Cancer and non-cancer brain and eye effects of chronic low-dose ionizing radiation exposure
© Picano et al.; licensee BioMed Central Ltd. 2012
Received: 2 January 2012
Accepted: 27 April 2012
Published: 27 April 2012
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© Picano et al.; licensee BioMed Central Ltd. 2012
Received: 2 January 2012
Accepted: 27 April 2012
Published: 27 April 2012
According to a fundamental law of radiobiology (“Law of Bergonié and Tribondeau”, 1906), the brain is a paradigm of a highly differentiated organ with low mitotic activity, and is thus radio-resistant. This assumption has been challenged by recent evidence discussed in the present review.
Ionizing radiation is an established environmental cause of brain cancer. Although direct evidence is lacking in contemporary fluoroscopy due to obvious sample size limitation, limited follow-up time and lack of focused research, anecdotal reports of clusters have appeared in the literature, raising the suspicion that brain cancer may be a professional disease of interventional cardiologists. In addition, although terminally differentiated neurons have reduced or mild proliferative capacity, and are therefore not regarded as critical radiation targets, adult neurogenesis occurs in the dentate gyrus of the hippocampus and the olfactory bulb, and is important for mood, learning/memory and normal olfactory function, whose impairment is a recognized early biomarker of neurodegenerative diseases. The head doses involved in radiotherapy are high, usually above 2 Sv, whereas the low-dose range of professional exposure typically involves lifetime cumulative whole-body exposure in the low-dose range of < 200 mSv, but with head exposure which may (in absence of protection) arrive at a head equivalent dose of 1 to 3 Sv after a professional lifetime (corresponding to a brain equivalent dose around 500 mSv).
At this point, a systematic assessment of brain (cancer and non-cancer) effects of chronic low-dose radiation exposure in interventional cardiologists and staff is needed.
The characterization of health effects (cancer and non-cancer) of chronic low-dose radiation (LDR) is still incomplete and difficult. The UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) 2009 clearly recommends paying more attention “to other non-cancer disease entities, in addition to circulatory diseases”, encouraging “future epidemiological studies designed to assess clinical and subclinical endpoints, as well as biomarkers, since this information is more likely to lead to insights” . In 2006 the National Academy of Sciences BEIR VII committee identified as one of the top ten research needs “future occupational radiation studies”, which should include highly exposed populations with full record of exposure and well-suited to assessing the effects of long-term, low-level radiation exposure in humans . The International Commission on Radiological Protection (ICRP) stated in 2011 that “particular attention should be paid to radiation effects in the lens of the eye and on the cardiovascular system, because of recent published observations of radiation effects in these systems occurring at much lower doses than reported previously”, and that brain irradiation can have direct radiation effects on the thyroid and pituitary glands, as well as subtle effects on the hypothalamic-pituitary-adrenal axis and the hypothalamic, pituitary-gonadal axis .
Within the general framework of the still-elusive assessment of cancer and non-cancer effects of LDR, high and unprecedented levels of radiation exposure in the contemporary population of interventional cardiologists and other paramedical staff working at the catheterization laboratory clearly represent a challenge and an opportunity, especially if we wish to characterize the brain effects of LDR. The brain is a paradigm of a highly differentiated organ with low mitotic activity, thus considered radio-resistant according to a fundamental law of radiobiology (“law of Bergonié and Tribondeau”, 1906). In fact, the brain is one of the main target organs of radiation exposure in the catheterization lab [4, 5], and is usually unprotected due to the myth of its radio-resistance . The brain and head effects of LDR may include stochastic and deterministic effects. Stochastic or probabilistic effects of low-dose radiation consist primarily of cancer, which is the main effect recognized at a regulatory and radioprotection level . In theory, stochastic effects may well include other non-cancer effects such as neuro-vascular and neuro-degenerative effects, for which there is clear experimental evidence . Another clinically relevant radiation effect on the head is eye cataract, previously thought to be deterministic (tissue reactions) and currently recognized as possibly stochastic in nature, and occurring at much lower radiation exposure level than previously thought . In general, there is a striking lack of evidence systematically collected in exposed medical professionals.
Tissue weighting factors from ICRP (2007 vs 1991 and 1997)
ICRP 60 (1991)
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Lower large intestine
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Shifting from a radioprotection to an oncology perspective, ionizing radiation is one of the few established causes of neural tumors. The sensitivity of the brain tissues to develop benign and malignant tumors after diagnostic X-rays was shown in several case–control studies, four of them from dental exposures, and with relative risks ranging from 1.6 to 10 . Studies of the incidence of nervous system tumors in atomic bomb survivors concluded that exposure to radiation doses of less than 1 Sv is associated with an increased incidence of nervous system tumors . A review of cohort mortality studies among workers exposed to ionizing radiation in U.S. nuclear programs was reported in 1991 and reappraised in 2001 , with 3.8 person-years of observation among 140,000 white male workers. The increased risk of brain tumor was highly consistent, persistent, and stable, on the order of magnitude of 15–30%. As a consequence of these data, policy makers have identified brain cancer as a "specified" cancer potentially related to occupational exposures under the Energy Employees Occupational Illness Compensation Program Act . Cosmic radiation can also probably provoke brain tumors. In a large German cohort of 6,017 cockpit and 20,757 cabin crew members, Zeeb et al. reported an increased fatal brain tumor risk among cockpit (not cabin) crew, with the relative risks of 1, 2.49 and 3.56 for workers with 10–20 years, 20–30 years, and > 30 years duration of employment, respectively .
Reports of brain cancer incidence in physicians, radiologists and interventionalists
Matanoski et al., 1975 
Cohort study of mortality in 6,500 US male radiologists (years first worked 1920–1969) over a 50-year period
Excess cancer risk among radiologists compared with other physicians
Wang JX et al., 1990 
Cohort study of Chinese diagnostic x-ray workers (1950 to 1985)
Trend of excess cancer risk (standardized incidence ratio 1.2 for employment duration 10–14 years; 2.3 for 15–19 years) compared to non-radiation medical workers, not available for brain cancer
Andersson M et al., 1991 
Cohort study of Danish radiation therapy workers
Trend of excess cancer risk (standardized incidence ratio 1.09 with measured radiation dose < 5 mSv, and 2.23 with dose 5–50 mSv), not available for brain cancer
Carozza et al., 2000 
Case–control study of occupation and glioma
Physicians at increased, albeit imprecise, risk of glioma (OR 3.5, CI 0.7- 17)
Andersen M et al., 1999 
Population-based study of occupation and cancer incidence (from the 1990s to 1980s)
Brain cancer increased among physicians in general; no breakdown by specialty
Hardell et al., 2001 
Case control study of 233 gliomas
Excess cancer risk of 6.0 in fluoroscopists
Blettner et al., 2007 
Case control study of German patients (age 30–59 years at diagnosis) with brain cancer in 2001–2003
Occupational exposure (physicians, nurses, radiographers) with OR 2.49 (0.74–8.38) for neurinoma, OR close to 1 for glioma and meningioma
Finkelstein et al., 1998 
Report of a case cluster (1990s)
Brain cancer in two interventionalists
Roguin et al., 2012 
Report of a case cluster (2000s)
3 brain gliomas and 1 meningioma, left-sided, in 4 interventional cardiologists
In general, we should consider some important methodological aspects: 1) timing of studies; 2) sample size; 3) changing levels of exposure [41, 42]. Most studies were conducted at a time when interventional cardiology was still a relatively new phenomenon with low levels of use compared with today. For most known carcinogens, identification of increased risk of solid tumors (particularly brain tumors) has required long follow-up periods of subjects with substantial exposure. For example, while the atomic bombs were dropped on Hiroshima and Nagasaki in August 1945, an excess risk of solid tumors was reported in the survivors only in the 1960s, and no elevation in risk of brain tumors was noted for about 50 years . Another important issue is that exposure from interventional cardiology is very asymmetrical, with the left side twice more exposed that the right side [4, 13]. The risk, if it exists, is therefore likely to be more pronounced on the left side. Therefore, studies now at the starting blocks should enroll a well-characterized population of catheterization lab workers, record all (including non-fatal and non-malignant) cases of brain cancer and other non-brain head cancers, such as salivary glands, and assess the possible asymmetry of incidence (left- side cases being possibly more frequent than right-sided cases) mirroring the asymmetry of dose exposure.
Another potentially useful approach is the use of registry data. In some countries of Europe and the US, there are updated and reliable registries that can link occupational exposure with death and hospitalization records for a large number of individuals exposed many years ago [36, 38].
Radiation effects on the vascular system are not limited to macrovessels such as carotid arteries but may also involve small arterioles and microcirculatory function in vessels too small to be imaged by angiography [54, 55]. It is now well-recognized that many of the same risk factors that cause heart disease also can lead to vascular dementia in the elderly  and microvascular brain damage – the result of age-associated alteration in large arteries and the progressive mismatch of their cross-talk with small cerebral arteries – a potent risk factor for cognitive decline and the onset of dementia in older individuals . Morphological and functional alterations of the dermal microcirculation identified by capillary microscopy have been identified in 145 physicians exposed to low-dose ionizing radiation (radiologists, cardiologists and orthopaedic specialists) compared to 105 non-exposed controls . The combination of macro- and micro-vascular damage can thus, in principle, exert negative effects on the neurovascular and neurocognitive function of subjects exposed to ionized radiation.
Previous studies suggested that radiation exposure might represent a risk for schizophrenia in humans [75, 76]. In 10,834 individuals irradiated in childhood for tinea capitis (mean dose = 1.5 Gy), no association was found between radiation exposure and risk of schizophrenia, although for the subgroup irradiated at < 5 years of age a trend was found (hazard ratio = 1.18, 95% CI = 0.96–1.44, p = 0.1) . Recent data showed that rats exposed to fractionated radiation dose present reduction of neurogenesis in DG and SVZ associated with schizophrenia-like behavior . Finally, it should be remarked that neural stem cells and microglial cells can be impaired several years before clinically overt neurodegenerative diseases such as sporadic Alzheimer’s and Parkinson’s disease [66, 78]. At a molecular level, the major fundamental mechanism triggered in the irradiated brain and responsible for structural alterations is DNA damage followed by pro-oxidant, pro-inflammatory and enhanced apoptotic response . These effects have all been described in circulating lymphocytes and plasma of interventional cardiologists [80, 81]. In the brain, apoptosis of neuronal stem cells and reduction of their proliferation rate following irradiation has been repeatedly associated with cognitive deficits in adult mammals [70–73]. However, the molecular substrate of cognitive impairment following low-dose radiation is still debated; in particular, the question of when and to what extent synaptic transmission/plasticity is affected by fractionated radiation is by and large unanswered. Previous results showed that hippocampal slices undergo changes in neuronal excitability following moderate doses of ionizing radiation . More recently, in the mouse brain, Silasi et al.  reported perturbations in cell signaling associated with impairment of hippocampal neurogenesis. This issue is becoming even more relevant following recent observations by Mancuso et al.  on changes occurring in unexposed regions neighboring damaged cells, due to cell-to-cell communication or soluble factors released by irradiated cells. Thus, an accurate investigation of fractionated vs acute radiation damage to neuronal/neural cells in different brain areas is needed in order to understand the link between molecular mechanisms of radiation-induced alterations and cognitive impairment. This represents an important topic, since outside the field of radiation therapy , the evidence linking radiation exposure to cognitive disorders is weak, especially in the case of occupationally exposed medical workers [76, 78]. Yamada et al. reported no relationship between radiation exposure (< 4 Gy) and dementia in 2,286 aging atomic bomb survivors . Less reassuring data are available regarding occupational exposures in the low-to-moderate dose range (< 500 mSv). Death from dementia was significantly associated with total lifetime radiation doses in 69,976 female nuclear power plant workers , pre-senile dementia was more frequent in dentists , and elevated mortality from intentional self-harm, alcoholism and drowning was found in 11,311 former US flight attendants . In 100 Chernobyl liquidators and 100 patients who suffered the acute radiation sickness in Chernobyl, schizophrenia-like disorders were more frequent in presence of over- irradiation (> 300 mSv) . Mental disorders (including mental retardation and behavioral disorders) were most frequent in 544 Chernobyl prenatally irradiated children (with an estimated dose > 0.30 Sv to pregnant mothers) compared to non-irradiated controls born in radioecological “clear” regions . There is no doubt that Chernobyl had an effect on mental health of adults directly affected by the event, especially the liquidators and women with young children, which is why the 2006 Chernobyl Forum report regarded mental health as the major public health consequence . However, the scope and magnitude of the mental health effects cannot be specified with the data at hand . The interpretation of these findings remains difficult due to confounding factors such as environmental mental stress, other possible chemical or physical contaminants in work habitat, night shift, and socio-economic confounders. Radiation is only a potential - but unproven - source of bioeffects, but certainly more data are warranted .
The radiation protection standards formulated by the United States National Council on Radiation Protection and Measurements (NCRP) and the International Commission on Radiological Protection (ICRP) are all based on the belief that lens opacities (cataracts) are deterministic radiation-induced effects and appear only if a dose threshold is exceeded. Cataract, or opacification of the lens, is often associated with visual impairment and may be classified into three main categories: nuclear, cortical, and posterior subcapsular, according to their anatomic location . Among the three major areas of age-related cataracts, posterior subcapsular is the least common but it is the one most frequently associated with ionizing radiation exposure. The mechanism of cataract formation remains partially unknown. There is a transparent layer of cells covering the interior frontal side of the capsule that covers the lens. This layer maintains the function of the lens by slowly growing toward the center, achieved through cell division at the periphery. Because radiation is especially harmful to dividing cells, exposed cells at the equator are most prone to damage. For unknown reasons, damaged cells move toward the rear of the lens before converging on the center. Such cells prevent light from travelling straightforward resulting in opacity. Because of their location along the lens’ visual axis, relatively minor posterior subcapsular cataracts can have great impact on vision. The estimated eye dose is around 0.5 mGy/procedure, when no eye protection is used. Until recently, the dose threshold for radiation-induced lens opacities were considered 2 Gy for a single dose or 5 Gy for fractionated dose . However, several epidemiological studies among Chernobyl clean-up workers, A-bomb survivors, astronauts, residents of contaminated buildings, and surveys of staff in interventional rooms indicate that there is an increased incidence of lens opacities at doses below 0.5 Gy and even suggest a stochastic hypothesis (non-threshold effect) . Whether deterministic or stochastic in nature, cataracts can be found in up to 50% of interventional cardiologists .
The reasons for this high prevalence are threefold: first is that operator’s eyes are exposed to scattered x-rays. Without lead protection, the operator’s eyes receive a mean entrance skin dose of 165 μSv per coronary angiography session, but the use of lead eyeglasses reduces this level to 37 μSv . Second (avoidable) is the frequent failure of some cardiologists to use protective leaded eyewear ; and probably third, that the allowed occupational dose limits were too high to even keep an alert in mind. On April 21, 2011, ICRP slashed the earlier dose limit of 150 mSv in a year for the lens of the eye to the present 20 mSv in a year, averaged over a defined period of 5 years, with no single year exceeding 50 mSv .
Ongoing studies on interventional cardiologists
NIH and NCI
Italian CNR National Research Council-IFC, Institute of Clinical Physiology
Scientific Societies endorsement
Multispecialty Occupational Health Group
Italian Society of Invasive Cardiology (GISE)
· 44,000 fluoroscopists (interventional cardiologists, radiologists, neuroradiologists)
· 42,000 non-interventional radiologists
· 101,000 non-exposed physicians
· 500 exposed interventional cardiologists (nurses, technicians)
· 500 non exposed clinical cardiologists (nurses, technicians)
Epidemiological clinical endpoints (cancer, cataract, vascular events)
Surrogate biomarkers of genetic, vascular, reproductive, cognitive effect
In Italy, The Healthy Cath Lab study is organized by the Italian National Research Council with endorsement of the Italian Society of Invasive Cardiologists, and is designed by interventional cardiologists for interventional cardiologists. The Italian study population will consist of 500 exposed (high, medium, and low exposure) interventional cardiologists and staff (technicians and staff) and 500 unexposed controls (clinical cardiologists and nurses). With this limited sample size, the detection of potentially increased health risks remains difficult using the epidemiological approach. Therefore, as an alternative to the epidemiological approach, the Healthy Cath Lab study will assess brain effects though “early warning signs”, which evaluate initial damage through surrogate endpoints that are easy to measure, non-invasive, and able to identify long-term risk for subsequent clinically overt disease. Other effects evaluated in the study are endocrine, reproductive, and atherosclerotic functions. Examples of surrogate end-points adopted in the study are carotid-intima media thickness for cerebrovascular atherosclerotic disease , olfactory dysfunction for neurodegenerative disorders , and circulating plasma brain-derived neurotrophin, which is directly linked to hippocampal neurogenesis and is reduced in pre-depressive and neurodegenerative conditions . Both the North American and Italian studies will bring the safety issue center stage and are destined to increase awareness of ionizing radiation in the catheterization laboratory and generate relevant data for better understanding of the most serious health effects of professional chronic low-dose radiation exposure, eventually bridging the experimental and epidemiological divide between high-dose (radiotherapy) and chronic low- to moderate doses (professional exposure) . Taken together, these studies should remind the interventional cardiology community that “the responsibility of all physicians is to minimize the radiation injury hazard to their patients, to their professional staff and to themselves” .
The brain is among the most critical dose-limiting organs in radio-therapy, mainly due to the development of cognitive dysfunction following white matter disruption. The neuro-vascular unit is also vulnerable to radiation effects, and cerebro-vascular atherosclerotic damage is now considered proven with epidemiological evidences for doses > 500 mSv. The head doses involved in radiotherapy are high, usually above 2 Sv, whereas the low-dose range of professional exposure typically involves lifetime cumulative whole-body exposure in the low-dose range of < 200 mSv, but with head exposure which may (in absence of protection) arrive at a head equivalent dose of 1 to 3 Sv after a professional lifetime (corresponding to a brain equivalent dose around 500 mSv). At this point, a systematic assessment of brain (cancer and non-cancer) effects of chronic low-dose radiation exposure in interventional cardiologists and staff is needed.
Central nervous system
International Commission of Radiological Protection
Low dose radiation
United Nations Scientific Committee on the Effects of Atomic Radiation.
This work received financial support from the Italian Ministry of Health (Strategic Project 2010, Istituto Superiore di Sanità: Health and Safety in the Workplace). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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