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RADIATION INDUCED CANCER IN HUMANS

A Study Guide: Issues & data analysis
Summary of the work of John W. Gofman, MD,PhD

By Gary Evans, MD

PURPOSE

To discuss the cancer risks associated with commonly used medical diagnostic x-ray exposures. The study of radiation induced cancer brings many groups to the table. These include the D.O.E. with interest in nuclear materials manufacturing, storage, shipping and waste management, the D.O.D. with interest in nuclear weapons manufacturing, storage, and deployment, and the nuclear power industry (GE, Westinghouse, etc.) who have major financial incentives to develop and export nuclear technologies. The DOE and the GAO estimated in the late 1980's that nuclear site cleanup will total between 63 and 175 billion dollars [NYT-88, NYT-89]. If radiation risk estimates are increased, the cost of cleanup will increase dramatically as will the cost of radiation protection in general - recently estimated at $2000.00 per exposure rem [H.Phys1997]. The overall dollars involved are estimated to be over a trillion when plutonium trade and reactor exports are considered. Past low radiation risk estimates & statements of threshold or even beneficial effects of irradiation have been all but discarded by most committees as new data has become available. Whether the 3 mile island & Cherobyl disasters and the subsequent decreased public tolerance for reactor construction, waste processing and storage has played a roll in data acquisition and analysis is an interesting and open question.. Agencies involved include: NCRP, BEIR, UNSCEAR, IRCP, NRC, RERC, IEA, EPA, and groups of independent scientists.

 

ORGANIZATION OF DISCUSSION

Radiation basics:
Units of radiation exposure;
High vs. low LET radiation; X-ray energy content,generation;
Biologic response to radiation: Mutagenesis; Adaptive responses
Calculation: Radiation induced cancer rate per radiation dose.
  * Mathematics of risk: Relative vs. absolute
  * Shape of Dose-Response Curve: Linear vs. linear-quadratic vs. quadratic 
    (Concave UP or DOWN)
  * Threshold level of low dose radiation exposure and cancer induction
  * Risk at low doses and dose rates vs. high acute doses. 
    [DREF's - dose rate effectiveness factor]
  * Radiosensitivity to cancer induction with respect to age and sex.
  * Duration of excess cancer risk

Application of risks derived from one population to another population.
Risk assessments applied to common medical X-ray exams.
[Radionuclides, RBE factors for neutron and alpha emitters, etc. not discussed]

PHYSICAL DEFINITIONS AND PROPERTIES OF RADIATION
(Definitions of Ionizing Particles)

Alpha : Helium nuclei = 2 protons, 2 neutrons; Range in tissues 30-40:m (< sheet of paper) but intensely damaging. [KeV-MeV] : Enormous collision energy deposited along short track leaving great damage to localized area (High LET).

Beta : Nuclear electron ejected at high speed; Range in tissues a few millimeters. [KeV-MeV]

Neutron : Neutral particle with high LET but not as interactive as Alpha; Produced in nuc. disint.(key to chain reactions) [KeV-MeV]

Gamma : Photons generated in nuclear decay; Penetrating, less interactive w/ matter (Low LET) [KeV-MeV]

X-ray : Photons of lower energy than gamma, generated the atomic electron cloud level; [med=KeV] : Penetrate tissues similar to gamma radiation but recent evidence of 2x the risk of cancer induction over gamma.

UV : Photons of lower energy than X-Ray and Gamma, but ionizing level; Less penetrating than X-Ray or Gamma. [>4.13eV]

-- Photons below ionization energy: Visible [1.77 - 4.13 eV], IR [10-3 eV], microwaves [10-5 eV], radiowaves [10-10 eV]

 

UNITS OF RADIATION

Based on Energy deposition per mass of target [KE= mv2 - for equal KE radiation,heavier particle moves proportionately slower]

ROENTGEN: 1 electrostatic unit of charge/0.001293 gms air (0 deg.C & 760mmHg) = 83 ergs/gm air = 93 ergs /gm tissue

RAD: 10-5 joules per gram of material irradiated = 102 ergs per gram = 6.24 x 1010 KeV per gram

Note - Typical biochemical bond broken by 5-7 eV and electron ionized off of hydrogen atom by 13.6eV. 1 rad of radiation = 4.59 x 1012 tissue ionizations [2.08 x 109 photons/rad x30KeV/photon/13.6eV/H-ion] 1 PA CXR (6 yo) = 15 mrad = 6.9 x 1010 tissue ionizations [3.12 x 107 photons/15mrad x30KeV/photon/13.6eV/H-ion]

REM: "Roentgen equivalent man" - RAD x RBE in human RBE = Exp. & theoretical relative biologic effectiveness of given radiation type. [Relative to gamma: Alpha ~ 10-20x, Neutron ~1-10x, X-ray=2x]

ENERGY DEPOSITION: Whatever the type and/or source of radiation, when a beam passes through tissues a track of ionized atoms is generated via the stripping off of electrons from their orbits - resulting in broken chemical bonds. Those initially freed electrons then move off at high speed & collide w/ other atoms causing further ionizations. In this way a cascade of electrons (& broken bonds) percolate through the irradiated tissue until finally most of the energy is absorbed in new, often aberrant, chemical bonds. Most of the total number of X-ray photons generated by diagnostic machines are absorbed; only a small fraction are required for collision w/ the detector or film. [Note: Med. X-rays absorbed via Compton scattering &/or photoelectric effect w/ lower energy photons (mammography 25-27 KeV) absorbed predominantly by the photoelectric mechanism resulting in electrons w/ higher LET (more dangerous) than are generated by higher energy X-ray photons].

 

BJR89 TRACK CALCULATION FOR TYPICAL 90 KEV X-RAY BEAM:

1 rad of low LET radiation: deposition of 10-5 Joules / gram of tissue = 6.24 x 1010 KeV/gm Medical X-ray typically 90KeV peak = 30KeV average photon. [RADPRT81, RADPRT83] (6.24 x 1010 KeV/gm) / (30KeV/photon) = 2.08 x 109 photons/gm Range of 30KeV photons in tissue = 19.779m = 1.735 cells traversed per initial photon (2.08 x 109 photons/gm) x (1.735 cells traversed/photons) = 3.61 x 109 cells traversed/gm Nucleus is ~ 0.25 of volume of cell (3.61 x 109 cells traversed) x (0.25 nuclei volume / cell volume) = 9.03 x 108 nuclear volumes tracked / gm There are 6.75 x 108 nuclei per gram of tissue (9.03 x 108 nuclear vol's traversed / gm) / (6.75 x 108 nuclei./gram) = 1.3378 nuclear tracks / nucleus [at 1 rad] Dose resulting in one nuclear track (on average) per initial photon = (1/1.3378) x (1 rad) = 747.5 mrad Poisson distribution: At 750 mrad: 1 nuclear track (on average) / nucleus are actually distributed as follows: 37% will have no tracks, 37% will have single tracks, and 26% will have two or more tracks Chem. bonds are broken by 5-7 eV collisions:For 30KeV photons: 30KeV/6eV = 5000 bonds broken/init.photon [max]. Thus a typical 90 KeV diagnostic X-ray machine yielding a tissue dose of 750 mrad will generate up to ~ 5000 broken bonds in 2/3'rds (Poisson distribution) of ~ 109 nuclei per gram of tissue irradiated. BIOLOGIC EFFECTS OF LOW DOSE EXPOSURE, DNA

 

DNA DAMAGE - MALIGNANCY

MATH:

Dosimetry; Linearity vs. quadratic vs. linear-quadratic; DDREF's, Adaptation kinetics; Threshold vs. no threshold; Latency (genomic instability); Duration of risk Relative vs. absolute; Effect of age, sex, other factors (smoking)

DNA DAMAGE:

Ionizing radiation results in the freeing of electrons from target atoms. These travel at extremely high speeds and occasionally strike a critical region of DNA and if accurate repair is ineffective, cancer is one possible result. The common DNA lesions documented can be grouped into the following: [see also Jeggo PA]

* SSB: Linear w/ dose. Unusual end groups unlike physiol. oxidation lesions [Ward  1990]
* DSB Repair mech. error prone [GOF-90][Ward1988][Pfeiffer1998] 
* DNA-PROTEIN  X LINKS Error prone repair [see p3 NCRP draft] 
* MULTIPLY DAMAGED SITES Error prone repair [see p3 NCRP draft]
  "Ionizing radiations produce many different possible clusters
  of spatially adjacent damage, & analysis of track structures
  from different types of radiation has shown that clustered DNA
  damage of severity at least >/= double strand breaks can occur
  at biologic relevant frequencies at any dose."  
  [Brenner&Ward1992] Other ref's:[Goodhead1994][Hei,et.al.1997]  

The susceptibility to these lesions has been found (in vitro) to depend on cell type, on cell cycle phase, etc. Spont. rate of cell lesions ~24,000/cell/d [Helbock et al 1998]; these oxid. lesions are easily/accurately repaired [Ward 85,'95]

SUMMARY:

A 90KeV (peak) X-ray beam delivering a 750 mrad tissue dose will result in electron tracks through a large majority of cellular nuclei along the beam path (37% of nuclei w/ 1 trk.+26% nuclei w/ 2-3 trks). This causes breakage of up to 5000 bonds / ave.nucleus. The true ave. collision = 60 ev or 8-10 x that needed for simple bond breakage; the energy remaining is kinetic causing physical disruption after breakage. Repeat radiation exposures generate additive statistical risks of non-repairable or mis-repaired lesions occurring in critical DNA regions. Many studies have now demonstrated <100% DNA repair at moderate & low doses. Radiation induced cancer has been documented to follow multiple low (average of < 1 trk/nucl.) doses of medical X-ray irradiation given over time frames greater than the known DNA repair mechanisms which are completed in times of several minutes to 8 hours.

DNA DAMAGE -> GENOMIC INSTABILITY:

Mouse cells irradiated in vitro, placed into host mouse - no tumors created. If instead, post irradiated cells are grown to approx. 30 generations then injected into host animal, tumors result. This is not true for control cells not irradiated but grown in vitro in the same way. "The loss of stability of the genome is becoming accepted as one of the most important aspects of carcinogenesis." "One of the hallmarks of the cancer cell is the inherent instability of the genome." [Morgan 1966 p247 and p254]. Other ref's:[Nowell 976] [Cheng1993] [Kadhim1992,1994,1995] [Holmberg1994] [Marder1993] [Mendonca1993] [Kronenberg1994] [Ullrich1998] " Instead, initiation [of cancer] more likely appears to be an event that increases the genomic instability of the cells of subsequent rounds of cell division." [BEIR V p138]

MONOCLONAL SOLID TUMOR ORIGIN:

Evidence is now quite strong that all cancers are monoclonal in origin - i.e. one transformed cell is the initial cause of all cancers. [Wainscoat & Frey 1990] [Worsham et al 1996] [Nowell 1976] [Noguchi 1992] [Fialkow 1976, 1984] [Arnold et al 1983] [Cleary et al 1988] [Levy et al 1977] [Minden et al 1985] [Evans 1979] [Lloyd 1988]

DISEASES ASSOCIATED WITH INABILITY TO REPAIR DNA LESIONS:

There are a variety of enzymes responsible for DNA lesion repair. Several diseases are associated with increased cancer risk and are known to have poorly functioning DNA repair systems [Borek1983] [Chan1987] [Willis1987] [Cleaver1968] [Hecht1987] [Khan SG1998] [Kikpi MO] [Groisman1999] [Becker1998]

Examples of diseases associated with an increase in malignancy risk:

* Ataxia Telangiectasia Synd.: Double Strand DNA break repair mechanism defect
* Coccayne's Synd.: TCR (transcription coupled repair enzyme)[Cooper et al 1997] 
* Nonpolyposis Colorectal CA: Mismatch repair enzyme system 
* Blooms syndrome DNA: ligase repair enzyme defect 
* Xeroderma pigmentosum: DNA excision repair mechanism defect 
* Hepatitis B: Hep.B Virus X protein interferes w/ DNA repair mechanism -> hepatic CA.

 

RELATIVE (MULTIPLICATIVE) RISK

Many studies have now convincingly shown that cancer incidence each year post-irradiation increases at a rate related to the spontaneous cancer rate, specific for age & population. E.g.: if colon cancer incidence rates increase each year through life then in an irradiated group, the incidence rate will increase faster than the control, non irradiated group. The higher rate is equal to a multiplier of the spontaneous rate; this is what is meant by relative risk increase following irradiation. For radiation-induced cancer, relative risk analysis is the accepted mathematical model. [GOF-81,90][BEIR-V][NCRP98], etc.

 

SHAPE OF DOSE : RESPONSE RELATIVE RISK CURVE

This is a debated issue. Some studies are consistent with a linear dose-response curve [RERF91][RERF92], whereas other studies are consistent with supralinear responses (larger effect at low doses than at high doses) [GOF-81,90]. This remains an open question. In terms of age at exposure, the data is clear that relative risk is much higher at younger ages at irradiation. [Gof-Tam '69,'70][NCRP98][BEIR V] [Most reasonable to consider dose-response curve as either linear or supralinear (convex up);exercise due caution until more is known.

 

NO-THRESHOLD FOR RADIATION INDUCED CANCER

Most radiation researchers agree that based on current data there is likely to be no low-dose threshold for cancer. Unlike chemical toxins which when given in sufficiently low doses are detoxified or removed before damage is done, radiation is delivered on the cellular level by high speed electrons that literally crash through the cellular machinery. Many of the lesions that occur are repaired by cellular mechanisms (estimated repair events number 10,000 -24,000 / cell per day). If, however, a high speed electron, set in motion by a medical X-ray photon, collides with a critical portion of DNA and repair systems are unable to properly undo the damage, a malignancy may result. [UNSCEAR 1993 Rpt, p.634, para.74][NCRP98 draft rpt] Furthermore, even if it is postulated that double track events are required for misrepair -- at any dose, the Poisson distribution insures that some nuclei are hit by more than 1 track at a dose that is calculated to deliver an average of much less than or equal to one track through an average nucleus [i.e. <<750mrad]. As one single track can damage the DNA, there is no theoretical threshold of risk - i.e. As the dose decreases, the only change is in the number of targets struck but at any dose at least one target may be hit and may then generate a lesion leading to malignancy. With reference to adaptive effects, experimental evidence suggests that at least 500 mrad is required and that this results in only a 50% reduction in lesions. Repair mechanisms are therefore unable to fully protect at any dose level. Thus, there is no theoretical basis for belief in a threshold dose below which no sustained damage could occur. [NCRP98]

 

DURATION OF INCREASE IN EXCESS RELATIVE RISK AFTER RADIATION EXPOSURE

Several studies, including those listed in this paper continue to demonstrate that radiation induced excess cancer rates continue for at least 40 years after exposure and perhaps for a lifetime. The A-Bomb survivors, now 54 years after their exposure, continue to show excess cancer rates. A-Bomb survivors have also been shown to continue to carry chromosome abnormalities for at least 40 years after the exposure with dose dependent numbers of abnormalities documented. [GOF-81 ->A-Bomb data, Hempleman 1975, Shore 1977, Boice-Monson 1977, etc.] The peak incidence rate for solid cancers (non-hematologic) appears to occur at 30-40 years post irradiation. [GOF-90] "In contrast to the rates for leukemia & bone cancer, the rates for most other cancers appear to have remained in excess for as long as most exposed populations have been followed" [BEIR V p52] A possible explanation for ~ 10 year latencies seen for solid tumors: A single cell is critically irradiated, resulting in genomic instability. Assuming no immune killing effects, after >30 gen.'s the cell mass = 109 (1gm) -1012 (1 kg) cells. With immune killing and suppression there would be long cancer latencies & incidence durations from the initial damage.


EFFECT OF AGE AND SEX ON RADIATION SENSITIVITY - CANCER INDUCTION
Gofman's findings (A-Bomb study as well as meta-analysis of multiple studies)  

Several studies [eg. RERF91a, see refs] have also shown that children are more radiation sensitive than are adults. This increased sensitivity follows the relative risk model, i.e. after irradiation in childhood, the risk of cancer induction 20-40 years later is higher than if the same irradiation occurred in adulthood with cancers detected 20-40 years later in older age.

Although risk per dose is proportionately higher as age decreases, overall risk from medical diagnostic X-rays works out to be highest at ages between 5-10 years, as between these years the entrance dose grows faster than the relative risk of cancer falls as the child ages.

 

ORGAN SPECIFIC CANCER RATES FOLLOW RELATIVE RISK MODEL

Organs that have the highest malignant transformation potential include: mouth, chest, abdomen, Pelvis. Several studies: [eg. RERF90a, RERF94] have demonstrated that radiation induced excess cancer risk is related to the baseline risk rate (organ specific relative risk). If a particular organ is more likely to generate a cancer than another organ, when both are exposed to the same radiation dose, the increase in cancer rates of each will be proportional to the respective organ specific unexposed, spontaneous cancer rate.


BIOLOGIC EFFECTS OF LOW    DOSE EXPOSURE, ADAPTIVE RESPONSE
THE HISTORY OF "DDREFS"    

There has been a question as to whether a difference exists in cancer induction risk from acute delivery of a low radiation dose compared with fractionated, low delivery rate of a low total radiation dose. With animal based evidence only, a mathematical construct, "Dose and Dose Rate Effectiveness Factor" (DDREF) was created in the mid 1970's [UNSCEAR-77]. The logic for its initial use has been sited over the past 20 years despite increasingly conflicting human data. The current NCRP DRAFT (NCRP-98) report on Low Dose Radiation Effects makes a very strong case against the use of DDREF's or any other method that yields a non linear curve with lower effects at low doses. In fact there is now data suggesting a supralinear response with higher radiation induced cancer rates from low doses than from high dose exposure. [GOF-81, GOF-90]. In reference to low dose rate effects, there is a paucity of data to date. [Little 1999][Brenner 1999]

 

BEIR-V CONFLICTING REFERENCES:

"In spite of evidence that the molecular lesions which give rise to somatic and genetic damage can be repaired to a considerable degree, the new data do not contradict the hypothesis, at least with respect to cancer induction and hereditary genetic effects, that the frequency of such effects increases with low-level radiation as a linear, non-threshold function of the dose." [pg 4.] but then on pg.6: "For low LET radiation, accumulation of the same dose over weeks or months, however, is expected to reduce the lifetime risk appreciably, possibly by a factor of 2 or more." "For most other cancers in the LSS (A-Bomb Life Span Study), the quadratic contribution is nearly zero, and the estimated DREF's are near unity. Nevertheless, the committee judged that some account should be taken of dose rate effects and in chapter 1 suggests a range of dose rate reduction factors that may be acceptable." (pg.17) [see Tbl 1-4 "Summary of Dose Rate Effectiveness Factors for Low-LET Radiation" and on page 22: "There are scant human data that allow an estimate of the dose-rate effectiveness factor (DREF)"

 

MOST RECENT NCRP DRAFT REPORT:

"At the outset, it must be noted that radiation imparts its energy to living matter through a stochastic process, such that a single ionizing track has a finite probability of depositing enough energy in traversing a cell to damage a critical molecular target within the cell, such as DNA. Furthermore, the various types of DNA damage that are known to result from irradiation appear to increase linearly with the dose in low-to-intermediate dose range. Also, although most such DNA damage is reparable to varying degrees, some types of lesions - namely, double-strand breaks and multiply damaged sites - are often repaired through a process that is error-prone. Because of the vast number of target cells, vanishingly small frequencies of non-lethal, unrepaired or misrepaired lesions can nevertheless result in a finite number of cells undergoing a cancer-initiating event, even at low doses." [NCRP-Oct.98 p228] "Those lesions in DNA that remain unrepaired or are misrepaired may be expressed initially in the form of mutations, the frequency of which increases with the dose of radiation over the dose range in which the effects are amenable to measurement. Although the shape of the dose-response curve varies, depending on the LET of the radiation, the dose rate, the type of mutation, and other variables, it is noteworthy that mutation of types implicated in carcinogenesis - namely, point mutations and partial deletion mutations - have been observed to be inducible at relatively low doses, with apparently linear - nonthreshold dose-response relationships in various kinds of cells." AND pg. 229 "Thus, the data imply that traversal of the cell nucleus by a single low-LET radiation track may occasionally suffice to cause a chromosome aberration." Referring to a graph of excess relative risks established for solid tumor incidences, researchers at RERF stated: "clearly indicate that only LDEF [DDREF] values near 1 are consistent with the shape of the dose-response curve for solid tumor incidence. This suggests that a linear model provides a good description of these data and that no low-dose correction is needed." [RERF Update 4(3):5-6,1992] SUMMARY: Human data (& logic) are consistent w/ a linear dose-response curve at low doses & dose rates w/ some data consistent w/ supralinearity - i.e higher risks per rad at lower doses and/or dose rates than high and/or acute doses.


CRITICAL ANALYSIS AND CRITICISM OF BEIR V METHODOLOGIES
Summary of work of John Gofman, MD, PHD [GOF-90][GOF-96]

PROCEDURES THAT DIRECTLY UNDERESTIMATE RISK

1. Reliance on animal data The BEIR V report (p.22) states: "There are scant human data that allow an estimate of the dose-rate effectiveness factor." In its Executive Summary, however, the committee recommends use of a DREF (Dose and Dose Rate Effectiveness Factors) of at least two for environmental and occupational exposures with the evidence based largely on animal model experiments. This is the opposite of a conservative approach - that is, if one assumes that the data base (animal) is questionable, one should not decrease the assessed risk assessment applied to people. (DREF's lower the calculated radiation risk, based on the rate that doses are delivered - assuming that more slowly over time are less risky. The human data suggesting this is very unconvincing. Waldren C, et al; "Measurement of low levels of x-ray mutagenesis in relation to human disease"; Proc Natl Acad Sci USA 83: 4839-44 (1986) Found that conventional methods for measuring mutagenesis in mammalian cells seriously underestimated the contribution of radiation to cancer and genetic diseases. They found a 200 fold higher mutation frequency in the 0-50rad range then some previous conventional studies had found. They also found the curve of dose:mutation to be supra-linear.

Little, JB; "Low-Dose Radiation Effects: Interactions and Synergism" Health Phys 59: 49-56 (1990) Found significant differences with regard to inhibitory effects of DMSO, dose response and the effects of changes in dose-rate for radiogenic induction of mutations in rodent, compared with human cells. He found reduced effects in rodent cells when the dose was delivered at low rates but at high total doses, but did not find these effects in human cells between doses of 0-250rads. Thus the use of rodent cells to infer human cellular response is questionable.

Carnes BA, Fritz TE; "Responses of the beagle to protracted irradiation" Rad Res 128:125-32 (1991) 378 beagle dogs with accumulated doses between 450 and 3000 rads at varying rates between 3.8 and 26.3 rads/day showed no relationship between tumor mortality and dose rate but a clear linear relation with accumulated dose.

2. Discarding data The BEIR V report also discards data with little scientific basis for doing so. For example, a.) cancer deaths in A-bomb survivors over 75 years old are discarded owing to uncertainties of proper ascertainment of cause of death and b) breast cancer rates following fluoroscopic irradiation in women with tuberculosis were 6x higher in the Nova Scotia group than in another Canadian study group - they therefore chose to discard that data: "Within the Canada-TB cohort, the estimated risk per Gray for women treated in Nova Scotia was about six times that for women treated in other provinces. This difference is highly significant (p<0.001) the higher risk observed among Nova Scotia women is not attributable to non-linearities in the dose response. Since there is currently no explanation for thedifference within the Canadian-TB cohort and since the Committee was generally interested in low dose effects, it was decided to use the data on the Canadian-TB cohort without the Nova Scotia women, as the basis for risk estimates in the parallel analysis" [BEIR-V p255][see also GOF-96]


CRITICISMS OF RERF -    IMPROPER HANDLING OF A-BOMB DATA 
[1986 REFR COHORT CHANGES DISPUTED]

IMPROPER, NONBLINDED ALTERATION OF DOSE GROUP COHORTS:

After the 1982 analysis, RERF shifted thousands of people from one cohort to another in developing the new dosimetry. Those who worked on revising the dosimetry had knowledge of expected results therefore the change did not occur under blinded conditions. In addition, in 1986 RERF added 11,393 Nagasaki survivors who were exposed at a distance of 2500 to 9999 meters from the hypocenter and for whom complete follow-up during 1950 - 1982 was available. These 11,393 people were assigned to the 0 dose group to increase the precision of the background mortality rate estimates and consequently the excess risk estimates in Nagasaki. Again this was done in a non-blinded fashion. In 1987 the cohort was changed from 91,231 to 75,991 with 15,240 persons moved into suspension as the corrections made from the T65DR dosimetry to the DS86 dosimetry was not possible given a lack of relevant information. (This is 31% of the Hiroshima Dose-Group 2 cohorts!). The remaining 75,991 was denoted as the DS86 cohort group. Because of this nonblinded alteration of dosimetry and cohort status, Gofman chose to analyze the available data of all survivors through 1982 (37 years after the bombings) for analysis in his 1990 report.

COHORTS IMPROPERLY CONFIGURED - NOT AGE (ATB) AND SEX MATCHED

Therefore even without irradiation, risk of cancer and leukemia are different for these groups. The Gofman analysis removes this bias by reconfiguration of cohorts of dose groups. In the Gofman analysis, the only variable is therefore irradiation dose. Raw RERF data is not properly normalized for age & sex (groups must be equal to properly evaluate rad effect) Age Normalization: * RERF Ref. grps 1+2 used as model for all other dose grps (male & female) using ratio of each age band : total * From Table 11-D rows 17-21: Age bands 1-5 -- ratios: 0.180, 0.193, 0.241, 0.230, 0.156 respectively are used (Total # in each dose band) x (Approp. ratio above). Enter # as the norm'ed # in each age band for that dose. * Recalc. Observations: (Norm'ed # people / raw # people) x (raw observed #) = Norm'ed observations. * Recalc. Total observations for each dose group. Sex Normalization: * Use ratio found in reference group 1+2 (Tables 11-B,D Col's F where M/F = 27585/38443 = 0.717556) * Find total people in dose group - eg. Grp.1: (15,406 M + 21,767 F = 37,173). * Let F = age and sex norm'ed #females in Grp.1. Then 0.717556 x F is age and sex normed #males in Grp1 * F + 0.717556*F = 37,173 which is equiv. To 1.717556 * F = 37,173. Therefore F = 37,173/1.71756. * M=37,173 - F or M=37,173 - 37,173/1.71756 = 15,530.02 persons to enter into row 11G, Col.F (Row132) * Using same calculation, enter norm'ed numbers for each dose group after which all dose groups are norm'ed. * Recalc. Observations: (Norm'ed # people / raw # people) x (raw observed #) - Norm'ed observations.

DS86 DOSIMETRY Several dosimetry systems since the A-Bomb study began in 1950 as new information has been discovered. These include: T57D, T65D, T65DR and the current DS86 dosimetry systems. The new dosimetry was introduced simultaneous to the breaking of the initial cohort groups within the ongoing RERF study population. There are many variables in considering true exposure: not an exact system.

* Gamma vs. Neutron exposures: U235 in Hiroshima (10% neutron), Pu239 in Nagasaki (nearly all gamma).

* Neutron RBE, Activation nuclide generation and exposure, neutron and gamma shielding and capture, etc.

* Fallout and environmental exposure after the initial (less than 1 microsecond) gamma and neutron flux.

APPLICATION OF DATA TAKEN FROM STUDY POPULATION TO US POPULATION [GOF-90]

There is debate about the transfer of information from, for example, A-Bomb survivors to a mixed US population. In Japan there is a higher rate of stomach cancer than in the U.S. and in the U.S. there is a higher rate of breast cancer than in Japan. It has been argued that using the relative risk method and A-Bomb data could therefore inflate the projected risk of stomach cancer and underestimate the risk of breast cancer in a mixed exposure in the U.S.

ESTIMATE OF ONGOING RADIATION INDUCED CANCER FOR U.S. POPULATION (GOF-90; 25-15) In the U.S.: approx. 22% die of cancer = 2,200 cancer deaths / 10,000 people From GOF-90, pg25-15 26 cancer deaths / 10,000 people per rem of full body exposure 60 year dose accumulation calculation:


THE DIAGNOSTIC X-RAY RISK TABLES FOLLOWING BASED ON:
37.30 FATAL CA/104 PERSON*RAD  [GOF-85] 

Diagnostic X-rays increase a patients lifetime risk of cancer - the risk is quantifiable and has been quantified. There is no threshold of risk with respect to diagnostic X-rays or any other type of ionizing radiation. Most conservative model of risk: supralinear at low doses; certainly no less than linear dose - response. Malignant transformation is related to high speed electron tracks through cell nuclei resulting in ionization of portions of the DNA strands and subsequent misrepair of those strands. If the wrong portion of the molecule is damaged, malignancy can be the result. Radiation risk is additive with respect to total lifetime dose & multiplicative with respect to risk of cancer induction [ (excess risk) x (unexposed cancer rate) ] i.e. relative risk model is consistent with data

Metaphor: blindfolded person firing gun in random directions from 1000 yds away; target at 1000 yds distant is unlikely to be struck over 1 minute if the gun is fired at a 1x / min. rate. If, however, the target remains in place for several years, or if the gun is fired at a very rapid rate, the statistical risk becomes quite high that eventually, the target will be struck. Thus, exposure risk is independent of rate and is additive with respect to total exposure.

Dose to peak effect = 40 years after latency of 10-12 years for solid cancers and for leukemia peak effect = 7-10years. Duration of increased relative risk of cancer appears to be lifelong and follows the relative risk model Cancer risk is dependent on age at irradiation, sex and baseline organ specific cancer rates. Medical X-rays are twice as damaging to biologic systems as are gamma rays produced by radionuclides Minimum risk est. for mixed U.S. pop. from gamma: 1 extra cancer fatality / 268 - 2878 people irradiated w/ 1 rad. Conservative risk est. " " U.S. pop. from X-rays: 1 extra cancer fatality / 179 - 616 people irradiated w/ 1 rad. The diagnostic X-ray risk table to follow is based on:1 extra cancer fatality / 268 people irradiated w/ 1 rad

SUMMARY:

Exercise caution with x-rays, consider the organ dose & risk/benefits to pt. This diagnostic tool is not without significant risk of lifetime cancer induction. As information is available, we are obligated to obtain informed consent for any radiological procedure (w/ the understanding that full risk table accuracy must be given as a range of as much as 10x less risk than these tables state based on lowest risk assumptions of BEIR V. It is better to err on the side of conservatism & safety than to use risk assessments influenced by financial considerations of nuclear clean-up, worker safety, plutonium trade & nuclear technology export. Read radiation studies with care, common pitfalls include: small sample sizes, dosimetry errors (look for true organ doses), not controlling for sex & age at exposure, not calculating lifetime effect (ie. limited follow-up), and failing to analyze confounding variables (typical of environmental studies).

 

REFERENCES:

INTRODUCTION/PURPOSE:

NYT88 See GOF90 - New York Times pA-16, July 14, 1988 Wald, Matthew L., "Cleanup Estimate for A-Bomb Plants is Called Low,"

NYT89 See GOF90 - New York Times, 2/25/89 Associated Press, "Rise in Cleanup Cost Seen"

H. Phys1997 Health Physics 1997 Feb;72(2):204-21 Guenther CF, Thein C "Estimated cost of person-Sv exposure" ERRATUM appears in H.Phys. 1997 May;72(5):804

SUMMARY RISK TABLE

ICRU-86 Int.Commission on Radiation Units & Measurements 1986, "The Quality Factor in Radiation Protection"; ICRU report 40. Report to the ICRP and ICRU of a joint task group. Bethesda, Md. BEIR V Health Effects of Exposure to Low Levels of Ionizing Radiation, Committee on the Biological Effects of Ionizing Radiations. Board on Radiation Effects Research, Commission on Life Sciences, National Research Council; ISBN 0-309-03995-9 National Academy Press, Washington, D.C.

1990 GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF

1981 GOF85 Gofman, John W. & O'Connor, Egan X-Rays: Health Effects of Common Exams 439 pages, ISBN 0-87156-838-1, Sierra Club Books 1985

GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990.

US EPA94 EPA 402-R-93-076 June 1994 "Estimating Radiogenic Cancer Risks"

UNSCEAR88 United Nations Scientific Committee on the Effects of Atomic Radiation, 1988. Sources, Effects and Risks of Ionizing Radiation. New York. ISBN 92-1-142143-8

ICRP91 International Commission on Radiological Protection ICRP, Pub 60, Annals of the ICRP 21, Pergamon Press, NY

PHYSICAL PROPERTIES

GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF

1981 RADIATION UNITS GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF 1981

RADPROT81 Radiation Protection: A guide for Scientists and Physicians 2nd edition, Jacob Shapiro, Harvard Univ. Press; Cambridge, Mass. 1981 ISBN 0-674-74584-1

ENERGY DEPOSITION INTO TISSUES

GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF 1981 RPROTST83 Radiation Protection for Student Radiographers, Mary Alice Statkiewicz and E. Russell Ritenour, C.V. Mosby, St. Louis 1983 ISBN 0-940122-10-3 BJR89 Brenner DJ, Amols HI, Br. J. Radiol. 1989 Oct;62(742):910-4 "Enhanced risk from low-energy screen-film mammography X-rays. DNA DAMAGE Ward 1985 Rad.Research 103:383-392 "Mammalian Cells Are Not Killed by DNA Single-Strand Breaks Caused by Hydroxyl Radicals from Hydrogen Peroxide" Ward 1988 Progress in Nucleic Acid Research & Molecular Biol. V35:95-125 "DNA Damage Produced by Ionizing Radiation in Mammalian Cells: Identities, Mechanisms of Formation, and Repairability" Ward 1990 Int.Jrnl of Rad.Biol. Vol57:1141-1150 "The Yield of DNA Double-Strand Breaks Produced Intracellularly by Ionizing Radiation: A Review" Ward 1991 Rad.Research 126: 385-87 Letter "Comments to commentary by D. Billen" Ward 1995 Rad.Research 142: 362-368 "Radiation Mutagenesis: The initial DNA Lesions Responsible" Errata 143:355 Baverstock 1991 Rad.Research 126:383-84 Letter "Comments on the Commentary by D. Billen" Brenner & Ward 1992 Int.J.Radiation Biol, 61:737-748 "Constraints on energy depositions and target size of multiply-damaged sites associated with DNA double-strand breaks" (In NCRP 1998 Draft Rpt.) Goodhead, DT 1994 H.Phys. 55:231-240 "Spatial and temporal distribution of energy" (In NCRP 1998 Draft Rpt.) Jeggo PA Rad.Research 150 (Supppl.), S80-S91 1998 "Identification of Genes Involved in Repair of DNA Double-Strand Breaks in Mammalian Cells" Pfeiffer P 1998 Toxicology Letters 96, 97:119-129, 1998 "The mutagenic potential of DNA double-strand break repair"

DISEASES ASSOCIATED WITH INABILITY TO REPAIR DNA LESIONS

Borek CE, et al Nature 301:156-158, 1983 "X rays may be twice as potent as X rays for malignant transformation at low dose" Chan JYH et al Nature 325:357-359, 1987 "Altered DNA ligase I activity in Bloom's syndrome cells" Willis AE, Lindahl T. Nature 325:355-357, 1987 "DNA ligase I deficiency in Bloom's syndrome" Cleaver JE Nature 218:652-656, 1968 "Defective repair replication of DNA in xeroderma pigmentosum" Hecht F, Hecht BK Am.J. Pediatr. Hematol.Oncol 9:185-188, 1987 "Chromosome changes connect immunodeficiency and cancer in ataxia telangiectasia" Langlois RG, et al Proc. Natl. Acad. Sci. 86:670-674, 1989 "Evidence for increased in vivo mutation and somatic recombination in Bloom's syndrome" Khan SG, et al J Investigative Dermatology 111(5):791-796, 1998 "Xeroderma Pigmentosum Group C Splice Mutation Associated with Autism and Hypoglycinemia" Sikpi MO, et al Radiation Research 150:627-635, 1998 "Defective Modulation of Double-Strand Break Repair in Ataxia Telangiectasia Cells by Gamma Radiation" Groisman IJ, et al Carcinogenesis 20(3):479-483, 1999 "Downregulation of DNA excision repair by the hepatitis B virus-x protein occurs in p53-proficient and p53-deficient cells" Becker SA, et al Journal of Virology 72(1):266-272 1998 "Hepatitis B Virus X protein Interferes with Cellular DNA Repair" GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990.

GENOMIC INSTABILITY:

Morgan WF, et al Rad.Research 146:247-258 1996 "Genomic Instability Induced by Ionizing Radiation" Nowell 1976 Sci 194:23-28 (Oct'76) "The Clonal Evolution of Tumor Cell Populations" Cheng 1993 Adv. in Cancer Res. 60:121-156 "Genomic Instability and Tumor Progression: Mechanistic Considerations' Kadhim 1992 Nature 355:738-40 "Transmission of Chromosomal Instability after Plutonium Alpha-Particle Irradiation" Kadhim 1994 Lancet 344: 987-88 "Alpha-Particle Induced Chromosomal Instability in Human Bome-Marrow Cells" Kadhim 1995 Int. Journal of Radiation Biol 67:287-333 "Radiation-Induced Genomic Instability: Delayed Cytogenetic Aberrations and Apoptosis in Primary Human Bome-Marrow Cells" Holmberg 1993 Mutation Research 286:321-330 "Clonal Chromosome Aberrations and Genomic Instability in X-Irradiated Human T-Lymphocyte Cultures" Marder 1993 Molecular and Cell Biol 13:6667-77 "Delayed Chromosomal Instability Induced by DNA Damage" Mendonca 1993 Radiation Research 134:209-16 "Delayed Heritable Damage and Epigenetics in Radiation-Induced Neoplastic Transformation of Human Hybrid Cells" Kronenberg 1994 Int.Journal of Radiation Biol 66:603-609 "Radiation-Induced Genomic Instability" Ullrich RL & Ponnaiya B Int. J. Radiat. Biol. 74(6):747-754 "Radiation-induced instability and its relation to radiation carcinogenesis" BEIR V Pg.138 - Health Effects of Exposure to Low Levels of Ionizing Radiation, Committee on the Biological Effects of Ionizing Radiations. Board on Radiation Effects Research, Commission on Life Sciences, National Research Council; ISBN 0-309-03995-9 National Academy Press, Washington, D.C. 1990

MONOCLONAL CANCER ORIGIN:

Evans 1979 Evans,HL Nature 277: 531-534 2/15/79 "Chromosome aberrations in nuclear dockyard workers"; Lloyd 1988 Lloyd International Journal of Radiation Biology 53 #1 p49-55, 1988 "Frequencies of chromosomal aberrations in human blood lymphocytes by low dose of x-rays" Wainscoat&Frey 1990 Cancer Res. 50:1355-1360 "Assessment of clonality in human tumors: a review" Worsham, MJ et al 1996 Modern Pathology 9:163-165 "Molecular genetic fingerprints: clues to monoclonal origin of multifocal disease" Nowell 1976 Sci 194:23-28 (Oct'76) "The Clonal Evolution of Tumor Cell Populations" Noguchi 1992 Cancer Res. 52: 6594-6597 "Clonal analysis of human breast cancer by means of polymerase chain reaction" Fialkow 1976 Biochem. Biophys. Acta 458:283-321 "Clonal origin of human tumors" Fialkow 1984 "Clonal evolution of human myeloid leukemias," p215-226 in Genes and Cancer: UCLA Symposia on Molecular and Cellular Biology, Bishop and Rowley Eds., NY Arnold et al 1983 NEJM 309:1593-1599 "Immunoglobulin gene rearrangements as unique clonal markers in human lymphoid neoplasms" Cleary et al 1988 J. Exp. Med. 167:582-597 "Single cell origin of bigenotypic and bigenotypic B cell proliferations in human follicular lymphomas" Levy et all 1977 J. Exp. Med 145:1014-1028 "The monoclonality of human B. cell lymphomas" Minden et al 1985 Proc. Natl. Acad. Sci. 82:1224 "Somatic rearrangement of T-cell antigen receptor gene in human T-cell malignancies"

RELATIVE RISK RESPONSE

Gof-Tamplin 1969 Gof-Tamplin 1970 GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF 1981 GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990. NCRP98 National Council on Radiation Protection and Measurements (NCRP) Draft Report SC 1-6. Oct. 1998 "Evaluation of the Linear Nonthreshold Dose-Response Model" , Bethesda, Maryland GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF 1981

SHAPE OF RELATIVE RESPONSE CURVE

Gof-Tamplin 1969 Gof-Tamplin 1970 NCRP98 Oct'98 NCRP Draft Rpt SC 1-6 "Evaluation of the Linear Nonthreshold Dose-Response Model" BEIR V Health Effects of Exposure to Low Levels of Ionizing Radiation, Committee on the Biological Effects of Ionizing Radiations. Board on Radiation Effects Research, Commission on Life Sciences, National Research Council; ISBN 0-309-03995-9 National Academy Press, Washington, D.C. 1990 GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF 1981 GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990. RERF91 RERF Update 3(4):14, 1991 [see www.rerf.or.jp/] RERF92 Voeth,M. Preston, D.L, RERF Update 4(3):5-6, 1992 "Extrapolating Life Span Study cancer risk estimates to low dose exposure"

NO THRESHOLD

UNSCEAR93 United Nations Scientific Committee on the Effects of Atomic Radiation. Sources and Effects of Ionizing Radiation: UNSCEAR 1993 Report to the General Assembly, with Scientific Annexes. 922 pages. ISBN 92-1-142200-0 GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990. NCRP98 Oct'98 NCRP Draft Rpt SC 1-6 "Evaluation of the Linear Nonthreshold Dose-Response Model"

DURATION OF EFFECT

GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF 1981 GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990. BEIR V Pg.52 Health Effects of Exposure to Low Levels of Ionizing Radiation, Committee on the Biological Effects of Ionizing Radiations. Board on Radiation Effects Research, Commission on Life Sciences, National Research Council; ISBN 0-309-03995-9 National Academy Press, Washington, D.C. 1990

AGE & SEX EFFECT ON RADIATION SENSITIVITY

GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF 1981 Hemplemann et al 1975 Journal of Nat.Can.Institute 55:519-30 "Neoplasms in persons treated with X-rays in Infancy: fourth survey in 20years Shore et al 1977 Journal of the National Cancer Institute 59:813-22 "Breast neoplasms in women treated with X-rays for acute postpartum mastitis" Boice, Monson 1977 Journal of the National Cancer Inst. 59:823-832 1977 "Breast cancer in women after repeated fluoroscopic examinations of the chest" Shore et al 1976 Archives of Environmental Health 31:21-28 "Follow-up study of patients treated by X-ray epilation for tinea capitis. Re-survey of post-treatment illness and mortality experiences" RERF91a RERF 3(2):10, 1991

ORGAN SPECIFIC CANCER RATES FOLLOW RELATIVE RISK MODEL

RERF90a Mabuchi,K. RERF 2(2) 5-6, 1990 "LSS Cancer Incidence Tracked by Tumor Registries" RERF94 Mabuchi, K. Preston, D. RERF 6(1):3-4, 1994 "Cancer Incidence in Atomic-bomb Survivors" GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF 1981 GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990. Land CE, Sinclair WK 1991 Annals of the ICRP 2#1:1991 In Risks Associated with Ionizing Radiations: "The relative contributions of different organ sites to the total cancer mortality associated with low-dose radiation exposure"

ADAPTIVE RESPONSE

UNSCEAR 1977 p378 - United Nations Scientific Committee on the Effects of Atomic Radiation 1977. Sources and effects of ionizing radiation. Report to the General Assembly, with annexes. United Nations, New York. NCRP98 BEIR V Health Effects of Exposure to Low Levels of Ionizing Radiation, Committee on the Biological Effects of Ionizing Radiations. Board on Radiation Effects Research, Commission on Life Sciences, National Research Council; ISBN 0-309-03995-9 National Academy Press, Washington, D.C. 1990 RERF92 RERF Update 4(3):5-6, 1992 Voeth, M. Preston, D.L. "Extrapolating Life Span Study cancer risk estimates to low dose exposure" Little MP & Boice JD Rad.Research 151:218-224, 1999 "Comparison of Breast Cancer Incidence in the Massachusetts Tuberculosis Fluoroscopy Cohort and in the Japanese Atomic Bomb Survivors" Brenner DJ Rad.Research 151:225-229, 1999 "Does Fractionation Decrease the Risk of Breast Cancer Induced by Low-LET Radiation?"

DATABASE - PERFECT EXAMPLE

GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF 1981 GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990.

DATABASE - HUMAN

GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990. MacMahon, B. J. of Nat.Cancer Inst. 28:1173-1191 1962 "Prenatal X-Ray Exposure and Childhood Cancer" Harvey E.B., et al NEJM 312#9:541-545 2/28/1985 "Prenatal X-Ray Exposure and Childhood Cancer in Twins" Hoffman, D.A. et al J. of Nat.Cancer Inst 81#17:1307-1312 9/6/1989 "Breast Cancer in Women with Scoliosis Exposed to Multiple Diagnostic X-Rays" Miller, A.B. et al NEJM 321#19:1285-1289 "Mortality from Breast Cancer after Irradiation during Fluoroscopic Examinations" Baverstock, KF, Vennart, J. H.Phys 44, Suppl.#1:575-577, 1983 "A note on Radium Body Content and Breast Cancers in UK Radium Luminisers" Baverstock, K,Papworth D. Br.J.Radiol., Suppl. BIR Rpt 21:71-76, 1987 "The U.K. Radium Luminizer Study" Daverst, et al Lancet 1:430-433, 2/21/81 "Risk of Radiation at Low Dose Rates" GOF-81 John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF 1981 Beebe, Kato & Land1978 Rad.Research 75:138-201 "Studies of the mortality of A-bomb survivors: 6 Mortality & radiation dose, 1950-1974 Nishiyama et al 1973 Cancer 32:1301-09 "The incidence of malignant lymphoma and multiple myeloma in Hiroshima and Nagasaki atomic bomb survivors 1945-1965 UNSCEAR 1977 p378 United Nations Scientific Committee on the Effects of Atomic Radiation 1977. Sources and effects of ionizing radiation. Report to the General Assembly, with annexes. United Nations, New York. Takeichi et al 1976 Cancer 38:2462-68 1976 "Salivary gland tumors in atomic bomb survivors, Hiroshima, Japan" Boice et al 1979 Radiology 131:589-597 "Risk of breast cancer following low-dose radiation exposure" BEIR III 1979 The effects on populations of exposure to low levels of ionizing radiation DRAFT RPT. Division of Medical Sciences. Assembly of Life Sciences, National Research Council, National Academy of Sciences. Hemplemann et al 1975 Journal of Nat.Can.Institute 55:519-30 "Neoplasms in persons treated with X-rays in Infancy: fourth survey in 20years Janower & Miettenen'71 Journal of the American Medical Association 215:753-56 "Neoplasms after childhood irradiation of the thymus gland" Conti et al 1960 Radiology 74:386-391 "Present health of children given X-ray treatment to the anterior mediastinum in infancy Shore et al 1977 Journal of the National Cancer Institute 59:813-22 "Breast neoplasms in women treated with X-rays for acute postpartum mastitis" Mettler, et al 1969 Journal of the Nat.Cancer Institute 43:803-11 "Breast neoplasms in women treated with X-rays for acute post-partum mastitis; a pilot study" Boice, Monson 1977 Journal of the National Cancer Inst. 59:823-832 1977 "Breast cancer in women after repeated fluoroscopic examinations of the chest" Boice, J.D. Rad.Research 73:373-390, 1978 "Estimation of Breast Doses and Breast Cancer Risk Associated with Repeat Fluoroscopic Chest Examination" Delarue et al Canadian Med. Association Journal 112:1405-13 "Multiple fluoroscopy of the chest: carcinogenicity for the female breast and implications for breast cancer screening programs" Myrden in BEIR III p679: Canadian Med. Assoc.Jrnl 100:1032-1034, 1969 "Breast Cancers Following Multiple Fluoroscopies during Artificial Pneumothorax Treatment of Pulmonary Tuberculosis" Shore et al 1976 Archives of Environmental Health 31:21-28 "Follow-up study of patients treated by X-ray epilation for tinea capitis. Re-survey of post-treatment illness and mortality experiences" Moden et al 1977 Radiology 123:741-44 "Thyroid cancer following scalp irradiation" Modan, B et al 1989 Lancet 1:629-631, 3/25/89 "Increased Risk of Breast Cancer after Low-Dose Irradiation" Brinkley & Haybittle '69 British Journal of Radiology 42:519-21 "The late effects of artificial menopause of X-radiation" Court,Brown,& Doll '65 British Med. Journal 2:1327-32 "Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis" Baral et a l 1977 Cancer 40:2905-10 "Breast cancer following irradiation of the breast" BEIR V Health Effects of Exposure to Low Levels of Ionizing Radiation, Committee on the Biological Effects of Ionizing Radiations. Board on Radiation Effects Research, Commission on Life Sciences, National Research Council; ISBN 0-309-03995-9 National Academy Press, Washington, D.C. 1990 RERF Pierce DA, Vaeth M "Cancer risk estimation from the A-bomb survivors: Extrapolation to low doses, use of relative risk models, and other uncertainties"; RERF CR 2-89 (1989); "The shape of the cancer mortality dose-response curve for atomic survivors"; RERF TR 7-89; and Radiat Res 121:1 20-41 (1990) Shimizu Y, et al Life Span Study Report 11. Part 2: "Cancer mortality in the years 1950-1985 based on the recently revised doses (DS86)"; RERF TR 5-88 and Radiat Res 126:36-42 (1991) Darby, SC, et al 1987 Br. J. Cancer 55:179-190, 1987 "Long-term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis" Hrubec, S, et al 1989 Cancer Res. 49:229-234, 1989 "Breast cancer after multiple chest fluoroscopies: Second follow-up of Massachusetts women with tuberculosis" Shore, RE, et al 1985 J. Natl. Cancer Inst. 74:1177-1184, 1985 "Thyroid tumors following thymus irradiation" Shore, RE, et al 1986 J. Natl. Cancer Inst. 77:689-696, 1986 "Breast cancer among women given x-ray therapy for acute postpartum mastitis" Ron E 1998 Rad.Research 150 (Suppl.), S30-S41, 1998 "Ionizing Radiation and Cancer Risk: Evidence from Epidemiology"

DATABASE - IN VITRO [VERY SMALL SAMPLE]

Brown, J.M. 1976 Health Physics 31:231-245 "Linearity versus non-linearity of dose-response for radiation carcinogenesis. Brown J.M. 1977 Rad.Research 71:34-50 "The shape of the dose-response curve for radiation carcinogenesis: extrapolation to low doses" Evans et al 1979 Nature 277:531-534 "Radiation-induced chromosome aberrations in nuclear-dockyard workers" Grosovsky AJ, Little JB "Evidence for linear response for the induction of mutations in human cells by x-ray exposures below 10 rads. Proc Natl Acad Sci USA 82: 2092-2095 (1986)

DATABASE - ANIMAL [VOLUMINOUS] see BEIR-V pp125-134, 153-160, 334-351

CRITICISM OF BEIR V AND RERF

GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990. GOF-96 John W. Gofman, Preventing Breast Cancer: The Story of A Major, Proven, Preventable Cause of This Disease" 2nd ed. 424 pages. ISBN 0-932682-96-0. Committee for Nuclear Responsibility, San Francisco 1996. GOF85 Gofman, John W. & O'Connor, Egan X-Rays: Health Effects of Common Exams 439 pages, ISBN 0-87156-838-1, Sierra Club Books 1985 Roesch, William C. ed U.S.-JAPAN JOINT REASSESSMENT OF ATOMIC BOMB RADIATION DOSIMETRY IN HIROSHIMA AND NAGASAKI: FINAL REPORT, VOL. 1., DS86 DOSIMETRY SYSTEM 1986, Hiroshima: RERF. DATA ANALYSIS TECHNIQUES GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990.

DATA TECHNIQUE: APPLICATION TO US POPULATION

GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990.

CANCER RATES FOR US POPULATION - ORGAN SPECIFIC PER RADIATION DOSE

GOF-90 John W. Gofman, Radiation-Induced Cancer from Low-Dose Exposure: An Independent Analysis. 480 pages. ISBN 0-932682-89-8. Committee for Nuclear Responsibility, San Francisco 1990. GOF-85 Gofman, John W. & O'Connor, Egan X-Rays: Health Effects of Common Exams 439 pages, ISBN 0-87156-838-1, Sierra Club Books 1985

RISK TABLES - COMPARING MAJOR AGENCIES

EPA 1994 EPA402-R-93-076 June 1994 "Estimating Radiogenic Cancer Risks" GOF-81 pg314: John W. Gofman, Radiation and Human Health. 908 pages. ISBN 0-87156-275-8. Sierra Club Books, SF 1981

ROUTINE DIAGNOSTIC X-RAY TABLES

GOF85 Gofman, John W. & O'Connor, Egan X-Rays: Health Effects of Common Exams 439 pages, ISBN 0-87156-838-1, Sierra Club Books 1985