8 - Understanding Risk from Radiation Ex

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Understanding Risk from Radiation Exposure : 

Understanding Risk from Radiation Exposure

Understanding Risk from Radiation Exposure : 

Understanding Risk from Radiation Exposure Effects of ionizing radiation exposure on biological systems. Short term and latent effects, exposures of the embryo and fetus will be evaluated, along with special consideration of internally deposited radionuclides of importance in occupational settings. Radiation bioeffects are put into perspective by discussion of dose response and risk models.

Radiobiology : 

Radiobiology The study of the action of ionizing radiations on living things. Biology primer see http://www.biology.arizona.edu/cell_bio/tutorials/cell_cycle/main.html

Biological Effects : 

Biological Effects Absorption of energy in biological material leads to excitation or ionization. excitation: raises electron to higher energy state without ejecting it from the atom. Radiations can be emitted from this process ionization: ejects electron from the atom. Radiation is also released in the process

Energy absorption in Radiobiology : 

Energy absorption in Radiobiology Photons absorbed Energy deposited in cells and tissues unevenly in discrete packets typical energy per ionizing event ~ 33 eV Typical C=C bond is 4.9 eV Where does remainder go?

Direct and Indirect Action : 

Direct and Indirect Action Biological effects of radiation result principally from damage to DNA DNA the “critical target” Target can be directly damaged by radiation Target can be indirectly damaged

Direct and Indirect Action of Radiation in Biological Systems : 

Direct and Indirect Action of Radiation in Biological Systems Indirect Action Direct Action OH· 2 nm 4 nm

Chain of events in X-ray absorption : 

Chain of events in X-ray absorption Incident X-ray beam ß Fast electron (e-) ß Ion Radical ß Free Radical ß Chemical changes from bond breakage ß Biological Effects

Time Scale of Events : 

Time Scale of Events Initial ionization: 10-15s Ion radical lifetime: 10-10s Free radical lifetime: 10-5s Breakage of bonds and expression of biological effects: hours, days, months, years cell killing: hours to days oncogenic: years mutation in germ cell: generations

Contrast Between Neutrons & Photons : 

Contrast Between Neutrons & Photons X and ?-rays indirectly ionizing produce fast moving secondary electrons Neutrons indirectly ionizing produce recoil protons, alphas, and heavier atoms

Neutron Interactions : 

Neutron Interactions Direct action dominates for densely ionizing radiations 20 charged particles result in a dense column of ionizations more likely to interact with the DNA Free radicals are also produced Recoil protons, alphas, heavy fragments massive -similar size to medium densely ionizing positively charged

Direct and Indirect Action of Radiation in Biological Systems - Neutrons : 

Direct and Indirect Action of Radiation in Biological Systems - Neutrons Indirect Action Direct Action OH· 2 nm 4 nm fast neutron

Summary of Pertinent Conclusions : 

Summary of Pertinent Conclusions X- and ?-rays indirectly ionizing produce fast recoil electrons Neutrons are indirectly ionizing produce fast recoil protons, ?-particles, hcp Biological effects due to direct action indirect action about 2/3 of X-ray damage is by indirect action Photons - Indirect action dominates Heavy particles - direct action dominates

Radiobiological Studies : 

Radiobiological Studies Methods Used to Assess Radiation Effects

Radiation Effects: Determining the Mechanism of Cell Killing : 

Radiation Effects: Determining the Mechanism of Cell Killing Sensitive sites are The nucleus Not the cytoplasm Early studies microbeams nonmammalian cells cytoplasm or nucleus irradiated

Nucleus vs Cytoplasm - Radiosensitivity : 

Nucleus vs Cytoplasm - Radiosensitivity Habrobracon (wasp) eggs Average # of incident a’s needed to reduce hatchability to 37%: nucleus: 1 cytoplasm: 17.6 x 106 150mm 39mm Penetration of 210Po a

Irradiation of Cytoplasm : 

Irradiation of Cytoplasm Irradiation of part of cytoplasm of a cultured Chinese Hamster cell by a-particles from a polonium-tipped micro-needle The irradiated volume is limited by the range of the particles Cover slip ? range Irradiated volume Polonium-tipped needle

Other Evidence for Chromosomes As Primary Target in Cell Killing : 

Other Evidence for Chromosomes As Primary Target in Cell Killing Cells killed by radioactive tritiated thymidine incorporated into DNA Structural analogues of thymidine when incorporated substantially increase radiosensitivity of cells Transplantation of irradiated nucleus into unirradiated cell is lethal at doses that an unirradiated nucleus can survive

Other Methods in Radiation Effects Research : 

Other Methods in Radiation Effects Research Methods for assessing dose response in vitro: cell survival curves irradiate seeded cells assess colony formation determine surviving fraction in situ - clonogenic endpoints clones regrowing on irradiated skin Whole animal studies

In Situ Tests - Clonogenic Endpoints : 

In Situ Tests - Clonogenic Endpoints 3000 rads surficial 30 kV x-rays no dose, shielded Test dose, D Assess regrowth cells/cm2 Moat size of irradiated area will depend on dose

Skin Studies - Example Data : 

Skin Studies - Example Data Dose in Rad 500 1000 1500 2000 2500 104 103 102 101 100 10-1 10-2 Number of surviving cells per cm2 of skin Split Doses, 24 hours Single Doses

Another “functional” endpoint : 

Another “functional” endpoint Expose animals to graded dose Wait 3 days Sacrifice animal Thin-section jejunum Score for regenerating crypts per circumference

Fractionating dose extends survival : 

Fractionating dose extends survival Dose in Rad 200 300 102 101 100 10-1 Surviving crypt cells per circumference 1 2 3 5 20 (fractions)

What Have We Learned in Radiation Response of Tissues : 

What Have We Learned in Radiation Response of Tissues Response is a function of Cell sensitivity Cell population kinetics Cell survival curves irrelevant in highly differentiated cells (no mitotic future) Closed population of mature cells very resistant Self-renewing tissues: dividing cells are weak link

Cell Sensitivity - Cell Type Matters : 

Cell Sensitivity - Cell Type Matters

Cell Types : 

Cell Types Stem Differentiated Functional (mitotically dead) spermatozoa red blood cells specialized cells - no nucleus, don’t regenerate Self sustaining, population remains stable

Tissue response, cont’d : 

Tissue response, cont’d Loss of reproductive capacity occurs after a few Gy Impact to tissue/organ after dosing depends on how well it can function with reduced number of cells Time between dose & expression of damage is variable lifetime of mature cell time for stem cell to mature to functional state

Radiation Response, cont’d : 

Radiation Response, cont’d Blood cells lifetime 3-4 months damage to stem cells not evident until red blood cell pool dies off Intestinal epithelium mature villi - short lifespan impact obvious within few days

Cell Sensitivity - Population Kinetics : 

Cell Sensitivity - Population Kinetics

The Cell Cycle : 

The Cell Cycle An ordered set of events, culminating in cell growth and division into two daughter cells Tc, full mitotic cycle Only mitosis can be distinguished when examining cells under a scope - chromosomes are condensed mitosis ~ 1 hour Radiography used to study G2 (2nd gap) M (mitosis) S (DNA Synthesis phase) G1 (1st gap) Cells that cease division

Mitosis : 

Mitosis

Length of Cell Cycle : 

Length of Cell Cycle M, S, G2 vary little between cells Tc varies 10 hours - 100’s of hours - mainly due to G1 In all cell lines cultured or in vivo, S never exceeds 15 h

X-Ray Sensitivity of Synchronous Cells : 

X-Ray Sensitivity of Synchronous Cells Chinese Hamster cells in culture Irradiated with 6.6 Gy after mitosis time of exposure varied cells irradiated at different stages in cell cycle Shown in next figure Key points mid-late S least sensitive

X-Rays & Synchronously Dividing Cell Cultures after 6.6 Gy : 

X-Rays & Synchronously Dividing Cell Cultures after 6.6 Gy

Radiosensitivity & Mitotic Cycle : 

Radiosensitivity & Mitotic Cycle Sensitivity Cells most sensitive close to mitosis Resistance greatest in latter part of S For long G1’s, there is an early resistance period followed by sensitive one at the end of G1 G2 ~ M in sensitivity Probably Repair is the key

Why’s & Wherefores of Sensitivity : 

Why’s & Wherefores of Sensitivity Cellular progression controlled by “checkpoint” genes ensure completion of events prior to progression through cell cycle, at G2 cells are halted to inventory & repair damage before mitosis cells where checkpoint gene inactivated these cells move directly to mitosis with damaged chromosomes are more sensitive to UV or g radiation or any DNA damaging agent

Cell Cycle Summary : 

Cell Cycle Summary Cell cycle components M, G1, S, G2 Cycles in culture crypt cells, 9 - 10 hours stem cells (mouse skin) 200 hr due to G1 Cells most radiosensitive in M, G2 Resistant in late S

Effect of Oxygen on Cells : 

Effect of Oxygen on Cells OER oxygen enhancement ratio aerated cells more sensitive typical values 2.5 - 3 for g and x-rays oxygen reacts with free radicals to produce peroxide - non repairable damage G1: 2.3 - 2.4 S: 2.8 - 2.9 G2 intermediate Implications are in radiation therapy

Oxygen Fixation Hypothesis : 

Oxygen Fixation Hypothesis “R”, functional group free radical, unpaired electron In general, the free radical reactions go like this: + O2 RO2· this is an organic peroxide RO2· + R¢H RO2H, which may be stable, but it’s not what you started with (fixed) ion pairs free radicals

Radiosensitivity & O2 Concentration : 

Radiosensitivity & O2 Concentration O2 levels 20 % normal 16% dizziness 10% immediate unconsciousness 2% is ~ plateau 0.5% is 50% effect Doesn’t take much for impact

Other Factors Affecting Dose Response : 

Other Factors Affecting Dose Response Relative Biological Effectiveness General rule - high LET radiation more damaging than low LET Different radiations can be compared: RBE = Dx/D D is dose of a given radiation required to produce a specific biological endpoint Dxis the X-ray dose needed under same conditions to produce same endpoint RBE results used to produce Q, wR values

Other Factors Affecting Dose Response : 

Other Factors Affecting Dose Response Dose Rate LD50, Gy Dose-rate, Gy h-1 15 10 5 10-2 102 100 Mice irradiated with 60Co

Other Factors Affecting Dose Response : 

Other Factors Affecting Dose Response Chemical Modifiers Sensitizers Oxygen Radioprotectors Sulfhydryl compounds (free radical scavengers) Heat

Radiation Effects on Living Systems : 

Radiation Effects on Living Systems Varies with: dose magnitude duration of exposure region exposed Responses categorized: stochastic: mutagenic/carcinogenic/ teratogenic nonstochastic (deterministic) - threshold

Radiation Effects : 

Radiation Effects Cellular Level cell function cell division chromosomal damage neoplastic transformation Organs prompt (death) delayed (fibrosis) Individual

Factors Affecting Cellular Radiosensitivity : 

Factors Affecting Cellular Radiosensitivity Cells that divide more rapidly are more sensitive to the effects of radiation ... … essentially because the resulting effect is seen more rapidly.

Factors Influencing Biological Effect : 

Factors Influencing Biological Effect Total absorbed energy (dose) Dose rate Acute (seconds, minutes) Chronic (days, years) Type of radiation Source of radiation External Internal Age at exposure

Factors Influencing Biological Effect : 

Factors Influencing Biological Effect Time since exposure Area or location being irradiated Localized (cells, organ) Extremities (hands, forearms, feet, lower legs) Entire body (trunk including head) Superficial dose (skin only - shallow) Deep tissue (“deep dose”)

Categorizing Exposure : 

Categorizing Exposure Acute Single, large, short-term whole-body dose Characterized by four sequential stages Initial (prodromal) - lasts 48 hrs Latent - 48 hr to 3 weeks Manifest illness - 6 to 8 weeks postexposure Recovery (if death does not occur) weeks-months Chronic Lower, protracted dose

Terms : 

Terms Acute exposure - dose received in a short time (seconds, minutes) Acute effects - symptoms occur shortly after exposure Chronic exposure - dose received over longer time periods (hrs, days) Delayed effects - symptoms occur after a latent (dormant) period

Terms : 

Terms Somatic effects - those which occur in the person exposed Genetic effects - those which occur in the offspring of exposed persons Stochastic effects - likelihood of effect is random, but increases with increasing dose Non-stochastic effects - likelihood of effect is based solely on dose exceeding some threshold

Symptoms of Acute Radiation Sickness : 

Symptoms of Acute Radiation Sickness Three categories (E. Hall, 1994) Hemopoietic: 3-8 Gy LD50/60 radiation damages precursors to red/white blood cells & platelets prodromal may occur immediately symptoms: septicemia, survival mixed examples include Chernobyl personnel (203 exhibited symptoms, 13 died)

Symptoms, continued : 

Symptoms, continued Gastrointestinal : >10 Gy radiation depopulates GI epithelium (crypt cells) abdominal pain/fever, diarrhea, dehydration death 3 to 10 days (no record of human survivors above 10 Gy) examples include Chernobyl firefighters Cerebrovascular : > 100 Gy death in minutes to hours examples include criticality accidents

Delayed Effects : 

Delayed Effects Some biological effects, either from acute or chronic exposure may take a long time to develop & become evident in exposed individual. Called delayed or late, somatic effects Cancer Leukemia Bone Cancer Lung Cancer Life Shortening Cataracts

Other Effects : 

Other Effects Mental Retardation Genetic Effects

Sources of Human Data : 

Sources of Human Data Considerable body of data exists Atomic-bomb survivors RERF 93,000 survivors 27,000 nonexposed comparators

Sources of Human Data : 

Sources of Human Data Medical patients Therapeutic Thymus treatments - increase in thyroid tumors Tinea capitis (ringworm of the scalp)- 10,000 children- 6 fold increase in malignant tumors of thyroid Ankylosing spondylitis (inflammatory arthritis that affects the spinal joints) - 14,000 patients - increase in leukemia Diagnostic

Sources of Human Data, cont’d : 

Sources of Human Data, cont’d Body of data, cont’d Radium dial painters - several hundred, bone cancer Uranium miners - thousands - lung cancer Accidents Critical assemblies Particle accelerators Radiation devices Weapons fallout Chornobyl

Examples of Dose-Response Relationships : 

Examples of Dose-Response Relationships Dose Response (e.g., Cancer Fatality or Cataract Induction) Linear, no threshold Linear, threshold Curvilinear

Non-Stochastic (Deterministic) Effects : 

Non-Stochastic (Deterministic) Effects Occurs above threshold dose Severity increases with dose Alopecia (hair loss) Cataracts Erythema (skin reddening) Radiation Sickness Temporary Sterility

Stochastic (Probabilistic) Effects : 

Stochastic (Probabilistic) Effects Occurs by chance Probability increases with dose Carcinogenesis Mutagenesis Teratogenesis

Dose Response: Radiation Carcinogenesis : 

Dose Response: Radiation Carcinogenesis Two effects of radiation exposure: deterministic (threshold) stochastic: cancer Radiation Standards set below threshold set to limit stochastic risk Controversy on “Risk” possibility of threshold low-dose data limited

Linear non-threshold hypothesis : 

Linear non-threshold hypothesis Fits data Single hit effect Accepted by most regulatory bodies Conservative Basis of current regulations

Biological Effects Data – An Overview of Factors Influencing our Understanding of Radiation Risk : 

Biological Effects Data – An Overview of Factors Influencing our Understanding of Radiation Risk

Current Issues in Radiobiological Research : 

Current Issues in Radiobiological Research There are several areas which are challenging our fundamental understanding of radiation damage at the cellular level (where DNA has historically been viewed as the principal target of concern). Three of these areas are now presented

Genomic Instability : 

Genomic Instability Also known as genetic and chromosomal instability Refers to genetic change occurring serially and spontaneously in cell-populations as they replicate. Radiation can induce a genome-wide process of instability in cells. Transmitted over many generations leads to enhanced frequency of genetic changes among progeny of the original irradiated cell. Observed with Cell systems in vivo and in vitro and Low as well as high-LET radiation. Adjacent, un-irradiated cells. Generally accepted Unanswered questions mechanisms, how it is initiated and how it is maintained

Bystander effects : 

Bystander effects Conventional model of radiation-induced damage requires damage of DNA either from direct interactions of radiation or from free radicals created nearby. Recent studies have demonstrated damage (such as altered gene expression) occurring in cells not directly exposed to radiation. Evidence that damage may be a consequence of intercellular signaling, production of cytokines, or free-radical generation. Thought that these effects are related to inflammatory-type responses. Significance of the bystander effect as it relates to consequences of radiation exposure is not yet known.

Adaptive Response : 

Adaptive Response Increasing number of studies show adaptive protection responses occur in living cells after single or protracted exposures to X- or ?-radiation at low doses. Observed both in vivo and in vitro Documented across a wide range of organisms from bacteria, and viruses to plants and animals. Two types of protection are identified: Prevention and repair of DNA damage. Removal of damaged cells. Mechanism is not immediate, but develops, presumably in response to physiologic stress. Manifests within hours and may persist weeks to months. No strong data supporting adaptive response following exposures to high LET radiation.

An Overview of the BEIR VII Report : 

An Overview of the BEIR VII Report Summarizing the Content of a Recently Issued Report of the NAS

Purpose of this Presentation : 

Purpose of this Presentation Provide a overview of the contents of the report of the BEIR VII committee Place the results of the BEIR VII study in the context

Limitations of Presentation : 

Limitations of Presentation Results are taken from the uncorrected prepublication version The content could change after final editing

Background : 

Background Since 1972, the National Academies has published a series of reports on the Biological Effects of Ionizing Radiation (BEIR) which augment other National Academies reports (dating back to 1956) on the health effects of low level radiation. At the request of the NRC, the Environmental Protection Agency, and the Department of Energy (DOE), the National Academies initiated in 1996 the first phase of a two-phase study to conduct a comprehensive review of the health risks associated with exposure to low-doses of ionizing radiation.

Background : 

Background When completed, this would be the seventh in a series of National Academies reports by a BEIR committee (BEIR VII). The purpose of the first phase of the study was to review the scientific literature and decide whether there was sufficient new information to warrant a full study. The National Academies concluded in the phase one report that it was an opportune time to proceed with a comprehensive re-analysis of the health risks associated with low levels of ionizing radiation because substantial new information had become available.

Previous Radiation Risk Studies : 

Previous Radiation Risk Studies BEARa I 1956 Low LET BEIR I 1972 Low LET BEIR III 1980 Low LET BEIR IV 1988 High LET BEIR V 1990 Low LET BEIR VI 1999 High LET BEIR VII 2005 Low LET a(Biological Effects of Atomic Radiation)

Purpose of the BEIR VII Study? : 

Purpose of the BEIR VII Study? To develop the best possible risk estimate for exposure to low dose, low energy transfer (LET) radiation in human subjects Low dose defined as exposures between 0 and 100 mSv (10 rem) or 100 mGy (10 rads). Low linear energy transfer (LET) radiation considered x-rays and ?-rays and low doses of neutron radiation

Purpose, continued : 

Purpose, continued The sponsoring agencies asked the National Academies to consider factors (e.g., age, gender, dose rate, diet) that may influence individual response to radiation exposure and to develop models that describe the causes of both cancer and non-cancer diseases attributable to radiation exposure. The sponsoring agencies would then use this information to assess the health risk to humans of exposure to low levels of ionizing radiation.

Purpose of the BEIR VII Study? : 

Purpose of the BEIR VII Study?

Primary Finding of BEIR VII : 

Primary Finding of BEIR VII “The current scientific evidence is consistent with the hypothesis that there is a linear, no-threshold dose-response relationship between the exposure to ionizing radiation and the development of cancer in humans.” However, details presented in the body of the report suggest that this conclusion is not definitive. The Committee could not definitively exclude the possibility of a threshold for radiation effects lower than 0.1 Sv (10 rem) of lifetime exposure in human studies and 20 mGy (2 rads) in DNA studies.

Issues : 

Issues Assessing the health risks associated with exposure to low doses of ionizing radiation is difficult because methods have not yet been developed that can deliver very low dose, low-LET ionizing radiation to a specific target. Similarly, techniques have not yet been developed that can detect and quantify any adverse or beneficial changes in cells or tissues that are associated with low dose radiation exposure. However, new information that has become available since the 1990 publication of the BEIR V report has improved our understanding of the health risks associated with radiation exposure.

Issues : 

Issues For reasons of practicality and with some exceptions, the Committee reviewed information that had been published through early 2004. An information cut-off date was established to allow the Committee to finalize the BEIR VII report. Consequently, many research findings published after the information cut-off date (e.g., studies funded by the DOE’s Low Dose Radiation Research Program) were not included in the BEIR VII report.

How was BEIR VII Review Achieved? : 

How was BEIR VII Review Achieved? Conducted a comprehensive review of pertinent epidemiological data Established principles for quantitative analysis of low dose and dose rate effects Assessed status and relevance of risk models and models of carcinogenesis

Epidemiological data : 

Epidemiological data The BEIR VII Committee examined several sources of epidemiologic data, including medical exposures of patients, occupational exposures of physicians and nuclear industry workers, and studies of groups of persons exposed to low levels of ionizing radiation (e.g., Chernobyl cleanup workers). The Japanese atomic bomb survivors from the cities of Hiroshima and Nagasaki are the single most important source of epidemiologic data that the BEIR VII Committee used to evaluate the risks of exposure to ionizing radiation at low (< 0.1 Sv or 10 rem) and moderate exposures (< 1 Sv or 100 rem). A group, or cohort, of atomic bomb survivors was established in 1950 using population census information to study the effects of ionizing radiation. This group, named the Life Span Study (LSS) cohort, is characterized by the following information:

Epidemiological data: Life Span Study (LSS) Cohort : 

Epidemiological data: Life Span Study (LSS) Cohort The available demographic information for the cohort encompasses 120,000 persons of both sexes and all ages. It was possible to estimate dose for approximately 87,000 members of the cohort who were present in Hiroshima or Nagasaki at the time of the bombings. The remainder lived in the cities, but were not present at the time of the bombings. Each member of the cohort was assigned a radiation exposure with values ranging from zero to several Sievert. Excellent medical data on cancer and non-cancer diseases has been collected for the cohort members.

How was BEIR VII Review Achieved? : 

How was BEIR VII Review Achieved? Considered: Relevant biologic factors Potential target cells and problems in determining dose to such cells. Recent evidence regarding genetic effects not related to cancer Considered all relevant data obtained from high radiation exposures or at high dose rates

Aside: Role in Radiological Protection Standards Development : 

Aside: Role in Radiological Protection Standards Development Radiation Effects Research Research Reviews: (Risk Estimates) BEIR UNSCEAR ICRP Recommendations ICRP IAEA NCRP National Standards EPA DOE NRC OSHA

Overview of the report : 

Overview of the report Excerpts

Risk Estimates : 

Risk Estimates Lifetime incidence and mortality risk for a population of 100,000 exposed to 10 Rad (0.1 Gy) 1 Rad (10 mGy) per year from age 18 to 65 0.1 Rad (1 mGy) per year for life A Dose and Dose Rate Effectiveness Factor (DDREF) of 1.5 applied Adjusted for US population

Dose and Dose Rate Effectiveness Factor : 

Dose and Dose Rate Effectiveness Factor The VII Committee considered the effect of dose rate on estimating radiation risk. It derived the estimated health risks from radiation exposure for the LSS cohort on the basis of individuals exposed to a single, acute exposure. These risk estimates are not applicable for individuals who receive multiple exposures or are exposed to radiation at very low dose rates for periods of several days, months, or years. A dose and dose rate effectiveness factor (DDREF) is used to account for the different radiation exposure conditions. The BEIR V Committee in 1990 recommended using a dose rate effectiveness factor of 2 for populations or persons exposed to small doses at low dose rates.

Dose and Dose Rate Effectiveness Factor : 

Dose and Dose Rate Effectiveness Factor In order to determine the DDREF value that should be recommended, the BEIR VII Committee employed a combined Bayesian analysis of dose response curvature for cancer risk using animal radiobiology data and medical data from the LSS cohort. It concluded that the DDREF values that could be used to adjust linear risk estimates for Japanese atomic bomb survivors range from 1.1 to 2.3. Using their collective judgment, the Committee selected a value of 1.5 as the DDREF for assessing health risks for solid tumors. However, they acknowledged that there is considerable statistical uncertainty in the DDREF selection.

Risk Estimates : 

Risk Estimates Estimates for: Leukemia and for all solid tumors Male, female and both sexes combined Specific organs Various ages

Risk Estimates - Data : 

Risk Estimates - Data The Japanese atomic bomb survivors were the primary source of data for estimating risks of most solid cancers and leukemia. For 2 of the 11 specific cancers evaluated, breast and thyroid cancer, atomic bomb survivor data were combined with data on medically exposed persons to estimate risks. Data from additional medical studies and from studies of nuclear workers were evaluated and found to be compatible with BEIR VII models.

Risk Estimates - Gender : 

Risk Estimates - Gender BEIR VII’s preferred estimate of lifetime attributable risk for cancer incidence and cancer mortality (Table 12-13) suggests that females are more sensitive than males to radiation exposure. Yet, the 95 percent subjective confidence intervals associated with estimated lifetime cancer risk for males and females suggest that the apparent gender difference may not be significant statistically.

Risk Estimates - Gender : 

Risk Estimates - Gender Consequently, the BEIR VII Committee combined the two risk estimates and cited an average value which also was done by the BEIR V committee. A potential gender difference was not discussed in the BEIR VII report

Risk Estimates : 

Risk Estimates Lifetime Risk to US Population All Solid Cancer: 5 x 10-2 per Sv (5 x 10-4 per rem) Leukemia: 6 x 10-3 per Sv (6 x 10-5 per rem) Does not appear different from BEIR V, ICRP, EPA and UNSCEAR estimates The new data and analyses have reduced sampling uncertainty, but the uncertainties remain very large with regard to transporting risk from the Japanese atomic bomb survivors to the U.S. population, and estimating risk for exposure at low doses and dose rates

Health Effects Other than Cancer : 

Health Effects Other than Cancer Other health effects (such as heart disease and stroke) occur at higher radiation doses, but additional data must be gathered before an assessment of any possible dose response can be made between low doses of radiation and non-cancer health effects.

Risk Estimates – Similarity Issues : 

Risk Estimates – Similarity Issues Despite the apparent similarity in estimated lifetime risk of solid cancer and leukemia, the technical basis used to develop the estimated risk by each organization is significantly different. UNSCEAR and ICRP values were calculated using the DS86 dosimetry system, Japanese cancer mortality data, and a DDREF of 2 to estimate risk to the global population. BEIR VII Committee used the DS02 dosimetry system, Japanese cancer incidence data, and a DDREF of 1.5 to estimate risk to the U.S. population..

Heritable Genetic Effects : 

Heritable Genetic Effects Adverse hereditary health effects that could be attributed to radiation exposure have not been observed in studies of Japanese children whose parents were atomic bomb survivors. However, studies of mice and other organisms have produced extensive data showing that radiation-induced cell mutations in sperm and eggs can be passed on to offspring.

Heritable Genetic Effects : 

Heritable Genetic Effects The BEIR VII Committee opined that there is no reason to believe that such mutations could not also be passed on to human offspring. For low or chronic doses of low-LET irradiation, the Committee assessed the genetic risks to be very small [30 to 47 cases per million first generation progeny per cGy (rad)] compared to the baseline or natural rates of genetic diseases (738,000 cases per million) in the population.

Mechanistic Studies : 

Mechanistic Studies Epidemiologic studies are unable to provide direct evidence of any dose response relationship at very low doses [0 to 100 mSv (10 rem)] because of the lack of sufficient statistical power to detect a health effect. Consequently, scientists are studying the effects of ionizing radiation in other systems such as single cells or in rodents. The Committee examined the relationship between radiation exposure and the induction of damage to DNA in cells.

Mechanistic Studies : 

Mechanistic Studies The Committee reviewed processes through which DNA damage is repaired or misrepaired, the subsequent appearance of gene and chromosomal mutations, and the development of cancer, to ascertain the dose response relationship for exposures less than 100 mGy (10 rads). The Committee acknowledged that the mechanisms that lead to adverse health effects after ionizing radiation exposure are not fully understood.

Mechanistic Studies : 

Mechanistic Studies The data that the BEIR VII Committee reviewed greatly strengthened their view that there are intimate links between the dose-dependent induction of DNA damage in cells and the development of cancer. When a photon or a single particle passes through a cell, the ionizing radiation produces several types of damage in DNA. The most important type of damage is formed at what are called “locally multiply damaged sites” – clusters of lesions or damage at a single site on a chromosome. These complex lesions are unique to radiation exposure and are not associated with normal metabolic oxidative processes.

Mechanistic Studies : 

Mechanistic Studies The number of locally multiply damaged sites created in a cell increase with both dose and LET. Experimental results in studies of chromosomal aberrations, malignant transformation, or gene mutations induced by relatively low total doses or low doses per fraction suggest that the dose-response relationship over a range of 20 to 200 mGy (2 to 20 rads) is generally linear.

Mechanistic Studies : 

Mechanistic Studies The BEIR VII Committee was uncertain whether a linear dose response relationship continues between 0 and 20 mGy (2 rads). In fact, the Committee noted that “the statistical power of the data was not sufficient to exclude the theoretical possibility of a dose threshold for radiation effects.”

Mechanistic Studies : 

Mechanistic Studies The BEIR VII Committee reviewed a large amount of phenomenological data for studies investigating adaptive response, low dose hypersensitivity, bystander effects, genomic instability, and radiation hormesis. The body of data suggests either an enhancement or reduction in radiation effects and, in some cases, the phenomena appear to be restricted to special experimental circumstances. Without a better understanding of the mechanism of action, the Committee could not predict how these phenomena will influence low-dose, low-LET dose response relationships.

Risk Estimates(per population of 100,000 exposed) : 

Risk Estimates(per population of 100,000 exposed) The estimates include 95% confidence intervals that reflect the most important uncertainty sources including statistical variation, uncertainty in adjusting risk for exposure at low doses and dose rates, and uncertainty in the method of transporting data from a Japanese to a U.S. population.

Committee’s Conclusions : 

Committee’s Conclusions Each of the Committee’s formal conclusions “contributes to refining earlier risk estimates, but none leads to a major change in the overall evaluation of the relationship between exposure to ionizing radiatation and human health effects.”

Conclusions : 

Conclusions Current knowledge on cellular/molecular mechanism of tumorgenesis support multiplicative risk projection over time Knowledge on adaptive responses, genomic instability, and bystander signaling that may act to alter radiation cancer risk was judged to be insufficient to be incorporated into modeling of epidemiological data

Conclusions : 

Conclusions The application of new approaches to genetic (heritable) risk estimation leads to the conclusion that low-dose induced genetic risks are very small when compared to baseline risks in populations The balance of evidence from epidemiological, animal and mechanistic studies tend to favor a simple proportionate relationship at low doses between radiation dose and cancer risk. Uncertainties on this judgment are recognized and noted.

Conclusions : 

Conclusions There are two competing hypotheses to the linear no-threshold model. One is that low doses of radiation are more harmful than a linear, no-threshold model of effects would suggest. BEIR VII finds that the radiation health effects research, taken as a whole, does not support this hypothesis. The other hypothesis suggests that risks are smaller than predicted by the linear no-threshold model are nonexistent, or that low doses of radiation may even be beneficial. The report concludes that the preponderance of information indicates that there will be some risk, even at low doses, although the risk is small.

Perspective – Changes since 1990 : 

Perspective – Changes since 1990 Three major changes have occurred since 1990 when BEIR V was published. First, an additional 12 years of follow-up medical data are available. Second, cancer incidence data for the cohort are available (previously, only mortality data was available).

Perspective – Changes since 1990 : 

Perspective – Changes since 1990 The impact of these two developments has been to reduce several sources of uncertainty in the assessment of cancer risk among the atomic bomb survivors. Third, the dosimetry system (DS86) used to assign radiation exposure to the atomic bomb survivors was replaced with an improved dosimetry system (DS02). Upon reviewing this information, the BEIR VII Committee made the following observations and conclusions:

Perspective – Changes since 1990 : 

Perspective – Changes since 1990 The DS02 estimates of neutron dose to cohort members do not differ greatly from the DS86 estimates. The health risk per Sievert for solid cancer and leukemia decreased by about 10 percent when estimated using the new dosimetry system. The new LSS cohort data provided additional evidence of a radiation-associated excess for all solid cancers at doses down to around 100 mSv (10 rem).

Perspective – Changes since 1990 : 

Perspective – Changes since 1990 The balance of scientific evidence tends to favor a simple proportional relationship between low radiation dose and cancer risk. The Japanese atomic bomb data are best characterized as a linear no-threshold dose response, although some low dose non-linearity is not excluded. The LSS dose response for leukemia is curvilinear with a statistically significant increase in leukemia observed at doses around 200 mSv (20 rem).

Perspective – Changes since 1990 : 

Perspective – Changes since 1990 It is unlikely that a threshold exists for the induction of cancer, but the occurrence of radiation-induced cancer at low doses will be small. The change in dosimetry systems have very little effects on factors that influence individual response to ionizing radiation exposure (e.g., gender, age at exposure, attained age since exposure, and time since exposure).

Perspective – Changes since 1990 : 

Perspective – Changes since 1990 The BEIR VII Committee uses radiation cancer risk estimates derived from the Japanese atomic bomb data to estimate radiation risk for the U.S. population. However, it is not necessarily straightforward to extend the risk estimates from the Japanese atomic bomb survivors to the U.S. population because the survivors of 1945 differ from the 21st century U.S. population.

Perspective – Changes since 1990 : 

Perspective – Changes since 1990 For example, the LSS cohort comprises Japanese subjects exposed to radiation under wartime conditions and the deprivations associated with a world war. Thus, the baseline (or natural) risks for developing cancer in any particular organ differ between Japanese and U.S. citizens (often as a result of dietary or environmental factors), and the BEIR VII Committee conceded that it was unclear how to account for those differences. Equally important, the incidence rates for several cancer sites have changed since 1950 as the Japanese culture has become more westernized.

Perspective – Changes since 1990 : 

Perspective – Changes since 1990 To account for these differences, the Committee used different radiation risk transport models to estimate organ-specific cancer risk in the U.S. population. However, the models used to transfer or “transport” cancer risk estimates to the U.S. population are not very precise. In some instances, the Committee augmented the Japanese atomic bomb data with medical information obtained from U.S. patients who received radiation therapy (e.g., for thyroid, breast, stomach and lung cancer).

Perspective – Changes since 1990 : 

Perspective – Changes since 1990 For most cancer sites, the Committee’s selection of a given transport model or combination of models was based on collective judgment. For many tissues, the uncertainty for cancer incidence and mortality estimates is very large with subjective 95 percent confidence intervals greater than an order of magnitude. The statistical uncertainty in the radiation risk estimates may obscure the potential impact of factors (e.g., age or gender at exposure) that affect individual radiation sensitivity.

Perspective : 

Perspective Is based primarily on epidemiological data Conservative interpretation of biological data Does not include data more recent than about 2 years old Only includes information that is formally issued in some manner: Peer reviewed literature Formal reports of government agencies and scientific organizations

Perspective : 

Perspective Does not appear to provide a basis for fundamental changes in radiation protection standards Risks not changed Risk model not changed

Ancillary Data for Your Own Persual : 

Ancillary Data for Your Own Persual Atomic Bomb Survivor Dataand Other Epid. Cohorts

Hiroshima : 

Hiroshima

Nagasaki : 

Nagasaki

Items of Importance : 

Items of Importance Bomb variations Neutron/gamma yield Dosimetry Shielding ABS Datasets

Bomb Specifics : 

Bomb Specifics Hiroshima (8/6/45) “Enola Gay” Pop = 245,000 “Little Boy” 120” x 28” dia. Gun Assembly Device U-235 (15 ktons) Deaths = 70 - 100,000 Nagasaki (8/9/45) “Bock’s Car” Pop = 230,000 “Fat Man” 128” x 60” dia. Implosion Device Pu-239 (21 ktons) Deaths = 60 - 70,000

Bomb Variations : 

Bomb Variations Difference in construction and fission material caused differences in neutron and gamma energy emission spectra The Nagasaki-type weapon was detonated at the Trinity Test Site in July 1945 and has been studied in other similar detonations The Hiroshima weapon was one of kind

Acute Effects : 

Acute Effects Immediate casualties caused by: Burns - 50% Radiation exposure - 30% Blast - 18% Other - 2% Many survivors had symptoms of acute radiation sickness Estimating doses is key to risk evaluation

ABCC : 

ABCC The Atomic Bomb Casualty Commission was established in 1947 to study the ABS cohort Four different estimates of dosimetry T57D T65D DS86 DS02 Latest considered most sophisticated

Slide 129: 

406th Medical General Laboratory--three railroad cars Traveling through Japan in 1946

ABCC to RERF : 

ABCC to RERF ABCC 1946 Presidential Directive from Harry Truman Funding through NAS/NRC from AEC Later US funding also from PHS, NCI Initial Japanese funding 1948 Ministry of Health and Welfare, Nat’l. Institute of Health Francis Committee 1955 Crow Committee 1975 RERF 1975

Dosimetry System 1986 (DS86) : 

Dosimetry System 1986 (DS86) Reassessment of the following: Number of fissions Neutron/gamma transport (through bomb material & air) Shielding by Japanese style houses Specifics of organ doses Gamma KERMA measurements Neutron-induced activity measurements National Research Council ... DS86 dosimetry “more accurate and more soundly based than those used previously”

Slide 132: 

Dose Comparison at Hiroshima and Nagasaki

Dose Distribution : 

Dose Distribution About 76,000 persons in the DS86 cohort KERMA distribution: No. of People 34,272 19,192 4,129 15,346 1,946 1,106 Dose (rads) < 1 1-5 6-9 10-99 100-199 = 200

DS86 Cohort : 

DS86 Cohort 5,936 cancer deaths (7.8%) as of 1985, with significant excess as follows: Cancer Type Stomach Lung Colon Leukemia Esophagus Breast Bladder Ovary Multiple Myeloma No. of Persons 2,007 638 232 202 176 155 133 82 36

DS86 Cohort : 

DS86 Cohort Remember that not all cases are necessarily radiation induced Natural cancer death rate in U.S.) ~ 17% Database also shows premature death, infertility, chromosomal abberations, birth defects, etc.

Hiroshima : 

Hiroshima FIA Kerma House Shield Kerma Organ Dose: Bone Marrow Organ Dose Equivalent: Bone Marrow Gy Gy Gy Sv g N g g g g g N N N N N

Nagasaki : 

Nagasaki

Estimating Individual Dose : 

Estimating Individual Dose Establish locations of exposed (and epicenter) Determine neutron & gamma energy spectra Determine shielding factors Develop in-air KERMA vs distance curves Develop ratios of KERMA to organ dose

Radioactive Impact on ABS : 

Radioactive Impact on ABS Prompt Radiation (instantaneous) KERMA at 1 km (w/ shielding): Hiroshima: 0.23 Gy (n) and 3.94 Gy (g) Nagasaki: 0.14 Gy (n) and 7.84 Gy (g) Delayed Radiation (fire ball) Dose at 1 km (w/o shielding): Both locations ~ 2.5 Gy

Radioactive Impact on ABS : 

Radioactive Impact on ABS Fallout Radiation (fission products) “Infinity Dose” at 3 km Hiroshima: 0.02 Gy Nagasaki: 0.3 Gy Residual Radiation (activation of soil) Area immediately around epicenter Short lived 0.1 Gy max; 0.01 Gy @ 0.5 km; 0.0002 Gy @ 1km

BEIR V ABS Database : 

BEIR V ABS Database The ABCC established the “Master File” to include those living in the cities on 10/1/50 As of 1991, the Master File contained nearly 750,000 individuals (exposed or unexposed, and their children) Various studies have been performed over the years on subsets of the Master File ABCC selected individuals for mortality and morbidity studies - “Master Sample”

ABS Database : 

ABS Database Master Sample 163,720 Life Span Study 120,132 Pathology Study 70,301 Adult Health Study 23,419 F1 Mortality Study 76,820 Biochemical Genetics 23,661 Cytogenetics 16,298 Master Sample Study Group F1 Study Group (children of exp & non-exp)

DS02 Revisions : 

DS02 Revisions The new DS02 system was developed by making more precise calculations based on the previous DS86 system; therefore, the revisions made were not fundamental. A comparison between DS86 and DS02 is shown in Table 1 for Hiroshima and Table 2 for Nagasaki. A major change is an increase of 7-10% in gamma rays for both cities. Although a change of neutrons is larger than that of gamma rays, this change is not large by comparison with the total dose since neutron dose was smaller than gamma-ray dose. The hypocenter has been repositioned only on the new and old maps. It does not mean that the hypocenter location has actually been repositioned on the ground. Radiation doses based on DS02 are shown in table 3.

DS86 vs DS02 : 

DS86 vs DS02 Table 1. Comparison between DS86 and DS02 (Hiroshima) DS86 DS02 Yield 15 kt 16kt Burst point 580m 600m Hypocenter 15m to the west Dose Gamma ray Increased by about 7% within 2km Neutron Increased by about 10% at 1km, decreased beyond 1km, and in agreement with DS86 at 1.8km

Table 2. Comparison between DS86 and DS02 (Nagasaki) : 

Table 2. Comparison between DS86 and DS02 (Nagasaki) DS86 DS02 Yield 21 kt No change Burst point 503m No change Hypocenter 2m to the west Dose Gamma ray Increased by about 10% at 1-2km Neutron Decreased by 10-30% at 1-2km

Table 3. Radiation doses based on DS02 : 

Table 3. Radiation doses based on DS02

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION : 

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION : 

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION : 

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION : 

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION : 

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION : 

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION : 

CURRENT EVIDENCE FROM ABCC/RERF STUDIES FOR LATE HEALTH-RELATED EFFECTS OF RADIATION

In Addition to the ABS : 

In Addition to the ABS ABS cohort is primary, but others used for: Confirmation DREF calculations Organ specifics High- and low-dose cohorts Small populations

Ankylosing Spondylitis : 

Ankylosing Spondylitis Spinal exposures of 14,106 patients from 1935 to 1954 in the UK Large fraction of the body receives dose Cancers seen at several sites (colon cancer believed to be associated with disease itself) In 1982, 727 cancer deaths w/ 104,146 p-yr of follow-up, but w/o dose information

Cervical Cancer Treatments : 

Cervical Cancer Treatments 150,000 women treated; 70% with implants Dosimetry determined for 11,000 women “Cases” - 2nd primary cancer developed in 4,188 women “Controls” - no 2nd primary cancer in 6,880 age-matched women Less healthy population since already diagnosed with one form of cancer

Canadian Fluoroscopy : 

Canadian Fluoroscopy 31,170 women treated for TB between 1930 and 1952 (multiple treatments) Breast-tissue dose determined 25% received more than 10 rads to breast Maximum of 2000 rads By 1980, 482 breast cancer deaths with 867,541 p-yr at risk Excellent data for fractionation effects

Massachusetts Fluoroscopy : 

Massachusetts Fluoroscopy 1,742 women treated for TB between 1930 and 1956 By 1980, 97% of cohort had been followed 74 breast cancer deaths; 30,932 p-yr at risk Small cohort, but very careful dosimetry

N.Y. Postpartum Mastitis : 

N.Y. Postpartum Mastitis 601 women having received radiotherapy during the 1940’s and 1950’s Matched with 1,239 women having disease but no radiotherapy Doses between 60 and 1,400 rads to breast 115 breast cancers in ~45 yrs of follow-up Small cohort

Radium Dial Painters : 

Radium Dial Painters Primarily women, ingesting Ra-226/228 during 1910’s and 1920’s (practice of tipping brushes abandoned in 1925) Of 1,474 persons in industry prior to 1930, 82 cases of “head carcinoma” have appeared Cancers mainly to sinus cavity and bones of the jaw and head

Underground Miners : 

Underground Miners World-wide cohort Exposed to radon progeny 22,562 persons followed for 30 yrs and a total of 433,019 p-yr at risk 459 lung cancer deaths (160 expected) Confounding is high: male subjects, limited age group, smoking not controlled, limited exposure time, not lifetime follow-up

Rochester Study : 

Rochester Study Children receiving radiotherapy to shrink enlarged thymus gland - 1930’s & 1940’s Irradiated at less than 1 yr old 2,652 children exposed 37 thyroid cancers observed

Israel Study : 

Israel Study Children (< 15 yrs) irradiated for “tinea capitis” (ringworm of the scalp) Average dose to the thyroid < 10 rads 10,834 children exposed 39 thyroid cancers observed

Diagnostic Radiography : 

Diagnostic Radiography Case-control study; leukemia patients asked to recall x-ray exams, then doses reconstructed From 3-20 years prior, more cases than controls had x-ray exams of their backs, GI tracts, and kidneys (and on multiple occasions) Strongest association between 6-10 yrs prior to diagnosis

Fallout : 

Fallout Three major study cohorts Residents in neighboring states Veterans participating in tests Global fallout Maximum doses of about 5 rem w/ about 50 rads to the thyroid Estimates suggest no significant increase in fatal cancer risk

Fallout - Utah Residents : 

Fallout - Utah Residents Death rates in Utah (by county) of childhood leukemia from 1944 to 1975 Utah residents divided as: Utah county rate > avg. county rate < avg. deaths <1951 <15 from ‘51-’58 born >1958 born >1958 <15 from ‘51-’58 deaths <1951 (exposed; unexposed)

Fallout - Utah Residents : 

Fallout - Utah Residents Mortality rates in all three groups of “below avg. counties” were comparable to U.S. avg. Unexposed groups in the “above avg. counties” had lower than U.S. avg. Exposed “above average” group had about 2.4 times the rate of the unexposed group (but, no significance at 90% confidence) BUT, all other cancers had rates lower in exposed and higher in unexposed groups?

Slide 173: 

National Cancer Institute Study Estimating Thyroid Doses of I-131 Received by Americans From Nevada Atmospheric Nuclear Bomb Tests http://rex.nci.nih.gov/massmedia/Fallout/contents.html

Fallout - Veterans : 

Fallout - Veterans U.S. study looked at ~50,000 vets and showed no excess leukemia British study - 22,000 - no excess Canadian study - 1,000 - no excess

Nuclear Veterans : 

Nuclear Veterans "Atomic veterans" qualify for disability compensation if they show any of 16 cancers and were stationed where radiation-causing activities occurred. Also covers workers at uranium enrichment plants in Paducah, Ky., Portsmouth, Ohio, and Oak Ridge, Tenn. Proposed for coverage are military personnel stationed on Amchitka Island, Alaska, before 1974. (Underground nuclear detonations were conducted in 1965, 1969 and 1971 at the island. )

Fallout - Global : 

Fallout - Global European study found no significant increase in leukemia U.S. study showed a peak in leukemia death rates during the 1960’s (increased fallout between 1957 and 1962) Death rates were highest in states with highest Sr-90 levels

Reactor/Facility Accidents : 

Reactor/Facility Accidents TMI Too early to see effects as of BEIR V Chernobyl 10,000 excess cancer deaths estimated in population of 75 million, but a natural expectation of 9.5 million deaths Increase may be detectable in Ukraine and Belarus Sellafield Increase in childhood leukemia fatalities

Nuclear Workers : 

Nuclear Workers Dosimetry very well known Healthy-worker effect = healthy population Many biases cloud the results No excess cancers shown to date (details in BEIR V, pgs. 381-382)

Recent Worker Study : 

Recent Worker Study Multiple myeloma for Oak Ridge, Hanford,  Los Alamos and Savannah River workers doses between 5 and 10 rems were associated with a threefold elevated risk doses over 10 rems were associated with a fivefold elevated risk None of the multiple myeloma cases had recorded doses over the current U.S. limit of 5 rems  per year.

High Natural Background : 

High Natural Background Normal terrestrial doses ~ 20 to 60 mrem/yr Brazil 6X global avg; increase in chromosomal aberrations India 4X global avg; increase in Down’s syndrome and CA China 10-20X avg; increase in CA, but not cancer mortality