The biological effects of diagnostic cardiac imaging on chronically exposed physicians: the importance of being non-ionizing

Ultrasounds and ionizing radiation are extensively used for diagnostic applications in the cardiology clinical practice. This paper reviewed the available information on occupational risk of the cardiologists who perform, every day, cardiac imaging procedures. At the moment, there are no consistent evidence that exposure to medical ultrasound is capable of inducing genetic effects, and representing a serious health hazard for clinical staff. In contrast, exposure to ionizing radiation may result in adverse health effect on clinical cardiologists. Although the current risk estimates are clouded by approximations and extrapolations, most data from cytogenetic studies have reported a detrimental effect on somatic DNA of professionally exposed personnel to chronic low doses of ionizing radiation. Since interventional cardiologists and electro-physiologists have the highest radiation exposure among health professionals, a major awareness is crucial for improving occupational protection. Furthermore, the use of a biological dosimeter could be a reliable tool for the risk quantification on an individual basis.     

Radiation Hormesis and Cancer

Despite the long history of radiation hormesis and the public health concerns with low-level exposures to ionizing radiation, there has been surprisingly little formal evaluation of whether hormetic effects are displayed with respect to radiation exposure and cancer incidence (i.e., reduced cancer risk at low radiation doses compared to controls, enhanced cancer risk at higher doses) until relatively recently. This paper reviews data relevant to the question of radiation hormesis and cancer with particular emphasis on experimental studies in animal models exposed to low levels of ionizing radiation. Data exist that provide evidence both consistent with and/or supportive of radiation hormesis. Other biomedical research provides potentially important mechanistic insight: low dose exposures have the capacity to activate immune function to prevent the occurrence of tumor development and metastasis; low doses of radiation have been shown to reduce mutagenic responses and induce endogenous antioxidant responses. These findings are consistent with epidemiological data suggesting an inverse relationship between background radiation and cancer incidence and with occupational epidemiological investigations in which low-dose exposure groups display markedly lower standardized mortality rates than the referent or control group.     

Medical diagnostic radiation exposures and risk of gliomas

High-dose ionizing radiation is an established risk factor for glioma, but it remains unknown whether moderate- and low-dose radiation increase glioma risk. In this analysis, we assessed the evidence that self-reported exposures to diagnostic ionizing radiation, including computerized tomography (CT) scans, is associated with increased risk of adult glioma. While no independent association was observed for CT scans alone (3+ scans compared to none P = 0.08 and 1-2 scans compared to none P = 0.68), our findings suggest an increased risk of adult gliomas with cumulative exposure to three or more CT scans to the head and neck region (OR = 1.97, 95% CI: 0.92-4.23) limited to those who reported a family history of cancer: the P value for the interaction between having three or more CT scans and family history of cancer was 0.08. The stratum-specific adjusted OR for those with family history of cancer was more than three times that for the sub-group without family history of cancer. While there is some potential for symptom-related bias, one might expect this to be present for all diagnostic procedures rather than specific to one procedure. The interaction between CT scans and glioma with family history of cancer supports the biological plausibility of our findings, because similar results have been found for breast cancer and radiation. This observational data will increase awareness about potential risks associated with CT scans and the need to minimize the use of unnecessary examinations.     

Exposure to ionizing radiation and brain cancer incidence: The Life Span Study cohort

BackgroundIonizing radiation is a cause of cancer. This paper examines the effects of radiation dose and age at exposure on the incidence of brain cancer using data from the Life Span Study (LSS) of atomic bomb survivors.MethodsThe Radiation Effects Research Foundation website provides demographic details of the LSS population, estimated radiation doses at time of bomb in 1945, person years of follow-up and incident cancers from 1958 to 1998. We modelled brain cancer incidence using background-stratified Poisson regression, and compared the excess relative risk (ERR) per Gray (Gy) of brain dose with estimates from follow-up studies of children exposed to diagnostic CT scans.ResultsAfter exposure to atomic bomb radiation at 10 years of age the estimated ERR/Gy was 0.91 (90%CI 0.53, 1.40) compared with 0.07 (90%CI −0.27, 0.56) following exposure at age 40. Exposure at 10 years of age led to an estimated excess of 17 brain tumors per 100,000 person year (pyr) Gy by 60 years of age. These LSS estimates are substantially less than estimates based on follow-up of children exposed to CT scans.ConclusionEstimates of ERR/Gy for brain cancers in the LSS and haemangioma cohorts seem much smaller than estimates of risk for young persons in the early years after exposure to CT-scans. This could be due to reverse causation bias in the CT cohorts, diagnostic error, measurement error with radiation doses, loss of early follow-up in the LSS, or non-linearity of the dose-response curve.     

Cancer risk related to low-dose ionizing radiation from cardiac imaging in patients after acute myocardial infarction

Background

Patients exposed to low-dose ionizing radiation from cardiac imaging and therapeutic procedures after acute myocardial infarction may be at increased risk of cancer.

Methods

Using an administrative database, we selected a cohort of patients who had an acute myocardial infarction between April 1996 and March 2006 and no history of cancer. We documented all cardiac imaging and therapeutic procedures involving low-dose ionizing radiation. The primary outcome was risk of cancer. Statistical analyses were performed using a time-dependent Cox model adjusted for age, sex and exposure to low-dose ionizing radiation from noncardiac imaging to account for work-up of cancer.

Results

Of the 82 861 patients included in the cohort, 77% underwent at least one cardiac imaging or therapeutic procedure involving low-dose ionizing radiation in the first year after acute myocardial infarction. The cumulative exposure to radiation from cardiac procedures was 5.3 milliSieverts (mSv) per patient-year, of which 84% occurred during the first year after acute myocardial infarction. A total of 12 020 incident cancers were diagnosed during the follow-up period. There was a dose-dependent relation between exposure to radiation from cardiac procedures and subsequent risk of cancer. For every 10 mSv of low-dose ionizing radiation, there was a 3% increase in the risk of age- and sex-adjusted cancer over a mean follow-up period of five years (hazard ratio 1.003 per milliSievert, 95% confidence interval 1.002–1.004).

Interpretation

Exposure to low-dose ionizing radiation from cardiac imaging and therapeutic procedures after acute myocardial infarction is associated with an increased risk of cancer.Studies involving atomic bomb survivors have documented an increased incidence of malignant neoplasm related to the radiation exposure.^1–4 Survivors who were farther from the epicentre of the blast had a lower incidence of cancer, whereas those who were closer had a higher incidence.⁵ Similar risk estimates have been reported among workers in nuclear plants.⁶ However, little is known about the relation between exposure to low-dose ionizing radiation from medical procedures and the risk of cancer.In the past six decades since the atomic bomb explosions, most individuals worldwide have had minimal exposure to ionizing radiation. However, the recent increase in the use of medical imaging and therapeutic procedures involving low-dose ionizing radiation has led to a growing concern that individual patients may be at increased risk of cancer.^7–12 Whereas strict regulatory control is placed on occupational exposure at work sites, no such control exists among patients who are exposed to such radiation.^13–16It is not only the frequency of these procedures that is increasing. Newer types of imaging procedures are using higher doses of low-dose ionizing radiation than those used with more traditional procedures.^8,11 Among patients being evaluated for coronary artery disease, for example, coronary computed tomography is increasingly being used. This test may be used in addition to other tests such as nuclear scans, coronary angiography and percutaneous coronary intervention, each of which exposes the patient to low-dose ionizing radiation.^12,17–21 Imaging procedures provide information that can be used to predict the prognosis of patients with coronary artery disease. Since such predictions do not necessarily translate into better clinical outcomes,^8,12 the prognostic value obtained from imaging procedures using low-dose ionizing radiation needs to be balanced against the potential for risk.Authors of several studies have estimated that the risk of cancer is not negligible among patients exposed to low-dose ionizing radiation.^22–27 To our knowledge, none of these studies directly linked cumulative exposure and cancer risk. We examined a cohort of patients who had acute myocardial infarction and measured the association between low-dose ionizing radiation from cardiac imaging and therapeutic procedures and the risk of cancer.     

A nested case-control study of lung cancer risk and ionizing radiation exposure at the portsmouth naval shipyard

Results have been inconsistent between studies of lung cancer risk and ionizing radiation exposures among workers at the Portsmouth Naval Shipyard (PNS). The purpose of this nested case-control study was to evaluate the relationship between lung cancer risk and external ionizing radiation exposure while adjusting for potential confounders that included gender, radiation monitoring status, smoking habit surrogates (socioeconomic status and birth cohort), welding fumes and asbestos. By incidence density sampling, we age-matched 3,291 controls selected from a cohort of 37,853 civilian workers employed at PNS between 1952 and 1992 with 1,097 lung cancer deaths from among the same cohort. Analyses using conditional logistic regression were conducted in various model forms: log-linear (main), linear excess relative risk (ERR), and categorical. Lung cancer risk was positively associated with occupational dose (OR = 1.02 at 10 mSv; 95% CI 0.99- 1.04) but flattened after the inclusion of work-related medical X-ray doses (OR = 1.00; 95% CI 0.98-1.03) in multivariate analyses. Similar risk estimates were observed in the linear ERR model at 10 mSv of cumulative exposure with a 15-year lag.     

Thyroid cancer risk 40+ years after irradiation for an enlarged thymus: an update of the Hempelmann cohort

Although ionizing radiation is a known carcinogen, the long-term risk from relatively higher-dose diagnostic procedures during childhood is less well known. We evaluated this risk indirectly by assessing thyroid cancer incidence in a cohort treated with "lower-dose" chest radiotherapy more than 55 years ago. Between 2004 and 2008, we re-surveyed a population-based cohort of subjects treated with radiation for an enlarged thymus during infancy between 1926 and 1957 and their unexposed siblings. Thyroid cancer occurred in 50 irradiated subjects (mean thyroid dose, 1.29 Gy) and in 13 nonirradiated siblings during 334,347 person-years of follow-up. After adjusting for attained age, Jewish religion, sex and history of goiter, the rate ratio for thyroid cancer was 5.6 (95% CI: 3.1-10.8). The adjusted excess relative risk per gray was 3.2 (95% CI: 1.5-6.6). The adjusted excess absolute risk per gray was 2.2 cases (95% CI: 1.4-3.2) per 10,000 person-years. Cumulative thyroid cancer incidence remains elevated in this cohort after a median 57.5 years of follow-up and is dose-dependent. Although the incidence appeared to decrease after 40 years, increased risk remains a lifelong concern in those exposed to lower doses of medical radiation during early childhood.     

No threshold for the induction of chromosomal damage at clinically relevant low doses of X rays

The recent steep increase in population dose from radiation-based medical diagnostics, such as computed tomography (CT) scans, requires insight into human health risks, especially in terms of cancer development. Since the induction of genetic damage is considered a prominent cause underlying the carcinogenic potential of ionizing radiation, we quantified the induction of micronuclei and loss of heterozygosity events in human cells after exposure to clinically relevant low doses of X rays. A linear dose-response relationship for induction of micronuclei was observed in human fibroblasts with significantly increased frequencies at doses as low as 20 mGy. Strikingly, cells exposed during S-phase displayed the highest induction, whereas non S-phase cells showed no significant induction below 100 mGy. Similarly, the induction of loss of heterozygosity in human lymphoblastoid cells quantified at HLA loci, was linear with dose and reached significance at 50 mGy. Together the findings favor a linear-no-threshold model for genetic damage induced by acute exposure to ionizing radiation. We speculate that the higher radiosensitivity of S-phase cells might relate to the excessive cancer risk observed in highly proliferative tissues in radiation exposed organisms.     

Out-of-field organ doses and associated risk of cancer development following radiation therapy with photons

Innovations in cancer treatment have contributed to the improved survival rate of these patients. Radiotherapy is one of the main options for cancer management nowadays. High doses of ionizing radiation are usually delivered to the tumor site with high energy photon beams. However, the therapeutic radiation exposure may lead to second cancer induction. Moreover, the introduction of intensity-modulated radiation therapy over the last decades has increased the radiation dose to out-of-field organs compared to that from conventional irradiation. The increased organ doses might result in elevated probabilities for developing secondary malignancies to critical organs outside the treatment volume. The organ-specific dosimetry is considered necessary for the theoretical second cancer risk assessment and the proper analysis of data derived from epidemiological reports. This study reviews the methods employed for the measurement and calculation of out-of-field organ doses from exposure to photons and/or neutrons. The strengths and weaknesses of these dosimetric approaches are described in detail. This is followed by a review of the epidemiological data associated with out-of-field cancer risks. Previously published theoretical cancer risk estimates for adult and pediatric patients undergoing radiotherapy with conventional and advanced techniques are presented. The methodology for the theoretical prediction of the probability of carcinogenesis to out-of-field sites and the limitations of this approach are discussed. The article also focuses on the factors affecting the magnitude of the probability for developing radiotherapy-induced malignancies. The restriction of out-of-field doses and risks through the use of different types of shielding equipment is presented.     

Predicted cancer risks induced by computed tomography examinations during childhood,by a quantitative risk assessment approach

The potential adverse effects associated with exposure to ionizing radiation from computed tomography (CT) in pediatrics must be characterized in relation to their expected clinical benefits. Additional epidemiological data are, however, still awaited for providing a lifelong overview of potential cancer risks. This paper gives predictions of potential lifetime risks of cancer incidence that would be induced by CT examinations during childhood in French routine practices in pediatrics. Organ doses were estimated from standard radiological protocols in 15 hospitals. Excess risks of leukemia, brain/central nervous system, breast and thyroid cancers were predicted from dose–response models estimated in the Japanese atomic bomb survivors’ dataset and studies of medical exposures. Uncertainty in predictions was quantified using Monte Carlo simulations. This approach predicts that 100,000 skull/brain scans in 5-year-old children would result in eight (90 % uncertainty interval (UI) 1–55) brain/CNS cancers and four (90 % UI 1–14) cases of leukemia and that 100,000 chest scans would lead to 31 (90 % UI 9–101) thyroid cancers, 55 (90 % UI 20–158) breast cancers, and one (90 % UI <0.1–4) leukemia case (all in excess of risks without exposure). Compared to background risks, radiation-induced risks would be low for individuals throughout life, but relative risks would be highest in the first decades of life. Heterogeneity in the radiological protocols across the hospitals implies that 5–10 % of CT examinations would be related to risks 1.4–3.6 times higher than those for the median doses. Overall excess relative risks in exposed populations would be 1–10 % depending on the site of cancer and the duration of follow-up. The results emphasize the potential risks of cancer specifically from standard CT examinations in pediatrics and underline the necessity of optimization of radiological protocols.     

Cancer incidence and mortality after low-dose radiation exposure: epidemiological aspects

Current recommendations for limiting exposure to ionizing radiation are based on the linear-no-threshold (LNT) model for radiation carcinogenesis under which every dose, no matter how low, carries with it some cancer risk. In this review, epidemiological evidences are discussed that the LNT hypothesis is incorrect at low doses. A large set of data was accumulated that showed that cancer risk after ordinarily encountered radiation exposure (natural background radiation, medical X-rays, etc.) is much lower than projections based on the LNT model. The discovery of the low-level radiation hormesis (stimulating effect) implies a non-linear dose-response curve in the low-dose region. The further studies in this field will provide new insights about the mechanisms of radiation carcinogenesis.     

Cancer incidence and mortality after low-dosage radiation exposure: Epidemiological aspects

Current recommendations for limiting exposure to ionizing radiation are based on the linear no-threshold (LNT) model for radiation carcinogenesis under which every dose, no matter how low, bears some cancer risk. In this review, epidemiological evidence is discussed that the LNT hypothesis is incorrect at low doses. A large set of data was accumulated that show that cancer risk after ordinarily encountered radiation exposure (natural background radiation, medical X-rays, etc.) is much lower than estimates based on the LNT model. The discovery of low-level radiation hormesis (stimulating effect) implies a non-linear dose-response curve in the low-dosage region. Further studies in this field will provide new insights into the mechanisms of radiation carcinogenesis.     

Sensitivity of germ cells and embryos to ionizing radiation

Experiments performed in laboratory animals suggest that ionizing radiation can induce DNA damage in the germ cells of exposed individuals and lead to various deleterious effects in their progeny, including miscarriage, low birth weight, congenital abnormalities and perhaps cancer. However, no clear evidence for such effects has been found in epidemiological studies of people exposed to radiation. The predicted risks of hereditary effects of any kinds resulting from parental exposure to relatively low doses of ionizing radiation remain very low, compared to the spontaneous risks in the absence of irradiation. Irradiation of the mouse embryo can lead to various effects (lethality, growth retardation, congenital abnormalities), depending on the period of gestation at which irradiation occurs. In humans, prenatal irradiation has only been exceptionally associated with congenital abnormalities, but irradiation between weeks 8-25 has been shown to be able to induce severe mental retardation. Although being not proven, the risk of developing a childhood cancer following prenatal irradiation may also not be excluded. Like for genetic effects, the risk of adverse effects following exposure of the embryo to relatively low doses remains quite low compared to the natural risks.     

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Working Paper 7/1/2. Shared risk factors for cancer and atherosclerosis--a review of the epidemiological evidence

This paper reviews the epidemiological literature of relevance for the hypothesis that somatic mutation is involved in the formation of the atherosclerotic plaque. Assuming that somatic mutations are involved in atherogenesis, one would expect at least some of the risk factors for cancer and for atherosclerosis to be identical. Therefore, the review covers the correlated occurrence of cancer and atherosclerotic disease. Special interest is given to populations at high risk of cancer, including subpopulations with certain genetic diseases, and populations exposed to certain carcinogenic environmental agents including ionizing radiation, vinyl chloride monomer (VCM), arsenic, tobacco, and various industrial combustion effluents containing polycyclic aromatic hydrocarbons (PAHs). Exposure to combustion effluents from burning of tobacco or fuel is associated with an increased risk of cancer and atherosclerotic disease. Combustion effluents constitute a complex mixture of potentially hazardous agents, however, and the observed correlation of cancer and atherosclerosis among exposed persons cannot be unambiguously interpreted as evidence of a common etiology of the two groups of diseases. For ionizing radiation, arsenic, and VCM there is suggestive evidence that these agents possess an atherogenic effect beside their well-known carcinogenic properties. Both arsenic and VCM seem to have a specific affinity to the vascular bed causing various lesions including angiosarcomas and atherosclerotic plaques. Regarding ionizing radiation, the atherogenic effects seem to be localized to heavily irradiated fields. Beside the carcinogenic and atherogenic effects, exposure to arsenic, VCM, and ionizing radiation brings about an increase in the incidence of mutations and chromosomal aberrations. A theory involving somatic mutation in the pathogenesis of the atherosclerotic plaque could be consistent with the observed biological effects of ionizing radiation, arsenic, and VCM. The scant data from families with certain inherited diseases may also be consistent with an involvement of the genome in the pathogenesis of atherosclerosis. In conclusion, there is strong epidemiological evidence that several factors associated with an increased risk of cancer are also associated with an increased risk of atherosclerosis.     

Childhood exposure to ionizing radiation to the head and risk of schizophrenia

While the association between exposure to ionizing radiation and cancer is well established, its association with schizophrenia is unclear. The aim of our study was to assess risk of schizophrenia after childhood exposure to ionizing radiation to the head (mean dose: 1.5 Gy). The study population included an exposed group of 10,834 individuals irradiated during childhood for treatment of tinea capitis in the 1950s and two unexposed comparison groups of 5392 siblings and 10,834 subjects derived from the National Population Registry individually matched to the exposed group by age, sex (when possible), country of birth, and year of immigration to Israel. These groups were followed for a median 46 years for diagnosis of schizophrenia updated to December 2002. The Cox proportional hazards model stratified by matched sets was used to compare the risk of schizophrenia between the groups. Based on 1,217,531 person-years of follow-up, 451 cases were identified. No statistically significant association was found between radiation exposure and schizophrenia for the total group (hazard ratio per 1 Gy to the brain: 1.05, 95% confidence interval: 0.93-1.18) or within subgroups of sex, dose categories or latent period. When comparing a subgroup of subjects irradiated under 5 years of age with the matched unexposed group, the estimated hazard ratio reached 1.18 (95% confidence interval: 0.96-1.44; P = 0.1). The results of our analysis do not support an association between exposure to ionizing radiation and risk of schizophrenia. More research on possible effects of early exposure to ionizing radiation on schizophrenia specifically and brain tissue in general is needed.     

Magnetic resonance imaging: present and future applications

Magnetic resonance (MR) imaging has created considerable excitement in the medical community, largely because of its great potential to diagnose and characterize many different disease processes. However, it is becoming increasingly evident that, because MR imaging is similar to computed tomography (CT) scanning in identifying structural disorders and because it is more costly and difficult to use, this highly useful technique must be judged against CT before it can become an accepted investigative tool. At present MR imaging has demonstrated diagnostic superiority over CT in a limited number of important, mostly neurologic, disorders and is complementary to CT in the diagnosis of certain other disorders. For most of the remaining organ systems its usefulness is not clear, but the lack of ionizing radiation and MR''s ability to produce images in any tomographic plane may eventually prove to be advantageous. The potential of MR imaging to display in-vivo spectra, multinuclear images and blood-flow data makes it an exciting investigative technique. At present, however, MR imaging units should be installed only in medical centres equipped with the clinical and basic research facilities that are essential to evaluate the ultimate role of this technique in the care of patients.     

RADIATION: MEDICAL DIAGNOSTIC USES

Use of radiologic procedures in diagnosis now contributes a significant dose of ionizing radiation to our population. Whether this presents a real risk to the health of the present and future population cannot be determined with certainty from evidence available at this time. Hence, it appears proper to keep the dose to every patient as low as practical consistent with good medical practice. The average dose can be significantly reduced by having more physicians apply the known techniques for minimizing the exposure to the patient.The medical profession has a direct professional concern for the actual or potential risk of damage resulting from the radiation that patients are exposed to during diagnostic x-ray procedures, since these procedures constitute the largest single man-made source of genetically significant radiation our population is now exposed to.It is important to distinguish two distinctly different types of radiation effects—somatic effect, in which the damage affects the health of the person irradiated, and genetic effect that is capable of producing constitutional defects in future progeny over many generations.     

Exposure to ionizing radiation during pregnancy: perception of teratogenic risk and outcome

We quantified the perception of teratogenic risk in women attending the Motherisk program for counseling about diagnostic radiation in pregnancy (n = 50) and compared it with a control group of women exposed to nonteratogenic drugs and chemicals (n = 48). Before receiving known information about the specific exposure, women exposed to radiation assigned themselves a significantly higher teratogenic risk compared with the control group (25.5 +/- 4.3% versus 15.7 +/- 3.0% for major malformations, P less than 0.01). The post-consultation perception of teratogenic risk did not differ between the two groups. Special consideration and attention should be given when counseling pregnant women exposed to low-dose ionizing radiation, as their misperception of teratogenic risk may lead them to unnecessary termination of their pregnancy.     

Cancer risk from chronic exposures to chemicals and radiation: a comparison of the toxicological reference value with the radiation detriment

This article aims at comparing reference methods for the assessment of cancer risk from exposure to genotoxic carcinogen chemical substances and to ionizing radiation. For chemicals, cancer potency is expressed as a toxicological reference value (TRV) based on the most sensitive type of cancer generally observed in animal experiments of oral or inhalation exposure. A dose–response curve is established by modelling experimental data adjusted to apply to human exposure. This leads to a point of departure from which the TRV is derived as the slope of a linear extrapolation to zero dose. Human lifetime cancer risk can then be assessed as the product of dose by TRV and it is generally considered to be tolerable in a 10^–6–10^–4 range for the public in a normal situation. Radiation exposure is assessed as an effective dose corresponding to a weighted average of energy deposition in body organs. Cancer risk models were derived from the epidemiological follow-up of atomic bombing survivors. Considering a linear-no-threshold dose-risk relationship and average baseline risks, lifetime nominal risk coefficients were established for 13 types of cancers. Those are adjusted according to the severity of each cancer type and combined into an overall indicator denominated radiation detriment. Exposure to radiation is subject to dose limits proscribing unacceptable health detriment. The differences between chemical and radiological cancer risk assessments are discussed and concern data sources, extrapolation to low doses, definition of dose, considered health effects and level of conservatism. These differences should not be an insuperable impediment to the comparison of TRVs with radiation risk, thus opportunities exist to bring closer the two types of risk assessment.

     

Radiation-induced carcinogenesis: mechanistically based differences between gamma-rays and neutrons, and interactions with DMBA

Different types of ionizing radiation produce different dependences of cancer risk on radiation dose/dose rate. Sparsely ionizing radiation (e.g. γ-rays) generally produces linear or upwardly curving dose responses at low doses, and the risk decreases when the dose rate is reduced (direct dose rate effect). Densely ionizing radiation (e.g. neutrons) often produces downwardly curving dose responses, where the risk initially grows with dose, but eventually stabilizes or decreases. When the dose rate is reduced, the risk increases (inverse dose rate effect). These qualitative differences suggest qualitative differences in carcinogenesis mechanisms. We hypothesize that the dominant mechanism for induction of many solid cancers by sparsely ionizing radiation is initiation of stem cells to a pre-malignant state, but for densely ionizing radiation the dominant mechanism is radiation-bystander-effect mediated promotion of already pre-malignant cell clone growth. Here we present a mathematical model based on these assumptions and test it using data on the incidence of dysplastic growths and tumors in the mammary glands of mice exposed to high or low dose rates of γ-rays and neutrons, either with or without pre-treatment with the chemical carcinogen 7,12-dimethylbenz-alpha-anthracene (DMBA). The model provides a mechanistic and quantitative explanation which is consistent with the data and may provide useful insight into human carcinogenesis.