Keto Info 5/28

[spEEdfrEEk]

This is a pretty dry medical document that demonstrates a point I

made in my last post. Many treatments used today to "treat" cancer

actually are key contributors to it..

:cool: TJ :cool:

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Confirmation that Ionizing Radiation Can Induce Genomic Instability: What

is Genomic Instability, and Why Is It So Important?

John W. Gofman, M.D., Ph.D., and

Egan O'Connor, Executive Director, CNR. Spring 1998.

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* Glossary

+ Genome

+ Genes and Chromosomes

+ The Code

+ The Mitochondrial DNA (mtDNA)

* Part 1 -- A Deep Insight from 1914, Slowly Confirmed

* Part 2 -- Ionizing Radiation as a Cause of Genomic Instability

* Part 3 -- Implications: Curing vs. Preventing Cancer

* Part 4 -- Five Key Facts and Three Restrained Comments

* References

* Genomic instability --- also called "genetic instability" and

"chromosomal instability" --- refers to abnormally high rates (possibly

accelerating rates) of genetic change occurring serially and spontaneously

in cell-populations, as they descend from the same ancestral cell. By

contrast, normal cells maintain genomic STABILITY by operation of

elaborate systems which ensure accurate duplication and distribution of

DNA to progeny-cells (Cheng 1993, p.124), and which prevent duplication of

genetically abnormal cells. These systems ("metabolic pathways") involve

an estimated 100 genes (Cheng 1993, p.142).

* Why is genomic instability so important? Many (not all) cancer

biologists now believe that genomic instability "not only initiates

carcinogenesis, but also allows the tumor cell to become metastatic and

evade drug toxicity" (Tlsty 1993, p.645), and "The loss of stability of

the genome is becoming accepted as one of the most important aspects of

carcinogenesis" (Morgan 1996, p.247), and "One of the hallmarks of the

cancer cell is the inherent instability of its genome" (Morgan 1996,

p.254).

* Although these observations are far from new, they certainly did

not receive the attention they merit until recently.

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>>>>> GLOSSARY <<<<<

* GENOME

* GENES AND CHROMOSOMES

* THE CODE

* THE MITOCHONDRIAL DNA (mtDNA)

* GENOME. A person's genome is one set of his (or her) genes. The

human genes, which control a cell's structure, operation, and division,

are located in the cell's nucleus. The full human genome (estimated at

50,000 to 100,000 genes) is present in every cell-nucleus, even though

many genes are inactive in cells which have some specialized functions

(the "differentiated" cells).

* GENES AND CHROMOSOMES. Genes are composed of segments of DNA. In

normal cell-nuclei, the DNA is distributed among 46 chromosomes (23

inherited at conception from a person's father, and 23 from the mother).

Each chromosome consists of one very long strand of DNA and numerous

proteins, which are required for successful management of the long DNA

molecule. The longest chromosomes each "carry" thousands of genes. Every

time a cell divides, the cell must duplicate the 46 chromosomes and must

distribute one copy of each to the two resulting cells.

* THE CODE. The DNA of each chromosome is composed of units ---

"nucleotides" of four different types (A, T, G, C). These nucleotides are

linked to each other in linear fashion. The sequence of the four types of

nucleotides is critical, because the sequence produces the "code" which

(a) determines the function of each particular gene, ( identifies the

gene's start-point and stop-point along the DNA strand, and © permits

certain regulatory functions. The code of the human genome consists of

more than a billion nucleotides.

* THE MITOCHONDRIAL DNA (mtDNA). Outside the nucleus, human cells

also have some "foreign" DNA located in structures called the

mitochondria. This small and separate set of DNA does not participate in

the 46 human chromosomes, and is not part of "the genomic DNA." The

mitochondria are inherited from the mother.

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Part 1 * A Deep Insight from 1914, Slowly Confirmed

* It was the year 1956 when the normal number of human chromosomes

per cell was firmly established as 46. Soon thereafter, it became clear

that cells of advanced cancers have often evolved an abnormal number of

chromosomes ("aneuploidy").

* Such observations were consistent with the prediction of Theodor

Boveri (Boveri 1914), a great German embryologist who postulated that

malignancy is the result of inappropriate balance of instructions (genetic

information) in the tumor cells. Such "imbalance" can result not only from

numerical chromosome aberrations, but also from structural alterations

within the 46 chromosomes. As a leading cause of structural chromosome

aberrations (deletions, acentric fragments, translocations, inversions,

dicentrics, etc.), ionizing radiation is well-established.

* When my colleagues and I (JWG) initiated a research program in

1963 (at the Atomic Energy Commission's Livermore National Laboratory), to

test Boveri's hypothesis, there was very little interest in the concept.

Although the techniques for detecting structural chromosome aberrations

were extremely crude then, compared with current techniques, we were

making gradual progress (Minkler 1970, + Minkler 1971). However, the

Atomic Energy Commission became angry with me after a paper I presented at

an IEEE Symposium (Gofman 1969), and canceled our funding in the early

1970s (Seaborg 1993, Chapter 8, "Challenge from Within," + Terkel 1995,

pp.406-408).

* In October 1976, the journal Science published Peter C. Nowell's

classic paper entitled, "The Clonal Evolution of Tumor Cell Populations"

--- a paper almost always cited by today's analysts of genomic

instability. Among other things, Nowell's 1976 paper discussed evidence,

from various analysts, indicating that as tumor cells become increasingly

aneuploid, the malignancy becomes increasingly aggressive (Nowell, p.25).

Reasoning from the available evidence at that time, Nowell proposed the

following model of multi-step carcinogenesis:

* Tumor initiation occurs by an induced change in a single,

previously normal cell, which makes the cell "neoplastic" (partially

liberated from normal growth controls) and provides the cell with a

selective growth advantage over adjacent normal cells (Nowell, p.23).

* "From time to time, as a result of genetic instability in the

expanding tumor population, mutant cells are produced ... Nearly all of

these variants are eliminated, because of metabolic disadvantage or

immunologic destruction ... but occasionally one has an additional

selective advantage with respect to the original tumor cells as well as

normal cells, and this mutant becomes the precursor of a new predominant

subpopulation" (Nowell, p.23). And:

* "Over time, there is sequential selection by an evolutionary

process of sub-lines which are increasingly abnormal, both genetically and

biologically ... Ultimately, the fully developed malignancy as it appears

clinically has a unique, aneuploid karyotype associated with aberrant

metabolic behavior and specific antigenic properties, and it also has the

capability of continued variation as long as the tumor persists" (Nowell,

p.23). And:

* "The major contention of this article is that the biological

events recognized in tumor progression represent (i) the effects of

acquired genetic instability in the neoplastic cells, and (ii) the

sequential selection of variant subpopulations produced as a result of

that genetic instability" (Nowell, p.25).

* The recent surge of interest in genomic instability reflects the

recognition that the cancer process represents a trip (or set of trips)

from the stable genome to the genome with diverse deviations. It has been

a long wait for Boveri.

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Part 2 * Ionizing Radiation as a Cause of Genomic Instability

* Today, laboratory researchers are performing reality-checks on

this logic: Genomic instability can be initiated and intensified by any

type of genetic mutation (including chromosome aberrations), when such

mutation alters some of the DNA which maintains genomic STABILITY. Of

course, such DNA includes the numerous DNA segments which govern DNA

synthesis, cell-division, and also the routine REPAIR of the genome ---

the "repair genes" (Cheng 1993, p.131; Morgan 1996, p.248).

* When a mutagen has induced genomic instability in a cell, some of

the cell's descendants will experience new and unrepaired genetic

abnormalities at an excessive rate, even though the descendants themselves

received no exposure to the mutagen used in the experiment. This occurs

because such cells have inherited a genome which was injured with respect

to maintaining genomic STABILITY.

* Very recently, a technique has been developed for efficiently

detecting three of the types of chromosome aberrations which are very

prominent in genomic instability: Aneuploidy (wrong number of

chromosomes), deletions (permanent removal of DNA segments, long or

short), and gene-amplifications (extra copies of specific DNA segments).

This technique, called Comparative Genomic Hybridization, was first

described by Kallioniemi (1992, in Science). However, such a technique

does not detect many other kinds of mutations.

* The nature of the genetic code is such that mutations need not be

gross in order to have gross biological consequences. For instance,

permanent removal of a single nucleotide (a micro-deletion) can totally

garble much of a gene's code, by causing what is called a "frame-shift."

Then this non-functional gene can be the phenomenon which wrecks part of

the system which would otherwise maintain genetic STABILITY.

* Amplification (instead of injury), of the crucial genes in the

stability-system, also can permit a cell to escape the controls which

otherwise prevent duplication of cells with injured genomes. Evidence is

developing that gene amplification is associated with dicentric

chromosomes and circular acentric fragments called "double minutes"

(DiLeonardo 1993, p.656) --- very well-known products among the

consequences of ionizing radiation.

* The sequence, in which various mutations accumulate in tumor

cells, may or may not matter. "For example, one or more pre-cancerous

mutations might lie dormant until additional mutations create an

environment in which the prior changes confer a selective advantage"

(DiLeonardo 1993, p.655, citing Kemp 1993, + Fearon 1990, + Temin 1988).

* The fact, that ionizing radiation is a mutagen capable of causing

all known types of genetic mutation --- from micro to gross, at any DNA

location along any chromosome --- made it utterly predictable that

ionizing radiation would be a cause of genomic instability. Indeed, one of

the last projects completed by our research group at the Livermore Lab,

before the Atomic Energy Commission shut down our work, was a

demonstration which showed that ionizing radiation can induce genomic

instability. Our experiments used gamma rays and cultured human

fibroblasts (Minkler 1971).

* During recent years, multiple experiments have confirmed the fact

that ionizing radiation can cause genomic instability. Such results have

been observed after both low-LET radiation (such as xrays and gamma rays)

and high-LET radiation (such as alpha particles). Among numerous papers,

see, for instance:

* Kadhim 1992;

* Holmberg 1993 (who cites Minkler 1971);

* Marder 1993 (especially p.6674);

* Mendonca 1993;

* Kadhim 1994;

* Kronenberg 1994 (radiation dose-response, p.605);

* Kadhim 1995;

* Morgan 1996 (review).

* In the mass media, some writers have expressed astonishment that

radiation-induced genomic instability is not detected until several

cell-divisions have occurred after the radiation exposure. They seem to

imagine that the delay reflects a mysterious discontinuity between cause

and effect. There is NO discontinuity, of course --- a point made

explicitly in Kadhim 1992 (p.739). With current techniques, and with

uncertainties about where to search closely among a billion nucleotides,

it is just not possible to detect every intermediate step.

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Part 3 * Implications: Curing vs. Preventing Cancer

* The induction of genomic instability in a cell does not guarantee

that it will become malignant. Genomic instability increases the RATE of

mutation in that cell and its descendants, and with this higher rate, the

cells each have a higher PROBABILITY that at least one of them will

accumulate all the genetic powers of a killer-cancer. These powers include

the ability to thrive BETTER than normal cells, to invade inappropriate

tissue, to adapt to the new conditions there, to recruit a blood supply,

to fool the immune system, and many other properties.

* No one claims, yet, that genomic instability must precede every

case of cancer. However, genomic instability helps to explain why cancer

is sometimes called "at least a hundred different diseases." Indeed,

genomic instability means that each case of cancer may develop a genome

like no other case. Is it any wonder that individual tumors often differ

in behavior from each other?

* Nowell's 1976 paper was certainly not the last one to observe that

cancers become increasingly deviant in their genomes, as they "advance."

Tlsty 1993 (p.645) cites several more recent papers. Near the end of his

paper, Nowell wrote (p.27):

* "The fact that most human malignancies are aneuploid and

individual in their cytogenetic alterations is somewhat discouraging with

respect to therapeutic considerations ... With variants being continually

produced, and even increasing in frequency with tumor progression, the

neoplasm possesses a marked capacity for generating mutant sub-lines,

resistant to whatever therapeutic modality the physician introduces ...

The same capacity for variation and selection which permitted the

evolution of a malignant population [of cells] from the original aberrant

cell, also provides the opportunity for the tumor to adapt successfully to

the inimical environment of therapy, to the detriment of the patient."

And Some Lessons:

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(A) * Genomic instability will probably keep cancer hard to cure.

( * The quickest path to less cancer-misery in the future would be a

policy of reducing exposure to carcinogens.

© * Ionizing radiation is almost certainly the most potent carcinogen to

which vast numbers of people are actually exposed (see Part 4).

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Part 4 * Five Key Facts and Three Restrained Comments

(1) * Ionizing radiation is a mutagen having special properties which make

some radiation-induced genetic injuries complex and impossible for a

cell to repair correctly --- quite unlike the routine damage from

endogenous free radicals (Ward 1988, + Gofman 1990, Chapter 18, Part

2, + Ward 1991, + Baverstock 1991, + Ward 1995, + Gofman 1997).

(2) * Ionizing radiation is a mutagen which undeniably can cause every

known kind of mutation, at any DNA location along any chromosome.

The body does not always eliminate cells having harmful mutations.

If it did, there would be no cancer or inherited afflictions.

(3) * Ionizing radiation is a mutagen known to induce genomic instability

(references provided in earlier sections).

(4) * Ionizing radiation is a human carcinogen at every dose-level, not

just at high doses; there is no threshold dose. A single photon or a

single high-speed particle can cause unrepairable genetic damage.

(See Gofman 1990, Chapters 18-21, + UNSCEAR 1993, Annex F,

especially p.636 para.84, p.680 para.323, + NRPB 1995, especially

pp.59-61, p.68, p.75, + Pierce 1996, p.9, + Gofman 1996, Chapter 45,

+ Riches 1997, p.519, + Hei 1997).

(5) * Ionizing radiation is a mutagen observed to induce virtually every

kind of human cancer (Gofman 1969, p.4, + BEIR 1980, Section 5, +

UNSCEAR 1988, p.460 para.394).

And the Comments:

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(1) * In view of all the five facts above, it would be inappropriate to

doubt the menace of low-dose ionizing radiation.

(2) * And in view of all the five facts, it is strange --- in studies

which attempt to explain a difference in cancer-rates between two

groups --- that the question is so seldom asked: How do the

radiation histories differ between the groups? In view of the five

facts above, it should be the FIRST question.

(3) * And in view of the five facts, it is sad that so many members of the

medical profession give only lip-service to the need to reduce the

unnecessarily high exposures to radiation administered by their own

profession (UNSCEAR 1993, Annex C, + Gofman 1996, Chapter 48).

Today, the two largest sources of voluntary radiation exposure are

(i) pre-cancer medical procedures, including CT scans and

fluoroscopy (NCRP 1987, p.59, + NCRP 1989, p.69) and (ii)

cigarette-smoking --- which delivers appreciable alpha-particle

radiation to the lungs (Martell 1974, 1975, 1983, + NCRP 1984, +

BEIR 1990, p.19). As for involuntary exposures accumulated from

nuclear pollution, they have been poorly ascertained --- to put it

in a kindly fashion.

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>>>>> Reference List <<<<<

* Baverstock 1991 (Keith F.), "Comments on the Commentary by D. Billen,"

Radiation Research 126: 383-384 (letter).

* BEIR 1980, Committee on the Biological Effects of Ionizing Radiation,

"The Effects on Populations of Exposure to Low Levels of Ionizing

Radiation." National Academy of Sciences, Washington DC.

* BEIR 1990 (see BEIR 1980), "Health Effects of Exposure to Low Levels of

Ionizing Radiation." 421 pages. ISBN 0-309-03995-9. National Academy of

Sciences, Washington DC.

* Boveri 1914 (Theodor), "The Origin of Malignant Tumors," first published

as a book in German; English-language translation published in 1929 by

Williams and Wilkins, Baltimore, Maryland, USA.

* Cheng 1993 (Keith C.) + Lawrence A. Loeb, "Genomic Instability and Tumor

Progression: Mechanistic Considerations," Advances in Cancer Research 60:

121-156.

* DiLeonardo 1993 (A.) + S.P. Linke + Y. Yin + G.M. Wahl, "Cell Cycle

Regulation of Gene Amplification," Cold Spring Harbor Symposia on

Quantitative Biology 58: 655-667.

* Fearon 1990 (E.R.) + Bert Vogelstein, "A Genetic Model for Colorectal

Tumorigenesis," Cell 61: 759+.

* Gofman 1969 (John W.) + Arthur R. Tamplin, "Low-Dose Radiation and

Cancer," IEEE Transactions on Nuclear Science NS-17, Vol.1: 1-9. Presented

October 29, 1969 at the 1969 Nuclear Science Symposium, Institute of

Electrical and Electronic Engineering. Proceedings published February 1970

by the IEEE, New York City.

* Gofman 1990 (John W.), "Radiation-Induced Cancer from Low-Dose Exposure:

An Independent Analysis." 480 pages. ISBN 0-932682-89-8. Committee for

Nuclear Responsibility Books, San Francisco. Also available on the

Internet.

* Gofman 1996 (John W.), "Preventing Breast Cancer: The Story of a Major,

Proven, Preventable Cause of This Disease." 422 pages. ISBN 0-932682-96-0.

Committee for Nuclear Responsibility Books, San Francisco. Also available

on the Internet.

* Gofman 1997 (John W.), "The Free-Radical Fallacy about Ionizing

Radiation: Demonstration That a Popular Claim Is Senseless," Committee for

Nuclear Responsibility, San Francisco. Also available on the Internet.

* Hei 1997 (T.K.) + 4 co-workers, "Mutagenic Effects of a Single and an

Exact Number of Alpha Particles in Mammalian Cells," Proceedings of the

National Academy of Sciences USA 94: 3765-3770.

* Holmberg 1993 (Kerstin) + Susann Falt + Annelie Johansson + Bo Lambert,

"Clonal Chromosome Aberrations and Genomic Instability in X-Irradiated

Human T-Lymphocyte Cultures," Mutation Research 286: 321-330.

* Kadhim 1992 (Munira A.) + D.A. MacDonald + Dudley T. Goodhead + Sally A.

Lorimore + 2 co-workers, "Transmission of Chromosomal Instability after

Plutonium Alpha-Particle Irradiation," Nature 355: 738-740.

* Kadhim 1994 (Munira A.) + Sally A. Lorimore + Mary D. Hepburn + Dudley

T. Goodhead + 2 co-workers, "Alpha-Particle-Induced Chromosomal

Instability in Human Bone-Marrow Cells," Lancet 344: 987-988.

* Kadhim 1995 (Munira A.) + Sally A. Lorimore + K.M.S. Townsend + Dudley

T. Goodhead + 2 co-workers, "Radiation-Induced Genomic Instability:

Delayed Cytogenetic Aberrations and Apoptosis in Primary Human Bone-Marrow

Cells," Internatl. Journal of Radiation Biology 67: 287-293.

* Kallioniemi 1992 (Anne) + Olli-P. Kallioniemi + Damir Sudar + 4

co-workers, "Comparative Genomic Hybridization for Molecular Cytogenetic

Analysis of Solid Tumors," Science 258: 818-821.

* Kemp 1993 (C.J.) + L.A. Donehower + A. Bradley + A. Balmain, "Reduction

of p53 Gene Dosage Does Not Increase Initiation or Promotion but Enhances

Malignant Progression of Chemically Induced Skin Tumors," Cell 74: 813+.

* Kronenberg 1994 (A.), "Radiation-Induced Genomic Instability,"

Internatl. Journal of Radiation Biology 66: 603-609.

* Marder 1993 (Brad A.) + William F. Morgan, "Delayed Chromosomal

Instability Induced by DNA Damage," Molecular and Cell Biology 13:

6667-6677.

* Martell 1974 (Edward A.), "Radioactivity of Tobacco Trichomes and

Insoluble Cigarette Smoke Particles," Nature 249: 215-217.

* Martell 1975 (Edward A.), "Tobacco Radioactivity and Cancer in Smokers,"

American Scientist 63: 404-412.

* Martell 1983 (Edward A.), "Bronchial Cancer Induction by Alpha

Radiation: A New Hypothesis," paper C6-11 in Proceedings of the 7th

International Congress of Radiation Research, edited by J.J. Broerse et

al. Published by Martinus Nijhoff, Amsterdam, Netherlands.

* Mendonca 1993 (Marc S.) + Ronald J. Antoniono + J. Leslie Redpath,

"Delayed Heritable Damage and Epigenetics in Radiation-Induced Neoplastic

Transformation of Human Hybrid Cells," Radiation Research 134: 209-216.

* Minkler 1970 (Jason L.) + John W. Gofman + Robert K. Tandy, "A Specific

Common Chromosomal Pathway for the Origin of Human Malignancy," British

Journal of Cancer 24: 726-740.

* Minkler 1971 (Jason L.) + Dolores Piluso + John W. Gofman + Robert K.

Tandy, "A Long-Term Effect of Radiation on Chromosomes of Cultured Human

Fibroblasts," Mutation Research 13: 67-75.

* Morgan 1996 (William F.) + 4 co-workers, (review paper) "Genomic

Instability Induced by Ionizing Radiation," Radiation Research 146:

247-258.

* NCRP 1984, National Council on Radiation Protection (USA), "Evaluation

of Occupational and Environmental Exposures to Radon and Radon Daughters

in the United States." NCRP Report 78. Bethesda, Maryland.

* NCRP 1987 (see NCRP 1984), "Ionizing Radiation Exposure of the

Population of the United States." 87 pages. ISBN 0-913392-91-X. NCRP

Report 93. Bethesda, Maryland.

* NCRP 1989 (see NCRP 1984), "Exposure of the U.S. Population from

Diagnostic Radiation." 105 pages. NCRP Report 100. Bethesda, Maryland.

* Nowell 1976 (Peter C.), "The Clonal Evolution of Tumor Cell

Populations," Science 194: 23-28.

* NRPB 1995, National Radiological Protection Board (Britain), "Risk of

Radiation-Induced Cancer at Low Doses and Low Dose-Rates for Radiation

Protection Purposes." 77 pages. Volume 6, No.1 in "Documents of the NRPB."

ISBN 0-85951-386-6. Sales agent in USA is Bernan Associates in Lanham,

Maryland: Tel 1-800-274-4447. Internet: <www.bernan.com>

* Pierce 1996 (Donald A.) + Yukiko Shimizu + Dale L. Preston + Michael

Vaeth + Kiyohiko Mabuchi, "Studies of the Mortality of Atomic Bomb

Survivors. Report 12, Part 1. Cancer: 1950-1990," Radiation Research 146:

1-27.

* Riches 1997 (A.C.) + Z. Herceg + P.E. Bryant + D.L. Stevens,

"Radiation-Induced Transformation of SV40-Immortalized Human Thyroid

Epithelial Cells by Single Exposure to Plutonium Alpha-Particles in

Vitro," Internatl. Journal of Radiation Biology 72: 515-521. (Experiment

includes gamma radiation.)

* Seaborg 1993 (Glenn T.) with Benjamin S. Loeb, "The Atomic Energy

Commission under Nixon: Adjusting to Troubled Times." 268 pages. ISBN

0-312-07899-4. St. Martin's Press, New York City.

* Temin 1988 (H.), "Evolution of Cancer Genes as a Mutation-Driven

Process," Cancer Research 48: 1697+.

* Terkel 1995 (Studs), "Coming of Age: The Story of Our Century by Those

Who've Lived It." 468 pages. ISBN 1-56584-284-7. The New Press, New York

City.

* Tlsty 1993 (T.D.) + 10 co-workers, "Loss of Chromosomal Integrity in

Neoplasia," Cold Spring Harbor Symposia on Quantitative Biology 58:

645-654.

* UNSCEAR 1988, United Nations Scientific Committee on the Effects of

Atomic Radiation, "Sources, Effects and Risks of Ionizing Radiation." ISBN

92-1-142143-8. United Nations sales number is E.88.IX.7. Sales agent in

USA is Bernan Associates in Lanham, Maryland: Tel 1-800-274-4447.

Internet: <www.bernan.com>

* UNSCEAR 1993 (see UNSCEAR 1988), "Sources and Effects of Ionizing

Radiation: Report to the General Assembly with Scientific Annexes." 922

pages (no index). ISBN 92-1-142200-0. United Nations sales number is

E.94.IX.2 (see above).

* Ward 1988 (John F.), "DNA Damage Produced by Ionizing Radiation in

Mammalian Cells: Identities, Mechanisms of Formation, and Reparability,"

Progress in Nucleic Acid Research & Molecular Biology 35: 95-125.

* Ward 1991 (John F.), "Response to Commentary by D. Billen," Radiation

Research 126: 385-387 (letter).

* Ward 1995 (John F.), "Radiation Mutagenesis: The Initial DNA Lesions

Responsible," Radiation Research 142: 362-368 (commentary). Errata:

Vol.143: 355.

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Committee for Nuclear Responsibiity, Inc. (CNR)

POB 421993, San Francisco, CA 94142, USA

Internet http://www.ratical.com/radiation/CNR/

An educational group since 1971. Gifts are tax-deductible.

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