BRAIN AND EYE AS POTENTIAL TARGETS FOR IONIZING RADIATION IMPACT: PART II - RADIATION CEREBRO/OPHTALMIC EFFECTS IN CHILDREN, PERSONS EXPOSED IN UTERO, ASTRONAUTS AND INTERVENTIONAL RADIOLOGISTS. / GOLOVNYI MOZOK TA ORGAN ZORU IaK POTENTsIINI MIShENI DLIa VPLYVU IONIZUIuChOGO VYPROMINIuVANNIa: ChASTYNA II ­ RADIATsIINI TsEREBROOFTAL'MOLOGIChNI EFEKTY U DITEI, OSIB, EKSPONOVANYKh VNUTRIShN'O/UTROBNO, ASTRONAVTIV TA INTERVENTsIINYKh RADIOLOGIV.

BACKGROUND: Ionizing radiation (IR) can affect the brain and the visual organ even at low doses, while provoking cognitive, emotional, behavioral, and visual disorders. We proposed to consider the brain and the visual organ as potential targets for the influence of IR with the definition of cerebro-ophthalmic relationships as the «eye-brain axis¼. OBJECTIVE: The present work is a narrative review of current experimental, epidemiological and clinical data on radiation cerebro-ophthalmic effects in children, individuals exposed in utero, astronauts and interventional radiologists. MATERIALS AND METHODS: The review was performed according to PRISMA guidelines by searching the abstract and scientometric databases PubMed/MEDLINE, Scopus, Web of Science, Embase, PsycINFO, Google Scholar, published from 1998 to 2021, as well as the results of manual search of peer-reviewed publications. RESULTS: Epidemiological data on the effects of low doses of IR on neurodevelopment are quite contradictory, while data on clinical, neuropsychological and neurophysiological on cognitive and cerebral disorders, especially in the left, dominant hemisphere of the brain, are nore consistent. Cataracts (congenital - after in utero irradiation) and retinal angiopathy are more common in prenatally-exposed people and children. Astronauts, who carry out longterm space missions outside the protection of the Earth's magnetosphere, will be exposed to galactic cosmic radiation (heavy ions, protons), which leads to cerebro-ophthalmic disorders, primarily cognitive and behavioral disorders and cataracts. Interventional radiologists are a special risk group for cerebro-ophthalmic pathology - cognitivedeficits, mainly due to dysfunction of the dominant and more radiosensitive left hemisphere of the brain, andcataracts, as well as early atherosclerosis and accelerated aging. CONCLUSIONS: Results of current studies indicate the high radiosensitivity of the brain and eye in different contingents of irradiated persons. Further research is needed to clarify the nature of cerebro-ophthalmic disorders in different exposure scenarios, to determine the molecular biological mechanisms of these disorders, reliable dosimetric support and taking into account the influence of non-radiation risk factors.

BRAIN AND EYE AS POTENTIAL TARGETS FOR IONIZING RADIATION IMPACT. PART III / FEATURES MORPHOMETRIC RETINAL PARAMETERS, AMPLITUDE AND LATENCY COMPONENTS OF VISUAL EVOKED POTENTIAL IN RADIATION EXPOSED IN UTERO. / GOLOVNYI MOZOK TA ORGAN ZORU IaK POTENTsIINI MIShENI DLIa VPLYVU IONIZUIuChOGO VYPROMINIuVANNIa: ChASTYNA III ­ OSOBLYVOSTI MORFOMETRYChNYKh PARAMETRIV SITChASTOÏ OBOLONKY TA AMPLITUDA I LATENTNIST' KOMPONENTIV ZOROVYKh VYKLYKANYKh POTENTsIALIV U OPROMINENYKh VNUTRIShN'OUTROBNO OSIB.

One of the current problems of modern radiobiology is determine the characteristics of the manifestation of radiation-induced effects not only at different dose loads, but also at different stages of development of the organism. In previous reports, we have summarized available evidence that at certain ages there is a comparative acceleration of radiation-induced pathological changes in the eye and brain, and the study and assessment of the risk of possible ophthalmic and neurological pathology in remote periods after contamination of radioactive areas. Data of irradiated in utero individuals are possible on the basis of observation of the state of the visual analyzer in persons who underwent intrauterine irradiation in 1986. Therefore, a parallel study of retinal morphometric parameters, amplitude and latency of components of evoked visual potentials in irradiated in utero individuals was performed. OBJECTIVE: to evaluate the retinal morphometric parameters, amplitude and latency components of the evoked visual potentials in intrauterine irradiated persons. MATERIALS AND METHODS: The results of surveys of 16 people irradiated in utero in the aftermath of the Chornobyl disaster were used; the comparison group were residents of Kyiv of the corresponding age (25 people). Optical coherence tomography was performed on a Cirrus HD-OCT, Macular Cube 512x128 study technique was used. At the same time, the study of visual evoked potentials on the inverted pattern was performed, and occipital leads wereanalyzed. Visual evoked potentials were recorded on a reversible chess pattern (VEP) - an electrophysiological test, which is a visual response to a sharp change in image contrast when presenting a reversible image of a chessboard. RESULTS: In those irradiated in utero at the age of 22-25 years, there was a probable increase in retinal thickness in the fovea, there was a tendency to increase the thickness of the retina in the areas around the fovea. When recording visual evoked potentials on a reversible chess pattern in this group, there was a tendency to decrease the amplitudes of components (N75, P100, N145, P200) in the right and left parieto-occipital areas and asymmetric changes in latency of these components. CONCLUSIONS: Early changes of fovea recorded in OCT and decreasing amplitudes of components of visual evoked potentials on the reversible chess pattern at the age of 22 25 years may indicate a risk of development in patients irradiated in utero, early age-related macular degeneration, as well as increased risk and increased risk structures of the visual analyzer.

DIFFUSION TENSOR MAGNETIC RESONANCE IMAGING IN EARLY DIAGNOSIS OF STRUCTURAL CHANGES IN BRAIN WHITE MATTER IN SMALL VESSEL DISEASE ASSOCIATED WITH ARTERIAL HYPERTENSION AND IONIZING RADIATION. / DYFUZIINO-TENZORNA MRT U RANNII DIAGNOSTYTsI STRUKTURNYKh ZMIN BILOÏ REChOVYNY GOLOVNOGO MOZKU PRY ASOTsIIOVANII Z ARTERIAL'NOIu GIPERTENZIIeIu TA IONIZUIuChYM VYPROMINIuVANNIaM KhVOROBI MALYKh SUDYN.

OBJECTIVE: to determine the early signs of structural changes in brain white matter in small vessel disease associated with arterial hypertension and exposure to ionizing radiation using DTI-MRI. MATERIALS AND METHODS: 45 patients (mean age (57.56 ± 6.34) years) with small vessel disease (SVD) associatedwith arterial hypertension (AH) were examined: group I - 20 patients, participants of liquidation of the accident atthe Chornobyl nuclear power plant (Chornobyl clean-up workers); group II - 25 patients not exposed to ionizingradiation. MRI was performed on an Ingenia 3T tomograph («Philips¼). The fractional anisotropy (FA) was determined in the main associative and commissural pathways, periventricular prefrontal areas (fasciculus fronto-occipitalis superior / anterior - f. FO ant., corona radiata anterior - CR ant.) and semioval centers (SC). RESULTS: No signs of cerebral cortex or brain white matter (WM) atrophy, intracerebral microhemorrhages, and widespread areas of leukoaraiosis consolidation were observed in the examined patients. In the Chornobyl clean-up workers a larger number of foci of subcortical leukoaraiosis was visualized (80 %) on MRI images including multiple -8 (40 %), > 0.5 cm - 10 (50 %), with signs of consolidation - 5 (25 %). The results of the FA analysis in semiovalcenters showed its significant decrease in the patients of groups I and II (p < 0,007), regardless of the presence orabsence of visual signs of subcortical leukoaraiosis (ScLA) (III gr.: 253-317, p < 0.00001; IV gr.: 287- 375,p < 0.001). FA indicators in f. FO ant. and CR ant. in the patients of groups I and II differed insignificantly but weresubstantially lower than controls (p < 0.05). FA was significantly lower, compared to reference levels, in visuallyunchanged f. FO ant. (0.389-0.425; p = 0.015) and CR ant. (0.335-0.403; p = 0.05). In patients with AH-associated SVD of middle age, regardless of the effects of ionizing radiation, no significant changes in FA in the mainWM associative and commissural pathways were found (p > 0.05). CONCLUSIONS: DTI-MRI allows to detect early signs of structural changes in the white matter of the brain - a significant decrease in fractional anisotropy indicators in visually unchanged periventricular and subcortical areas. Themain associative and commissural pathways of the brain remain intact in the absence of widespread consolidatedfoci of leukoaraiosis and lacunar infarctions. The negative impact of ionizing radiation on the course of SVD associated with arterial hypertension is manifested by more active processes of WM disorganization: the prevalence andtendency to the consolidation of periventricular and subcortical leukoaraiosis foci, a significant FA decrease in semioval centers.

NEUROENDOCRINE EFFECTS OF PRENATAL IRRADIATION FROM RADIOACTIVE IODINE (review). / NEY̆ROENDOKRYNNI EFEKTY PRENATAL'NOGO OPROMINENNIa RADIOAKTYVNYM Y̆ODOM (ogliad).

BACKGROUND: Neuroendocrine effects of the prenatal radiation exposure from radioactive iodine in an event of nuclear power reactor accidents are a key issue in the field of radiation medicine and radiation safety because of a dramatic radiosensitivity of the developing organism. OBJECTIVE: Review of contemporary epidemiological, clinical and experimental data on neuroendocrine effects of prenatal exposure to 131I. OBJECT AND METHODS: Search in the PubMed/MEDLINE and Google Scholar abstract databases, along with a manual search for the relevant data sources. RESULTS: Estimated absorbed doses of intrauterine thyroid irradiation from radioactive iodine were obtained based on ICRP Publication 88, both with estimates of effective radiation doses on embryo and fetus, and estimates of the brain equivalent doses upon exposure in utero. The latter ones are subject to updating. The evidence-based data has been presented regarding a radiation-associated reduction of head and chest circumference at birth, as well as a radiation-associated excess of goiter with large thyroid nodules, and possibly of thyroid cancer after a prenatal exposure to 131I radionuclides. Data on intrauterine brain damage are controversial, but most researchers share the view that there are cognitive and emotional-behavioral disorders due to prenatal and postnatal irradiation and psy- chosocial impacts. Incidence increase of non-cancerous endocrine disorders and degenerative vascular disease of retina was noted. An experimental model of intrauterine irradiation from 131I on Wistar rats was for the first time ever created, extrapolating the radioneuroembryological effects in rats to individuals prenatally exposed after the Chornobyl disaster. Late neuropsychiatric and endocrine effects may be resulted from the relatively short-term impact of ionizing radiation at a level previously been considered safe. The necessity of neuropsychiatric and endocrinological monitoring of individuals exposed prenatally to ionizing radiation after the Chornobyl catastrophe throughout their life is substantiated. Experimental animal studies are a key direction in the further research of radiation effects, especially associated with low radiation doses. Further experimental and clinical neuroradiobio- logical studies aimed at exploration of the effect of ionizing radiation on hippocampal neurogenesis are most rele- vant nowadays.

STATE INSTITUTION «NATIONAL RESEARCH CENTER FOR RADIATION MEDICINE OF THE NATIONAL ACADEMY OF MEDICAL SCIENCES OF UKRAINE¼ - RESEARCH ACTIVITIES AND SCIENTIFIC ADVANCE IN 2017. / REFORMUVANNIa SYSTEMY OKhORONY ZDOROV'Ia: ROL' I MISTsE ZAKLADIV OKhORONY ZDOROV'Ia TRETYNNOGO RIVNIa PRY RADIATsIINYKh NADZVYChAINYKh SYTUATsIIaKh V UMOVAKh VOIeNNOGO STANU.

The role and place of health care facilities of the highly specialized (tertiary) level in radiation emergencies in the conditions of martial law are considered taking into account the experience of overcoming of the Chornobyl catas-trophe consequences. The classification of emergencies and the main scenarios of radiation emergencies (nuclear terrorism, radiation accidents and incidents, the use of nuclear weapons) are presented. The principles of medical preparedness and providing the highly specialized medical care in a radiological emergency are presented on the base of the Chornobyl catastrophe experience. It is determined that the tertiary health care facilities in a radiological emergency should provide as follow: development and implementation of plans and protocols of highly specialized medical care; organization, direct provision, coordination and quality control of the highly specialized medical care; aggregation and coordination of efforts of all three levels of health care facilities; integration into the radiation emergency management system, and analysis and generalization of the experience gained.

COMPARATIVE CHARACTERISTIC OF «ALCOHOL DEPRESSION¼ IN PERSONS WHO PARTICIPATED IN COMBAT OPERATIONS (COMBATANS) AND AFFECTED BY RADIATION CATASTROP. / PORIVNIaL'NA KhARAKTERYSTYKA «ALKOGOL'NYKh DEPRESII¼ V OSIB, IaKI BRALY UChAST' U BOIOVYKh DIIaKh (KOMBATANTIV) I POSTRAZhDALYKh PRY RADIATsIINII KATASTROFI.

The relevance of work is conditioned by the considerable prevalence of depressive disorders and alcohol abuseamong people who participated in combat operations (combatants) and affected by a radiation emergency, whichneeds to be optimized for providing them with a comprehensive social, psychological-psychiatric, medication andsomato-neurological help on the basis of a biopsychosocial paradigm.The objective of the study was to increase the level of medical care to combatants of the Antiterrorist Operation /Joint Forces Operation (ATO/JFO) and person affected by the catastrophe at the Chornobyl NPP (ChNPP) with depres-sion associated with alcohol abuse through theoretical substantiation, development and implementation in theinstitutions of public health and other agencies involved of new principles and algorithms for diagnosis, treatmentand prevention.The object and methods of the study were 160 ATO/JFO combatants from the age of 22 to 56 years old (M ± SD:(41.5 ± 16.5) years) with alcohol and depressive disorders the main group. The comparison groups included 81Chornobyl catastrophe clean-up workers (liquidators) with post-traumatic stress disorder and comorbid chroniccerebrovascular pathology, as well as other contingents affected by the Chornobyl catastrophe. Clinical-anamnestic,socio-demographic, clinical psychopathological, psychodiagnostic, neurophysiological and neuroimaging methodswere used. Somato-neurological clinical examinations and laboratory tests have been applied. The analysis of thedata was performed using MS Excel spreadsheets and statistical package Statistica 10.0 (StatSoft) with the Studentt-criterion, paired t-test, criterion χ2, and Fisher exact test.The study design of the main group consisted of 5 stages: 1) screening; 2) inclusion; 3) randomization; 4) treat-ment and 5) catamnestic (follow-up) observation.Results. In the main group the distribution of depressive syndromes was revealed as follows: depressive-hypochon-dric - in 68 (42.5 %) patients; 2) asthenic-depressive - in 33 (20,6 %); 3) anxiety-depressive - in 31 (19.4 %); 4)depressive-dysphoric - in 14 (8.8 %); 5) apathetic-depressive - in 7 (4,35 %); and 6) simple depressive - in7 (4,35%). The combatants after participation in the ATO/JFO had personality deformation and irritative changes of thebrain bioelectric activity, thickening of the intima-media complex and venous dyshaemia in the basal veins ofRosenthal. In liquidators there is an excess of depressive disorders, the frequency and severity of which increase inproportion to the radiation dose. These disorders are characterized by progressive course, personality changes withpsychosomatic pre-disposition, comorbidity with cerebrovascular pathology, neurocognitive deficits and high fre-quency (24 %) of secondary alcohol abuse. The relationship between depressive disorders and alcohol dependencein the examined patients is diverse. Their variants differ in certain clinical manifestations and to a large extentdetermine the differential diagnosis and differentiated approaches to treatment, prevention and medical and socialrehabilitationConclusions. The comorbidity of depressive disorders with the abuse of alcohol by combatants and person affectedby the catastrophe at the ChNPP is gaining an increasing significance first of all because of the increased risk of suicidal behavior. The proposed diagnostic complex and differentiated approaches to treatment, prevention and med-ical and social rehabilitation may increase the level of medical care for the ATO /JFO combatants and the Chernobylcatastrophe survivors with depression associated with alcohol abuse.

Myastenia and small doses of ionizing radiation: experience of successful use of rituximab for treatment of an irradiated with myasthenia gravis. / MIASTENIIa I MALI DOZY IONIZUIuChOÏ RADIATsIÏ: DOSVID USPIShNOGO ZASTOSUVANNIa RYTUKSYMABU DLIa LIKUVANNIa OPROMINENOGO Z MYASTHENIA GRAVIS.

A clinical case of the rituximab («Rituksim¼, «Mabthera¼) use to treat a man affected by the Chornobyl NPP acci dent with malignant resistant form of myasthenia gravis in conjunction with chronic mixed infection by Toxoplasma, Epstein Barr virus, Cytomegalovirus and Herpes simplex virus is described. In the dynamics of two year's observa tion the clinical efficacy of monoclonal antibodies was shown as the main symptoms stabilization and reducing doses of glucocorticoid and anticholinergic therapy. The positive effect was marked in the nearest and remote peri ods. Taking to account the efficacy, safety and good tolerability of rituximab, it is advisable to recommend treat ment for people exposed to ionizing radiation and developing myasthenia associated with chronic mixed infection by Toxoplasma, Epstein Barr, Cytomegalovirus and Herpes simplex virus.

Psychophysiological characteristics in the ChNPP accident clean-up workers, exclusion zone evacuees and anti-terrorist operation servicemen. / PSYKhOFIZIOLOGIChNI OSOBLYVOSTI UChASNYKIV AVARIÏ NA ChAES, EVAKUY̆OVANYKh IZ ZONY VIDChUZhENNIa TA UChASNYKIV ANTYTERORYSTYChNOÏ OPERATsIÏ.

OBJECTIVE: Evaluation of interdependencies between psychometric parameters and spontaneous cerebral electric activity in the ChNPP accident clean up workers, evacuees from exclusion zone, and anti terrorist operation service men. OBJECT AND METHODS: Psychometric and neurophysiological parameters were reviewed in the study subjects retro spectively and in comparison. Study population included the ChNPP accident clean up workers (ACUW), evacuees from the 30 kilometer exclusion zone, specifically in a sample from a cohort of the NRCRM Clinical Epidemiological Register (n=316), and anti terrorist operation servicemen (n=81) undergoing rehabilitation in the NRCRM Radiation psychoneurology department. A control group of persons (n=84) was also involved in the study. Diagnostic method ology for the characteristic personality features, namely the personality test of character accentuation by G. Shmishek and K. Leonhard, and Eysenck Personality Inventory (by H. J. Eysenck) were applied. Computer EEGs were registered and analyzed on the 16 channel electroencephalograph DX 4000 (Kharkiv, Ukraine). RESULTS: In the aftermath of the emergency period, a personality deformation occurs in the clean up workers and survivors of the ChNPP accident, which is characterized by aggravation of such personality traits as jam (fixedness), emotiveness, pedantry, anxiety, cyclothymia, excitability and disthymia, with diminished hyperthymia and ostenta tion (demonstrability). Increased incidence of fixedness, pedantry, cyclothymia, affectability and disthymia with decreased hyperthymia were revealed in the group of ATO participants. Cerebral bioelectrical activity in the ChNPP ACUW was characterized by an increased delta activity power with decreased beta and theta activity power and dom inant frequency in comparison with all groups of survivors and control group. The ATO group was different from groups of survivors and control group with a lower power of delta, theta and beta activity, and a higher dominant frequency. Introversion featured a negative correlation with delta and theta activity index along with positive cor relation with alpha activity index. The absolute spectral power of beta, alpha and theta bands positively correlated with introversion. Increase in neuroticism featured a decrease in theta activity index and an increase in beta activ ity index along with decreased theta and delta band absolute spectral power. CONCLUSIONS: There is a deformation of personality in the group of ChNPP ACUW, evacuees from the 30 kilometer zone and ATO servicemen. Deformation of personality correlates with abnormal cerebral bioelectrical activity.

Cognitive evoked potentials P300 after radiation exposure. / KOGNITYVNI VYKLYKANI POTENTsIALY P300 PISLIa OPROMINENNIa.

OBJECTIVE: The study was aimed at evaluating features of brain information processes and cognitive functioning in the remote period after irradiation due to the Chornobyl accident by using cognitive evoked potentials P300. MATERIALS AND METHODS: The study included 128 people, 112 male Chornobyl clean up workers in 1986-1987 with the records of radiation doses available in Clinical and Epidemiological Registry (CER) of State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine¼ (NRCRM) (study group) and 16 unexposed persons due to the Chornobyl disaster (control group). At the time of the survey the average age of clean up workers (M ± SD) was (57.3 ± 5.9) years, range 44-65 years, and of unex posed persons was (57.3 ± 6.5) years, range 44-65 years. Radiation doses were within the range 0.0002-1.23 Gy, with the arithmetic mean dose (M ± SD) of (0.2 ± 0.2) Gy and the geometric mean dose of 0.1 Gy. RESULTS: The radiocerebral effect in the projection of the left posterior superior temporal gyrus (Wernicke's area) proportionally to the radiation dose with the possible threshold of 0.05 Gy of total irradiation was revealed, with increasing radiation dose cognitive component P300 amplitude reduces and its latency period (LP) increases, espe cially at doses > 0.3-0.5 Gy. At doses > 0.5 Gy the functional relationship with the radiation dose for LP P300 increase in the projection of Wernicke's area (r = 0.9; p = 0.027) has been found. CONCLUSIONS: The neurophysiological features detected are fully consistent with hypotheses both on radiosensitiv ity of human central nervous system and accelerated aging of the brain under the influence of small doses of ioniz ing radiation, and have questioned the feasibility of long term manned space flights (including Mars) until the development of adequate radiation hygiene standardization for space crews and invention of means for radiation protection of space flights. Further dynamic clinical and neurophysiological monitoring of individuals exposed to ionizing radiation is necessary. To identify the neurophysiological biological markers of ionizing radiation further international researches with adequate dosimetry support are needed.

Gene expression, telomere and cognitive deficit analysis as a function of Chornobyl radiation dose and age: from in utero to adulthood. / PORUShENNIa GENNOI EKSPRESII, TELOMER TA KOGNITYVNYY DEFITsYT IaK FUNKTsIIa DOZY U OPROMINENYKh IN UTERO TA V DOROSLOMU VITsI VNASLIDOK AVARII NA ChAES.

UNLABELLED: Objective - to estimate the possible effects of low dose ionizing radiation on human cognitive function in adult hood and in utero. MATERIALS AND METHODS: Cognitive tests, telomere length and expression of genes regulating telomere function were studied in Chornobyl cleanup workers who were exposed to doses under 500 mSv (n = 326) and subjects exposed in utero during the first days after the accident Prypiat town (n = 104). The neurocognitive assessment covered mem ory, attention, language, executive and visiospatial functions. In young adults after prenatal exposure a relation ship was analyzed between a cognitive function and radiation dose to foetus, brain and thyroid gland. Internal con trols were used for both groups - the group of Chornobyl cleanup workers exposed in doses less than 20 mSv and an age matched comparison group from radioactively contaminated areas for subjects exposed in utero. RESULTS: Cognitive functions in cleanup workers exposed to ionizing radiation at adulthood are characterized by symptoms of a mild cognitive impairment according to the MMSE (mean group score 25,58 ± 2,95) and a significant ly higher level of mental disorders according to the BPRS in a dose related manner. Cleanup workers exposed to doses over 500 mSv demonstrate a significant cognitive deficit in comparison with those exposed below 500 mSv and espe cially non exposed patients. Subjects exposed in utero during the check at age of 25-27 years exhibit an excess of the disorders of autonomic nervous system (ICD 10: G90). Neurological microsymptoms as well as neurotic, stress relat ed and somatoform disorders (F40-F48) dominate. Relationship were revealed between the TERT, TERF1, TERF2 genes expression, relative telomere length (RTL),cognitive deficit and cerebrovascular pathology, radiation dose and age. Telomere length in cleanup workers is sreduced after 50 years (6.1 %). The most significant reduction in telomere length is shown after 70 years (11.7 %). Negative correlation was found between telomere length and degree of cog nitive deficit (MMSE scale) and between age and degree of cognitive deficit. The RTL is significantly decreased in groups of persons with cognitive deficit compared to a comparison group. Telomere length at the late period after low dose radiation exposure is downregulated by the high TERF2 gene expression combined with low expression of TERT gene. After exposure to doses over 250-500 mSv a cognitive deficit and dementia were associated with a substantial increase in TERT gene expression, overexpression of TERF1 and decrease in expression of TERF2 gene. A relationship was revealed between the TERF2 gene expression and CD95+ cell fraction susceptible to apoptosis. CONCLUSIONS: This study shows that cognitive deficit in humans at a late period after radiation exposure is influ enced by dose, age at exposure and gene regulation of telomere function.