 MHz. The mobile phones had peak power of emissionof about 8–15 W for the 450 MHz system and of about 1 W for the 900 MHz telephony. In theearly 1990s second generation mobile phone systems were started in several European countries.
This system was a digital one that used frequency bands around 900 MHz (GSM) and later1800 MHz (DCS). This technology made compression of speech possible and thereforetransmission to and from several mobile phones using the same channel could be applied. Thistype of transmission is called TDMA. Up to eight mobile phones can use the same channel fortransmission. Each is given a time slot of 577 ms (hence the term TDMA: time division multipleaccess). Within this time slot a signal of analogue duration of 4.615 ms (called a frame) istransmitted by a microwave pulse (bit coding of the digital information is accomplished byGMSK). Hence the basic pulse frequency is 217 Hz. Furthermore, the system applies powerregulation to adjust output to the quality of the signal received and it is capable of discontinuoustransmission (DTX mode), thereby reducing the number of pulses emitted from the mobile phoneif the user is silent. Peak power output of the mobile phone antenna is 2 W (900 MHz) and 1 W(1800 MHz). Different TDMA systems operate in the USA, Japan, and other countries. Digitalcordless phones apply a similar technology, and despite considerably lower power may result inaverage exposures comparable to GSM mobile phones.
All mobile phone systems use microwaves (electromagnetic fields of frequencies between
300 MHz and 300 GHz) as carrier waves. The wavelengths are about 65 cm (450 MHz), 33 cm(900 MHz), and 17 cm (1800 MHz). The wavelength is not only important for the size of theantenna necessary for transmission but also for the determination of the area of near fieldexposure. The near field is subdivided into the reactive and radiating near field. The latter is
characterised by a non-unique relation between the electric and magnetic component of the
radiation (note that in the far field the electric and magnetic field vectors are orthogonal to each
other and to the direction of propagation and are coupled by the plane-wave impedance of about
377 ohm in vacuum or air). Within the reactive near field the emission interacts with an object
depending on its dielectric properties, and complicated exposure patterns may occur. Generally in
the near field exposure conditions are more complicated and measurements without considering
the exposed object that reacts with the field will give incorrect results. The border between near
compliant. However, depending on the type of antenna and
other features, SAR varies for different brands by about 1 to10.
CT: computed tomographyGSM: global system (service) for mobile telecommunicationDCS: digital cellular system
Evaluation of carcinogenicity in humans relies on three
sources of data: epidemiological, experimental animal, and in
vitro genotoxicity data. The different evaluation schemes
differ in some aspects, especially concerning the emphasis
IARC: International Agency for Research on Cancer
that is placed on the results of animal and genotoxicity
ICNIRP: International Commission for Non-Ionising Radiation
studies. The first one widely recognised was proposed by the
International Agency for Research on Cancer (IARC), a WHO
organisation. In spite of the mentioned differences, these
NRPB: National Radiological Protection Board
schemes agree in that an agent cannot be classified as
carcinogenic for the human unless there is substantial
epidemiological evidence supporting this assumption.
By definition epidemiological evidence can only be
provided if the agent under consideration is prevalent in a
proportion of the population. Considering the prolonged
duration necessary to detect a clinically relevant disease,decades of exposure may pass by until conclusions can bedrawn. Therefore animal and in vitro studies gain impor-
and far field is approximated by the Rayleigh distance
tance, not only in supporting epidemiological findings, but
2d2/l+l/2 (where d is the size of the antenna and l the
also to assess mechanisms of action and for early indications
wavelength). Assuming l/4 type antennas we get the border
of a possible risk to humans that may suffice to take action of
at approximately two thirds of the wavelength. Hence while
risk reduction. Furthermore, epidemiological studies are
holding a mobile phone to the ear the head is within the near
often insufficient to assess dose-response relations. In order
to quantitatively characterise the carcinogenic risk and to
Exposure to electromagnetic fields in the frequency range
develop guideline levels for limiting the exposure (in cases
from about 100 kHz to 10 GHz results in absorption of part ofthe energy carried by the waves within the body. The rate ofenergy absorption depends on the field strength, thewavelength, and polarisation of the electric and magneticfields with respect to the orientation of the body, thedielectric properties of the tissues, and other features.
Within a given volume of body tissue this rate of energyabsorption is proportional to the square of the internal fieldstrength; it is denoted specific absorption rate (SAR) andexpressed in watts per kilogram. It is practically impossible tomeasure SAR in the exposed organism, hence differentprocedures are applied to estimate it. One possibility is to usephantoms that are filled with an electrolyte gel that hassimilar dielectric properties as the tissues at that frequencyand to either measure electric field strength within thephantom or temperature increase (because absorbed energyis almost completely converted into heat). Another possibilityis to solve the Maxwell equations for small adjacent volumeelements of the body consecutively and compute the resultingfield strengths. Both methods have their limitations becauseof the gross differences in tissue structure and properties.
The International Commission for Non-Ionising Radiation
Protection (ICNIRP) has issued guidelines1 for limitingexposure to electromagnetic fields. Presently they recom-mend a basic restriction for SAR localised in the head of 2 W/kg averaged over any 10 g of tissue. More strict guidelines areused in the USA where the limit is 1.6 W/kg averaged over1 g of tissue. In Great Britain NRPB has issued guidelines2that limit localised SAR at 10 W/kg.
SAR from exposure to mobile phones varies considerably
for different types and brands not only with respect to
Figure 1 Schematic diagram of the process of malignant
maximal SAR but also with respect to exposure pattern. Older
transformation and development. Processes at which interference with
analogue phones sometimes exceeded the above mentioned
endogenous or exogenous agents may occur are shown in red. The
exposure limits while second generation mobile phones are
yellow flash sign denotes changes at the DNA level.
where a ban is not feasible) dose-response data from animal
the process that leads to fixation of deviant DNA or to
experiments may serve as a surrogate.
increased proliferation of deviant cell populations. There are,
Although for most types of cancer an understanding of the
however, many open questions: Which processes occur
details of the underlying processes is still far from being
upstream of the observed activation? Is the effect a
complete, there is sufficient knowledge to crudely different-
consequence of an EMF sensitive DNA element or is it due
iate the process into several distinct stages. An important
to an acceleration of enzymatic loops? What is the role of
distinction is that between ‘‘initiation’’, ‘‘promotion’’, and
duration of exposure? Which cell types are sensitive?
‘‘progression’’; and agents acting at these stages are often
Carcinogenic risk assessment for electromagnetic fields
termed initiating, promoting, or progressor agents.
and particularly for exposure to emissions from mobile
As fig 1 indicates, there are several steps at which
phones is complicated for several reasons:
endogenous and exogenous agents can exert influence on
Except for tissue heating there is no established interac-
malignant transformation and development. Concerning
tion mechanism between internal field strength and
exposure to microwaves, although almost nothing is known
about basic interaction mechanisms, most authors assume
Hence there is no evidence based starting point for
that if microwaves affect the process at all, they act as
And epidemiological studies cannot apply an exposure
metric derived from a sound mechanistic model.
The problem can be illustrated by the following considera-
tions. Assume that the basic interaction mechanism involves
It has been argued that due to the fact that microwave energy
resonance phenomena; for example, an effect at this level
as emitted by mobile phones is far too low to cause ionisation
may occur only if certain conditions about the mass and
it cannot be genotoxic. In fact, several reviews concluded that
charge of ions in the tissue and the low frequency component
there is at most weak evidence for genotoxicity of radio-
of the incident EMF are met; it follows that intensity of the
frequency fields and microwaves.3 However, all types of
field will be of minor importance; however, duration of
exposures have been combined in these analyses. It is as if,
exposure within the effective resonance window could be
for example, all organic compounds were classified at once
decisive. On the other hand, if the periods of relevant
according to their genotoxic potential. If specific aspects of
interaction are long, regulating cellular responses may be
the incident field such as frequency and modulation are
initiated that counteract the adverse reaction. If such
decisive, a general statement about all high frequency fields
conditions apply it will be very difficult to provide a
makes no sense. Furthermore, the argument that microwave
meaningful exposure meter. An example from a very
energy is too low to directly damage DNA does not preclude
different field where similar problems arise (although likely
an effect at initiation stage. Many experimental studies have
of less complexity) is sleep disturbance by noise. In this case,
applied procedures that have been developed for the
not the average noise level but the number of noise events
assessment of chemical carcinogenicity and are probably
exceeding a certain threshold is a first approximation to the
useless for investigating electromagnetic fields.
overall adversity of the environmental condition with respect
Another and more radical argument is based on equili-
brium thermodynamics. It is stated that unless the intensity
As mentioned above there are two entwined lines of
of the internal electric field exceeds the threshold of thermal
research that should be followed: a hunt for phenomena,
noise there cannot be an effect at all. While this argument,
following both in vitro and in vivo paradigms, and the
often referred to as the kT theory, poses a challenge to future
development of theories about fundamental interaction
theories of interaction between electromagnetic fields and
mechanisms. There is some reluctance of the broader
the organism at the cellular level, it cannot be considered
scientific community to take on this task, because many
uniformly valid because otherwise we would not be able to
share the opinion that too much energy has already been
hear (signal detection by hair cells of Corti’s organ is close to
wasted in the search for low level effects of EMFs. Especially
the quantum limit to measurement and well below thermal
concerning emissions from mobile phones it is argued that
evidence rather points against an association to the develop-
While the energy of the internal EMF as such might be too
ment of cancer. However, if one takes a closer look at the
low to alter the distribution of velocities of molecules in
evidence this may throw some doubts on this opinion.
tissues precluding an effect that solely relies on energytransfer, frequency and modulation of the EMF could be of
Aspects to be considered in assessing epidemiological
biological meaning. There are several biological effects that
have been consistently observed in independent investiga-
Some preliminary considerations are necessary to put the
tions which occurred below levels that are compliant with the
evidence into perspective. Most of these aspects have been
kT theory. Among these effects, despite some negative
more or less neglected in previous reviews.
studies, are activation of heat-shock proteins,4–8 leakage
First it has to be stressed that exposure to mobile phones is
of blood-brain barrier,9–12 increased frequency of micro-
considered to act as a promoter (if it has an effect at all). If in
nuclei,13 14 and alteration of calcium homoeostasis.15–17 Also
a cohort the incidence, say of a certain brain tumour, has a
of importance is the observation that effects of low frequency
specified age distribution, a promoter acting on the indivi-
modulated high frequency fields are similar or even equal to
duals in this cohort will only exert an effect in those that bear
those of low frequency fields, suggesting a demodulating
already a growing population of deviant cells. Its effect
capacity of tissues. Another, possibly fundamental process
amounts to increasing the growth rate. This will result in an
that has been shown in vitro as well as in animal experiments
earlier clinical manifestation. Furthermore, in some indivi-
is an increase in phosphorylation of enzymes. Thus trans-
duals that would have died of competing causes of death the
forming enzymes to their active state may play a key role in
brain tumour will be diagnosed during their life span. Hence
there is: (1) a shift of the distribution of age at diagnosis to
while telephoning, to some extend misclassification of
earlier age; and (2) a (small) increase of incidence due to
exposure at the site of interest is unavoidable. Calculation
surviving competing causes of death. What would be the net
of the internal field strength at the location of development
effect on relative risk? This depends on two factors: the
of the tumour would be the method of choice; however, data
duration of the activity of the promoter, and the magnitude
collected in studies published so far were insufficient to
of the promoting effect. In the worst case the shift of age at
accomplish this. Therefore, stratification according to the
diagnosis will be almost as great as the duration of exposure
following categories with increasing probability of exposure
(note that it cannot be greater). In most epidemiological
of the relevant region of the brain would be another
studies published so far, duration of exposure to mobile
possibility: no mobile phone use, use at the contralateral
phones was less than 3–4 years in almost all subjects.
side, use on both sides, and ipsilateral use. However, in this
Considering the age distribution of incidence for brain
case another problem has to be considered. During growth of
tumours that is roughly described by a log linear increase
the tumour, symptoms like tinnitus, hearing problems, and
between 20 years and 70 years of age, a shift by, say, 3 years
headaches may occur that could result in switching side of
will have only a very small effect on relative risk estimates
the head the telephone is held or to reduction or even
like odds ratios or incidence ratios. Even neglecting sampling
cessation of use. Especially for acoustic neurinoma such
error the relative risk will be not higher than 1.15. And this is
symptoms are prevalent and often the cause to seek medical
an overestimate because for very fast growing tumours like
advice. Therefore it is important to investigate the conditions
glioblastoma, the shift cannot be noticed at all, except if
exposure is also associated with progression. This follows
Unfortunately none of the studies investigated symptoms
from the fact that the upper limit of relative risk is equal to
that may interfere with using a mobile telephone, and
exp(bn), where b is the slope of the age/log incidence
especially with switching the side of the head against
relation, and n is the shift of age at diagnosis in years. (For b
which the telephone was used during conversation. A
a value of about 0.044 reflects overall brain tumour
minimal condition, however, for analysis of such tumours
is to account for reasonable periods of latency. At least the
Another aspect that has been neglected so far is related to
last year before diagnosis should be disregarded in the
the fact that brain tumours, the endpoint most often studied,
comprise a heterogeneous class of tumours of benign as well
as malignant type, with different cellular origin, clinical
Overall nine epidemiological studies of mobile phone use and
features, and prognosis. WHO stratifies them into four types
cancer have been published so far, four in the USA,20–24 two in
according to their malignancy. Glioblastomas belong to the
Sweden,25 26 and one each in Germany,27 Finland,28 and
type with highest malignancy. Up to now no environmental
Denmark.29 Most of these studies investigated brain tumours,
or occupational factor has been consistently associated with
one studied uveal melanoma, one additionally included
glioblastoma. Only little is known about induction period of
salivary gland cancer, and another malignancies of the
this tumour, however, duration between first clinical signs
haematopoietic and lymphatic tissues. Additionally a small
and diagnosis (or death) is weeks to at most months. Hence
case-control study30 of 18 intratemporal facial nerve tumour
it is impossible to detect an effect on growth rate in this type
cases has been published. Seven studies were case-control,
of tumour applying traditional case-control or cohort
two were cohort studies. Looking superficially at the results
approaches. Therefore the predominance of glioblastomas in
of these investigations one may conclude that there is
some of the investigations about the association between
evidence for the lack of an association with mobile phone
cellular telephone use and brain tumours results in a risk
use. Four of these nine studies found evidence for an
attenuating effect. Furthermore, because only for lower grade
increased risk, while five failed to find such an effect. Does
brain tumours can an effect possibly be detected in these
this indicate lack of an association? To evaluate epidemiolo-
studies, power is greatly overestimated if all types of tumours
gical findings it is important to base the assessment on
are combined. As long as exposure duration is as short as in
criteria that are related to study methodology and to the
the majority of case-control studies published so far, the
endpoint studied. Furthermore, specific considerations that
small relative risk of 1.15 that might be present would afford
apply to the respective field of study (see above) have to be
a sample size of more than 7000 cases and controls, to have a
power of 80% to detect it. If only lower grade tumours are
Tables 1 and 2 present an overview of the studies published
included, besides the effect of leaving out cases that cannot
so far, including evaluation of the most important criteria for
be affected by exposure, this has the advantage that the age/
studies investigating risk of mobile phone use. As mentioned
log incidence function is steeper and therefore the potential
above all studies have some deficiencies. Most important is
the lack of a proper exposure assessment and the too short
Of great importance is the localised nature of exposure
duration of use of a mobile phone in most of the studies.
when using a mobile telephone. In all investigations that
Concerning exposure, all except one of the case-control
included this aspect a great proportion of subjects used the
studies28 obtained information on mobile phone use by
phone predominantly on one side of the head only. In this
interviews. However, as mentioned above, there is great
case the contralateral side remains virtually unexposed.
variation between different types of phones and also
Because we are not dealing with initiation of tumours but
variability in individual habits of use that greatly influence
with effects on tumour growth, only exposures at the same
exposure. Note that due to the lack of an accepted and
side of the head as the tumour is located can have an effect.
experimentally corroborated theory of action of microwaves it
This precondition further reduces the number of evaluable
is impossible to decide whether number of calls, duration of
tumours to those that grow in a potentially irradiated area.
calls, or some other surrogate of exposure is important (see
Because this depends on type of phone and the position used
table 3). Assessment of mobile phone use in the two cohort
Table 1 Synopsis of epidemiological studies attributed as ‘‘negative’’ with respect to a possible association between mobilephone use and cancer
1–14 y of follow up. 20% users in cases,
increased (SIR 1.12). 2.2 y in controls.
No overall increased Tendency for greater
tumours andleukaemia for longestduration of use
Assessment oflaterality not possible.
Healthy group effect
*In addition to age and gender.
ÀBased on the assumption of a relative risk of 2.
Table 2 Synopsis of epidemiological studies attributed as ‘‘positive’’ with respect to a possible association between mobilephone use and cancer
population controls; 148hospital controls
digital and 28% cordless phones(combinations not specified)
Duration of follow up/ 37% users in cases, of these
Only prevalent cases. Response Only prevalent cases.
Confounding and bias Recall bias possible
1, 5, and 10 y (1–6, 6 y formalignant tumours)
*In addition to age and gender.
ÀBased on the assumption of a relative risk of 2.
studies, one from the USA20 21 and one from Denmark,29 was
recommended to carry a mobile phone for placing a call in
also insufficient and based solely on subscription records. In
case of emergency one would introduce a bias concerning
the Danish study, duration of use was obtained only for 57%
mobile phone use. It is important to note that all case-control
of the cohort and no data on intensity of use were available.
studies that found an effect of mobile phone use were
In all except three studies25–27 duration of mobile phone use
population based studies, while all such studies that were
was less than 5 years in the vast majority of cases, hence
negative were hospital based. There is no straightforward
these studies did not even come close to latencies that are
explanation for this discrepancy because there were a
meaningful in cancer research even if effects of promoters are
number of other differences that could have contributed.
However, one aspect could be the higher proportion of high
Concerning selection of study participants, the two cohort
grade tumours in hospital based studies. As mentioned above
studies20 21 29 and one case-control study28 neglected corporate
inclusion of these tumours attenuate risk estimates because
users, which are likely to be the heaviest users and those with
they cannot be affected by an exposure of such short duration
the longest duration of use. Although it is convenient to use
hospital controls in case-control studies, one has to consider
Concerning power to detect a moderately increased risk,
carefully whether control patients can be considered stem-
most studies were deficient because they had too low
ming from the same population as the cases obtained. For
numbers of relevant cases. Firstly, the proportion of cases
example, including patients with heart disease for which it is
and controls using a mobile phone was low in most studies;
Table 3 Weight-of-evidence criteria for mobile phone use and cancer and gaps in knowledge
Nine studies published, five negative and four positive. Eight studies
What stage of carcinogenesis is ‘‘sensitive’’ to exposure?
focusing on brain tumours, one about intraocular melanoma, and
Which aspect of exposure is important? Is there an
one additionally investigating salivary gland cancer and one
increased risk if exposure starts early in age (in childhood
haematopoietic cancers. Studies are lacking good quality data on
or adolescence), maybe due to exposure of bone marrow
exposure and have overall too short duration of mobile phone use.
Studies approaching reasonable latencies show moderately increased
Is there a lower limit for duration of use below which there
tumour risk. Relative risks (excluding studies with too short latencies)
is no increased risk? For which types of cancer (and
overall 1.3 to 4.6, increased risk with increasing latency, highest
benign tumours) is there a particularly high risk?
overall risk for acoustic neuroma (3.5) and uveal melanoma (4.2).
Significantly increased risk for ipsilateral use overall and for malignantbrain tumours.
Three brain tumour studies show consistently an association to mobile
Is there a method, feasible for epidemiological studies, that
phone use. Inconsistency may be due to insufficient latency and other
could effectively reduce possible response bias?
Little evidence for an association between intensity of use and risk to
Is there a meaningful exposure meter measuring the
develop brain tumours (for intraocular melanoma only heavy
‘‘dose’’ of exposure to emissions from mobile phones (note
occupational use was investigated), however, some evidence for an
that SAR as a rate cannot be used without further
association between duration (years) of use and risk.
consideration, it is not known whether one month exposureto, say, one W/kg is equivalent to 10 months exposure to0.1 W/kg, a.s.o.)?
Few long term animal studies, three on GSM type signals and three
What is a suitable exposure regimen in long term animal
on mobile phone standards used in the USA or Japan. Several short
studies? Which endpoints are sensitive to exposure? What
and medium term animal studies. In vitro genotoxicity studies of mobile are the crucial processes in the exposed cells? How is thephone frequencies cover different endpoints. Quality of the studies is
time course of reactions within cells? Are mechanisms
fair to good, however, their appropriateness cannot be assessed
invoked, depending on duration of exposure, that
without knowledge of the mechanism of action.
One long term animal study found significantly increased cancer
Is there a relation between duration of exposure and
genotoxicity or epigenetic rates. Several independent studies found increased micronuclei
effect? Are there differences between continuous and
frequencies and some other indications of interference at the genome
intermittent exposure? Is there a combination effect with
level. Furthermore, there is some evidence of activation of heat-shock
proteins that may have an impact on cell cycle control and apoptosis.
Consistency of laboratory Long term animal studies differ in essential features of experimental
What is the mechanism of action over the whole range of
methodology. Four long term animal studies found indications of an
exposures? Is there a change of essential features of the
effect of exposure, however: three a reduced and one an increased
mechanism at the transition between relevant temperature
risk. Such indications of hormetic effects at low doses are abundant in
cancer research. Overall consistency cannot be evaluated at presentdue to unknown mechanism of action and lack of exact replicationstudies.
Energy of the field too low to cause ionisation and signal to noise
Are there resonance like phenomena? Are there coherent
ratio too low to speculate about an effect relying on equilibrium
excitations at the cell membrane that could be responsible
thermodynamics. Other potential interaction mechanisms not
for a signal cascade? What is the role of gap junctions
between cells? Are there non-linear elements in tissuepropagation of the EMF that could act as demodulators? Isthe carrier frequency of the EMF important or is only thelow frequency modulation effective?
Some evidence of a carcinogenic effect from epidemiological studies
What is the mechanism of action? Which aspect of
weakly supported by long term animal experiments and in vitro
exposure is responsible? What is a suitable exposure
secondly, the number of subjects that accrued a relevant
x rays for meningioma. Confounding by therapeutic x rays
number of years of use was smaller still. The number of
has been considered in one investigation.25 Concerning uveal
subjects available to assess laterality (that is, the most
melanoma, an endpoint studied in the German investiga-
important aspect of analysis that relates side of predominant
tion,27 except age and gender, socioeconomic status, hair and
use of a mobile phone to the location of the tumour) was
eye colour have been analysed. There was some criticism that
negligibly small in most studies, especially if latency is
confounding by UV exposure has not been considered.
Indeed, UV exposure is potentially related to the risk of
Confounding has been considered in most studies.
intraocular melanoma; however, it is less reasonable that UV
Concerning brain tumours the most important confounders
exposure should be correlated to mobile phone use. Anyway,
are age and gender. Age and gender are indeed potential
inclusion of UV exposure as a possible confounding variable
confounders as they fulfil the necessary condition for
would have improved credibility of results of this study.
confounding—that is, they show a correlation to both, the
Obvious sources of bias have been avoided in most studies;
outcome and the exposure. Due to yet unknown factors brain
however, both in positive as well as negative studies there are
tumours have characteristic age distributions and most have
some conditions that may have biased results. In one
pronounced sex differences. Mobile phone use is more
positive28 and two negative studies20 21 29 corporate users of
prevalent in younger age groups and in males (however,
mobile phones have been excluded. Observer bias may have
due to the steep increase in mobile phone use with rates of
been present in several negative studies where interviews
use in excess of 75% in many countries these differences
have been conducted by personnel not blinded to case
prevailing in the published studies have almost vanished by
status.22–24 Recall bias may have shifted results towards a zero
now). Until now no other factor has unequivocally been
hypothesis in studies of brain tumours where interviews with
related to brain tumours with the exception of therapeutic
cases were done shortly after surgery.22 23 Response bias has
also been implied to affect results of two Swedish case-
cell population exposure can have no effect whatever the
control studies25 26 that found a significant relation between
intensity of internal field strength, the problem of assigning
side of the head of predominant mobile phone use and
controls an appropriate exposure meter points to the
location of the tumour. This points to a dilemma present in
inadequacy of the classical case-control approach. However,
many epidemiological investigations: important factors have
these weighted SAR values can be used as a predictor
to be assessed by questioning subjects that may, voluntarily
for tumour growth, the essential endpoint for internal
or involuntarily, give incorrect answers. The predominant
side of use of a mobile phone can hardly be independentlycorroborated by other evidence. Unlike intensity of use that
may be checked against provider records, no such confirma-
If epidemiological evidence is equivocal or there are inherent
tion is available for side of use. Proxy interviews will rather
methodological problems, long term animal experiments may
aggravate the problem, because even close relatives will have
provide support for or against the hypothesis of a carcino-
problems to recall this habit of use. Although a response bias
genic effect of an agent. Concerning high frequency EMFs,
cannot be completely dismissed, a close inspection of study
however, standard experimental procedures as routinely
conduct makes an impact on results unlikely. Questioning of
applied in chemical carcinogenicity studies are inappropriate.
subjects did not focus on mobile phone use but extended over
Typically such studies are conducted in small laboratory
a number of different topics such as occupational use of
animals such as mice and rats that receive doses just below
chemicals, x ray exposure, and light drinks; furthermore, at
levels of acute toxicity and (geometrically) declining doses
the time the study was conducted there was almost no public
approaching levels that may occur in human exposures.
discussion about a possible link between mobile phone use
Concerning EMFs the highest ‘‘doses’’ applicable are at levels
and cancer, and hence no conceivable tendency of subjects to
that are at the upper range occurring in humans—that is, at
blame the phone as a cause of their disease. In the second of
levels that cannot carry a very high risk (otherwise there
these studies26 only two of more than 1300 brain tumour
would be no controversy). To start at such low levels is
patients stated that they are thinking about mobile phone use
necessary to avoid interference with tissue heating (and
as a possible cause of their disease.
sensing of the presence of the field by the animals). If an
Statistical evaluation was done by standard methods in
increase of incidence of at most two- to three-fold is
most of the studies. Three US studies22–24 applied methods to
expected, this poses a number of problems to study design.
analyse laterality which neglected control subjects, thereby
Although spontaneous tumour rates are often surprisingly
losing control over confounders, and were therefore in-
high in inbred rodent strains (such as Fisher 344 rats), the
incidence of specific types of tumours (for example, brain
Summarising the compiled evidence from epidemiological
tumours) may be as low as 1% in a typical two year bioassay.
investigations it can be stated that all studies that
Hence in order to detect an increase to, say, 2%, at a
approached reasonable latencies25–27 found an increased risk
significance level of 0.05 with a probability of 90%, about
associated with mobile phone use. The most recent Swedish
3000 animals must be tested in each group. This is obviously
study26 even matched the criterion that both an overall
hardly feasible. Therefore, methods have to be applied that
increase of risk and a consistent laterality effect should be
guarantee increased spontaneous rates of the tumour in
observed. All positive studies found strong indications of an
increase of risk with increased duration of use and an
Essentially there are three methods that can be applied:
increase with longer latencies. On the other side, all negative
Using a strain that has an increased spontaneous cancer rate
studies have insufficient latencies and can detect an effect on
(for example, because of an oncogenic virus or gene
neither induction nor on promotion stage with reasonable
manipulation), using a known carcinogen to increase
power and hence cannot contribute to the assessment of
induction of cancer (for example, application of nitrosourea
evidence. While this does not prove an association between
or benzo(a)pyrene), or implantation of tumour cells. The first
mobile phone use and cancer, it suffices to increase the
study31 of low level long term exposure in experimental
efforts to clarify the issue by a concerted multinational
animals was conducted between 1980 and 1982. Concerning
mobile communication frequencies, so far three long termanimal experiments with exposures to GSM like signals have
Recommendations for future epidemiological studies
been conducted;32–34 additionally two short term experiments
Future epidemiological studies should put emphasis on the
have been published.35 36 Other types of mobile telecommu-
history of the disease. These data should be utilised for an
nication signals that are applied in the USA and Japan have
internal comparison of estimates of tumour growth rate as
been studied in four long term37–40 and two medium term
well as for censoring of mobile phone use. This would avoid a
animal assays.41 42 Results of these experiments are not easily
bias due to interference of the disease with mobile phone use.
summarised because of gross differences in methodology and
It should further be noted that as long as comparably short
exposure conditions. Exposure duration ranged from two
periods of use are prevailing, incidence ratios will greatly
times for half an hour per day, to 24 hours per day, or 4–7
underestimate a potential promoter effect if high grade brain
days a week; some experiments exposed animals in the far
tumours are included. An explorative analysis of different
field, and some in the near field; and specific absorption rate
exposure meters is mandatory because we have no reason to
in exposed animals ranged from about 0.04 to about 4 W/kg.
a priori prefer one over the other. If possible, SAR at the
Depending on the type of tumour studied and the model used
location of the tumour, given the anthropometric character-
(chemical induction, cell implantation, habitually increased
istics of the user’s head and the data about predominant
cancer incidence) different aspects of exposure may be crucial
mobile phone use, should be computed. These data may be
for the probability to detect an effect. Because we do not
weighted by intensity and duration of use. Because, presum-
know at which stage of carcinogenesis, if at all, exposure
ing a promotional effect, in control subjects without a deviant
exerts an effect, and due to the lack of a sound theory of
interaction at low levels of exposure, the small number of
to increase quantity and quality of scientific investigations.
animal carcinogenicity experiments cannot substantially
There seems to be a tendency for large scale studies,
experimenta crucis, designed to settle the controversy once
If we consider results of in vitro studies, duration of
and for all. However, the lack of theoretical understanding of
exposure could be important. It has been assumed that
the basic interaction mechanisms makes such a strategy
microwaves may act as promoters and therefore it has been
hopelessly inadequate. On the other hand, epidemiological
hypothesised that longer duration of exposure may be more
studies must be large enough to detect a moderately
effective. However, it has been shown by in vitro experiments
increased risk. This may imply a multinational approach
that some effects are transient or are stronger in intermittent
such as supervised by WHO in the Interphone project to study
exposures, and therefore it seems reasonable to assume that
brain tumours. Due to the vast increase in the proportion of
at longer exposure duration defence mechanisms are invoked
the population using a mobile phone it has become difficult if
that counteract the damage or changes induced by the
not impossible to define an unexposed cohort, and case-
exposure. Indications of such effects are found in several
control studies would face the same problem that almost all
experiments where exposed animals had lower cancer
subjects have used a mobile phone. Hence exposure has to be
quantified. But how should this be done without knowledge
Another crucial feature seems to be the time course of the
about the mechanism of interaction? While age at first
disease. If tumours appear fast or survival declines rapidly, no
exposure and years of exposure could be chosen as likely
effect of exposure has been detected. This points to an
important beforehand without reference to a mechanistic
indirect mechanism of action, maybe by an influence of
model, intensity of exposure cannot be defined. It is equally
exposure on cell cycle control and apoptosis. The only long
likely that total hours of use of a mobile phone, total number
term experiment that resulted in a significant increase of
of calls, duration of exposure above some threshold level,
cancer incidence was in a strain of transgenic animals with
duration of use within a certain window of time, or some
an increased spontaneous lymphoma rate that were exposed
other aspects are important. Innovative strategies to the
for only two times for half an hour per day, seven days a
definition of an exposure metameter are warranted, that may
week, during up to 18 months.32 In this animal model
even guide theoreticians to narrow down interaction
lymphoma appear slowly (at about 10 months of age), and
mechanisms that could be responsible. The same difficulties
during the following 10 months about 20% develop lym-
are apparent in long term animal experiments. There are too
phoma spontaneously. This rate was about doubled in
many parameters of exposure that must be varied and it is
exposed animals. Another experiment34 in the same strain
therefore premature to hope for a decision in the near future.
of mice applied a different experimental strategy: animals
At least the following variables must be considered: duration
were immobilised in tubes during exposure (a procedure that
of exposure, intensity of the field, near versus far field
has previously been shown to increase cancer incidence) and
exposure, continuous versus intermittent exposure, time of
exposure was only once a day for one hour, five days a week.
day of exposure, carrier frequency of the field (scaled or
In this experiment a reduction of lymphoma rate was found
unscaled; note that absorption pattern differs considerably
and the spontaneous rate was greatly enhanced, pointing to
between humans and experimental animals—we do not
the presence of nuisance factors. Hence the controversy about
know whether the frequency of the carrier wave is important
possible long term effects of exposure to mobile phone
at all, maybe only the pattern of absorption and the related
frequencies cannot be settled by available evidence from
distribution of internal field strength counts), and varying or
constant exposure pattern. If all these variables are con-
sidered the investigation would have several hundred
Mobile phones when operating close to the head of the user
independent experimental conditions. This is clearly not
result in comparably high levels of exposure to microwaves in
feasible. Therefore, innovations in design and execution of
the near field. Never before in history have such high
experiments must be introduced, starting from the scarce
exposures occurred on a regular basis in such a great
data basis available and proceeding from in vitro and short
proportion of the population. Consequently there is concern
term studies to long term experiments. Rather than waiting
that exposure may lead to long term adverse health effects
for the decisive experiments, groups of research projects with
and in particular to an increase in cancer incidence. The
specific aims should be defined that could lend support to
controversy about long term health effects from exposure to
each other without affording simple replication that is not
high frequency electromagnetic fields can only be settled by
very meritable in science. An example of such a research
both independently corroborated empirical evidence and a
strategy can be found in the study of activation of heat-shock
sound mechanistic model of basic interaction mechanisms at
proteins by microwaves that has been shown by in vitro
low intensities of the exposure. Although there is evidence
studies as well as animal experiments in different species. By
from independent epidemiological studies pointing to a
such a strategy it can be hoped that the controversy about
moderately increased cancer risk for subjects using a mobile
long term health effects of high frequency EMF exposure
phone for several years, there remains always the possibility
now lasting for at least 50 years can be settled without
of bias and confounding unless there is supporting evidence
another 50 years to come. In the meantime some precau-
from animal and in vitro studies as well as a mechanistic
tionary measures may be appropriate. Because epidemiologi-
explanation. While it is epistemologically invalid to dismiss
cal studies approaching meaningful latencies found evidence
findings because of a mere potential of bias and confounding
for an increased cancer risk and because there is corroborat-
(because there is no finite sequence of tests to disprove this
ing evidence from at least one long term animal experiment
assumption), the evidence is not yet strong enough to
and from other experimental in vitro and in vivo studies, the
convince the greater scientific community and regulating
fundamental pessimism of environmental hygiene forces the
authorities to take immediate action. Rather a case is opened
recommendation of caution and introduction of protective
measures that are easily implemented. Among these are
24 Muscat JE, Malkin MG, Shore RG, et al. Handheld cellular telephones and the
risk of acoustic neuroma. Neurology 2002;58:1304–6.
discouraging use of mobile phones in children and adoles-
25 Hardell L, Na¨sman A˚, Pa˚hlson A, et al. Use of cellular telephones and the risk
cents,43 recommending head sets, advising on reduction of
for brain tumors: a case-control study. Int J Oncol 1999;15:113–16.
c First epidemiologic study of brain tumours and mobile phone use.
length of calls and number of calls, and encouraging manu-
Reported an increased risk of brain tumours on the same side of the
facturers to design and market low emission phones (for
head as the mobile phone was predominantly used detailed in two
subsequent publications: Hardell L, Nasman A˚, Pa˚hlson A, Hallquist A.
example, with antennas transmitting away from the head).
Case-control study on radiology work, medical X-ray investigations,
and use of cellular telephones as risk factors for brain tumors.
MedGenMed 4 May 1999; and Hardell L, Mild KH, Pa˚hlson A, Hallquist
A. Ionizing radiation, cellular telephones and the risk for brain
1 International Commission on Non-Ionizing Radiation Protection (ICNIRP).
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Guidelines for limiting exposure to time-varying electric, magnetic, and
26 Hardell L, Hallquist A, Hansson Mild K, et al. Cellular and cordless telephones
electromagnetic fields (up to 300 GHz). Health Phys 1998;74:494–522.
and the risk for brain tumours. Eur J Cancer Prev 2002;11:377–86.
27 Stang A, Anastassiou G, Ahrens W, et al. The possible role of radiofrequency
c Basic guidelines paper by ICNIRP, a non-governmental organisation
consisting of about a dozen experts. Basis of these guidelines are
radiation in the development of uveal melanoma. Epidemiology
immediate effects such as tissue heating.
2 National Radiological Protection Board. 1999. Advisory Group on Non-
28 Auvinen A, Hietanen M, Luukonen R, et al. Brain tumors and salivary gland
ionising Radiation. Available at: www.nrpb.org.uk/Advice/Nir-is4.htm.
cancers among cellular telephone users. Epidemiology 2002;13:356–9.
3 Verschaeve L, Maes A. Genetic, carcinogenic and teratogenic effects of
29 Johansen C, Boice J, McLaughlin JK, et al. Cellular telephones and cancer—a
radiofrequency fields. Mutat Res 1998;410:141–65.
nationwide cohort study in Denmark. J Natl Cancer Inst 2001;93:203–7.
30 Warren HG, Prevatt AA, Daly KA, et al. Cellular telephone use and risk of
c Comprehensive review of in vitro and in vivo studies emphasising the
need to clarify the issue and pointing to the gaps in knowledge.
intratemporal facial nerve tumor. Laryngoscope 2003;113:663–7.
4 de Pomerai D, Daniells C, David H, et al. Non-thermal heat shock response to
31 Chou C-K, Guy AW, Kunz LI, et al. Long-term, low-level microwave
microwaves. Nature 2000;405:417–18.
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c First long term animal study of weak high frequency EMFs ever
c First of a series of ingenious experiments using a transgenic nematode
and showing activation of heat-shock proteins at non-thermal levels of
conducted. About three times more malignancies found in exposed as
5 Kwee S, Raskmark P, Velizarov S. Changes in cellular proteins due to
32 Repacholi MH, Basten A, Gebski V, et al. Lymphomas in Em-Pim1 transgenic
environmental non-ionizing radiation 1. Heatshock proteins. Electro-
mice exposed to pulsed 900 MHz electromagnetic fields. Radiat Res
Leszczynski D, Joenva¨a¨ra¨ S, Reivinen J, et al. Non-thermal activation of the
First long term animal study on exposure to GSM type mobile phone
hsp27/p38MAPK stress pathway by mobile phone radiation in human
signals. Significant increase of lymphoma incidence in exposed mice.
endothelial cells: molecular mechanisms for cancer- and blood-brain barrier-
33 Bartsch H, Bartsch C, Seebald E, et al. Chronic exposure to a GSM-like signal
related effects. Differentiation 2002;70:120–9.
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c In vitro study of responses of human endothelial cells to weak GSM
microwave radiation showing a vast but transient increase in
phosphorylation of a multitude of proteins in exposed cells and
34 Utteridge TD, Gebski V, Finnie JW, et al. Long-term exposure of Em-Pim1
activation of stress response pathways.
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7 Shallom JM, DiCarlo A, Ko D, et al. Microwave exposure induces hsp70 and
incidence. Radiat Res 2002;158:357–64.
confers protection against hypoxia in chick embryos. J Cell Biochem
35 Chagnaud JL, Moreau JM, Veyret B. No effect of short-term exposure to GSM-
modulated low-power microwaves on benzo(a)pyrene-induced tumours in rat.
Weisbrot D, Lin H, Ye L, et al. Effects of mobile phone radiation on
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microwave exposure in Drosophila salivary gland cells.
37 Higashikubo R, Culbreth VO, Spitz DR, et al. Radiofrequency electromagnetic
fields have no effect on the in vivo proliferation of the 9L brain tumor. Radiat
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increase the permeability to sucrose of the blood-brain barrier in vitro.
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change calcium efflux rates from synaptosomes. Bioelectromagnetics
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18 Adey WR. Bioeffects of mobile communication fields; possible mechanisms of
and a possible health hazard it recommends precaution.
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c Overview of proposed mechanisms concerning effects of
radiofrequency and microwave fields putting the various research
(1) Exposure to high frequency EMFs in the range of
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Results in absorption of part of the energy of the EMF
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telephone customers. Epidemiology 1996;7:303–5.
Produces, depending on intensity, an increase of
21 Dreyer NA, Loughlin JE, Rothman KJ. Cause-specific mortality in cellular
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temperature of part of the body or the whole body.
Has sufficient energy to break chemical bonds.
22 Muscat JE, Malkin MG, Thompson S, et al. Handheld cellular telephone use
Is more complicated to assess if the source is far
and risk of brain cancer. JAMA 2000;284:3001–7.
23 Inskip PD, Tarone RE, Hatch EE, et al. Cellular-telephone use and brain
tumors. N Engl J Med 2001;344:79–86.
Has considerably decreased in the past decades.
(2) Determine whether the following statements are true or
Is superfluous because these exposures are not
Epidemiological studies are essential in determining
Is difficult because of the long latency of cancer.
whether an agent is carcinogenic in humans.
(4) Epidemiological studies of mobile phone use:
Long term animal experiments would not be used in
Indicated that there is no increased risk of cancer in
this assessment, even if epidemiological findings are
Were predominantly about tumours localised in the
Experimental studies in animals should only use
exposure intensities of EMFs as high as tolerable.
Applied the most stringent methodologies available.
Exposure of isolated cells or tissues can be used to
Indicated an increased risk in long term users.
assess basic interaction mechanisms between EMFs
Were mostly based on accurate calculations of exposure.
(5) If exposure to microwaves emitted by mobile phones is
Dose-response relations cannot be determined in
associated with a promoter effect, what will be the effect on
(3) Assessment of carcinogenic risk of high frequency EMFs
It will increase relative risk especially if exposure
Has been thoroughly performed prior to marketing of
Relative risk will increase if incidence is similar in all
these products to ensure the public that these
Relative risk will not or only slightly increase if
Unequivocally resulted in the overall conclusion that
the weight of evidence points against an existing
Because relative risk is an estimate of the incidence
ratio it will increase proportional to the increase in
Is difficult due to the lack of an accepted mechanism
of action of these exposures in the low intensity
Relative risk will show no dependency on intensity of
The Electronic Commerce Act, 2000 was introduced to ensure that consumers and businesses could engage in e-commerce easily and securely. Outline the main provisions of the act and critically analyse its objective. The Electronic commerce act has two simple functions: 1) To provide for the legal recognition of Electronic contracts 2) To implement the EU directive on electronic signatu
Deciphering the Drug Rules As we look forward to the 2011 competition season in Ontario, one that will have beautiful weather with no torrential rain or excessive humidity, it is a good time to have another look at the Equine Canada medication rules for our horses. This is not an article that provides everything you need to know in order to avoid a positive test but it does address some freque