Nombre_________________________________________ Grupo_________a) ¿Cuáles son los 4 tipos principales de moléculas biológicas mencionadas en clase? Cite unafunción importante de cada tipo de molécula biológica celular. b) Responda brevemente las siguientes preguntas:I)¿Cuáles son las 2 diferencias principales entre las células procariotas y eucariotas?II) ¿En qué se diferencian los
Innenraumanalytik.atOccup Environ Med 2004; 61:560–570. doi: 10.1136/oem.2003.007724 Thecontinuedsuccessofmobiletelecommunicationproducingastillgrowingpopulationof 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 misclassification.
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).
tumours. Eur J Cancer Prev 2001;10:523–9.
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.
irradiation of rats. Bioelectromagnetics 1992;13:469–96.
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.
(mobile phone) does not stimulate the development of DMBA-inducedmammary tumors in rats: results of three consecutive studies. Radiat Res 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.
transgenic mice to 898.4 MHz microwaves does not increase lymphoma 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 reproduction and development in Drosophila melanogaster. J Cell Biochem Salford LG, Brun A, Persson BRR. Brain tumour development in rats exposed to electromagnetic fields used in wireless cellular communication. Wireless c Shows rapid induction of hsp70 at non-thermal levels of intermittent 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 9 Frey AH, Feld SR, Frey B. Neural function and behavior: defining the relationship. Ann N Y Acad Sci 1975;247:433–9.
38 Adey WR, Byus CV, Cain CD, et al. Spontaneous and nitrosourea-induced c First experimental evidence of blood-brain barrier permeability in rats primary tumors of the central nervous system in Fischer 344 rats chronically exposed to 836 MHz modulated microwaves. Radiat Res 10 Oscar KJ, Hawkins TD. Microwave alteration of the blood-brain barrier system of rats. Brain Res 1977;126:281–93.
39 Adey WR, Byus CV, Cain CD, et al. Spontaneous and nitrosourea-induced 11 Persson BRR, Salford LG, Brun A, et al. Blood brain barrier permeability in primary tumors of the central nervous system in Fischer 344 rats exposed to rats exposed to electromagnetic fields used in wireless communication.
frequency-modulated microwave fields. Cancer Res 2000;60:1857–63.
40 Zook BC, Simmens SJ. The effect of 860 MHz radiofrequency radiation on the 12 Schirmacher A, Winters S, Fischer S, et al. Electromagnetic fields (1.8 GHz) induction and promotion of brain tumors and other neoplasms in rats. Radat increase the permeability to sucrose of the blood-brain barrier in vitro.
41 Imaida K, Taki M, Watanabe S, et al. The 1.5 GHz electromagnetic near-field 13 Garaj-Vrhovac V, Fusic A, Horvat D. The correlation between the frequency of used for cellular phones does not promote rat liver carcinogenesis in a micronuclei and specific aberrations in human lymphocytes exposed to medium-term liver bioassay. Jpn J Cancer Res 1998;89:995–1002.
microwave radiation in vitro. Mutat Res 1992;281:181–6.
42 Imaida K, Taki M, Yamaguchi T, et al. Lack of promoting effects of the 14 Haider T, Knasmueller S, Kundi M, et al. Clastogenetic effects of electromagnetic near-field used for cellular phones (929.2 MHz) on rat liver radiofrequency radiations on chromosomes of Tradescantia. Mutat Res carcinogenesis in a medium-term liver bioassay. Carcinogenesis 15 Bawin SM, Kaczmarek LK, Adey WR. Effects of modulated VHF fields on the 43 Independent Expert Group on Mobile Phones (IEGMP). Mobile phones and central nervous system. Ann N Y Acad Sci 1975;247:74–80.
health. Chilton, Didcot, UK, National Radiological Protection Board, 2000 16 Blackman CF, Elder JA, Weil CM, et al. Induction of calcium ion efflux from brain tissue by radio frequency radiation: effects of modulation frequency and c Referred to as the Stewart report (Sir William chaired the expert field strength. Radio Sci 1979;14:93–8.
group). A broad and informative report about technical, scientific, and 17 Lin-Liu S, Adey WR. Low frequency amplitude-modulated microwave fields health issues of mobile phones. While there may be some criticism change calcium efflux rates from synaptosomes. Bioelectromagnetics concerning details of the report it must be emphasised that it applies a cautious strategy throughout, and where there are gaps in knowledge 18 Adey WR. Bioeffects of mobile communication fields; possible mechanisms of and a possible health hazard it recommends precaution.
cumulative dose. In: Kuster N, Balzano Q, Lin J, eds. Mobile communicationsafety. New York: Chapman and Hall, 1997:103–39.
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 19 Wrensch M, Minn Y, Chew T, et al. Epidemiology of primary brain tumors: current concepts and review of literature. Neuro-Oncology 2002;4:278–99.
Results in absorption of part of the energy of the EMF 20 Rothman KJ, Loughlin JE, Funch DP, et al. Overall mortality of cellular 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 telephone users. JAMA 1999;282:1814–16.
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
Articles Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data Lisa M Askie, Lelia Duley, David J Henderson-Smart, Lesley A Stewart, on behalf of the PARIS Collaborative Group* Background Pre-eclampsia is a major cause of mortality and morbidity during pregnancy and childbirth. Antiplatelet Lancet 2007; 369: 1791–98 agents, especiall