[ RadSafe ] French Acad of Sciences, Nat Acad of Med. LNT Rejection

[howard long]

Viva Hormesis!
 
Howard Long 

"Muckerheide, James" <jimm at WPI.EDU> wrote:
Subject: French Acad of Sciences and Nat Acad of Medicine report
Date: Fri, 15 Apr 2005 13:36:37 -0400
From: "Muckerheide, James" <jimm at WPI.EDU>
To: <rad-sci-l at WPI.EDU>
CC: <mbrexchange at list.ans.org>

Friends,

Our friends in France have updated their work documenting the fallacy of the
LNT. This report was UNANIMOUSLY approved by both of the Academies!

Let me know if you want a copy of the English version of the full report.
(It's about 50 pages and specifically addresses the ICRP Committee 1 report
and the David Brenner et al., disinformation paper in the PNAS that attempts
to justify the LNT. The Executive Summary is below. The final version of
this and the full report may have some editorial corrections from proof
reading prior to printing. 

The public release was scheduled for April 11. I have not heard anything
about it in the media. Has anyone heard anything?

Regards, Jim Muckerheide
=====================

Académie des Sciences [Academy of Sciences] - Académie nationale de Médecine
[National Academy of Medicine]

Dose-effect relationships and estimation of the carcinogenic effects of low
doses of ionizing radiation

March 6, 2005

André Aurengo[1] (Rapporteur), Dietrich Averbeck, André Bonnin1 (?) , Bernard
Le Guen, Roland Masse[2], Roger Monier[3], Maurice Tubiana1,3 (Chairman),
Alain-Jacques Valleron3, Florent de Vathaire

[1] Membre de l'Académie nationale de médecine [2] Membre correspondant de
l'Académie nationale de médecine [3] Membre de l'Académie des Sciences

Executive Summary

The assessment of carcinogenic risks associated with doses of ionizing
radiation from 0.2 Sv to 5 Sv is based on numerous epidemiological data.
However, the doses which are delivered during medical X-ray examinations are
much lower (from 0.1 mSv to 20 mSv). Doses close to or slightly higher than,
these can be received by workers or by populations in regions of high natural
background irradiation.

Epidemiological studies have been carried out to determine the possible
carcinogenic risk of doses lower than 100 mSv and they have not been able to
detect statistically significant risk even on large cohorts or populations.
Therefore these risks are at worse low since the highest limit of the
confidence interval is relatively low. It is highly unlikely that putative
carcinogenic risks could be estimated or even established for such doses
through case-control studies or the follow-up of cohorts. Even for several
hundred thousands of subjects, the power of such epidemiological studies
would not be sufficient to demonstrate the existence of a very small excess
in cancer incidence or mortality adding to the natural cancer incidence
which, in non-irradiated populations, is already very high and fluctuates
according to lifestyle. Only comparisons between geographical regions with
high and low natural irradiation and with similar living conditions could
provide valuable information for this range of doses and dose rates. The
results from the ongoing studies in Kerala (India) and China need to be
carefully analyzed.

Because of these epidemiological limitations, the only method for estimating
the possible risks of low doses (< 100 mSv) is by extrapolating from
carcinogenic effects observed between 0.2 and 3 Sv. A linear no-threshold
relationship (LNT) describes well the relation between the dose and the
carcinogenic effect in this dose range where it could be tested. However the
use of this relationship to assess by extrapolation the risk of low and very
low doses deserves great caution. Recent radiobiological data undermine the
validity of estimations based on LNT in the range of doses lower than a few
dozen mSv which leads to the questioning of the hypotheses on which LNT is
implicitly based: 1) the constancy of the probability of mutation (per unit
dose) whatever the dose or dose rate, 2) the independence of the carcinogenic
process which after the initiation of a cell evolves similarly whatever the
number of lesions present in neighboring cells and the tissue.

Indeed 1) progress in radiobiology has shown that a cell is not passively
affected by the accumulation of lesions induced by ionizing radiation. It
reacts through at least three mechanisms: a) by fighting against reactive
oxygen species (ROS) generated by ionizing radiation and by any oxidative
stress, b) by eliminating injured cells (mutated or unstable), through two
mechanisms i) apoptosis which can be initiated by doses as low as a few mSv
thus eliminating cells whose genome has been damaged or misrepaired, ii)
death at the time of mitosis cells whose lesions have not been repaired.
Recent works suggest that there is a threshold of damage under which low
doses and dose rates do not activate intracellular signaling and repair
systems, a situation leading to cell death c) by stimulating or activating
DNA repair systems following slightly higher doses of about ten mSv.
Furthermore, intercellular communication systems inform a cell about the
presence of an insult in neighboring cells. Modern transcriptional analysis
of cellular genes using microarray technology, reveals that many genes are
activated following doses much lower than those for which mutagenesis is
observed. These methods were a source of considerable progress by showing
that according to the dose and the dose rate it was not the same genes
whichgenes that were transcribed. 

For doses of a few mSv (< 10 mSv), lesions are eliminated by the
disappearance of the cells; for slightly higher doses damaging a large number
of cells (therefore capable of causing tissue lesions), the repair systems
are activated. They permit cell survival but may generate misrepairs and
irreversible lesions. For low doses (< 100 mSv), the number of mutagenic
misrepairs is small but its relative importance, per unit dose, increases
with the dose and dose rate. The duration of repair varies with the
complexity of the damage and their number. Several enzymatic systems are
involved and a high local density of DNA damage may lower their efficacy. At
low dose rates the probability of misrepair is smaller. The modulation of the
cell defense mechanisms according to the dose, dose rate, the type and number
of lesions, the physiological condition of the cell, and the number of
affected cells explains the large variations in radiosensitivity (variations
in cell mortality or probability of mutations per unit dose) according to the
dose and the dose rate that have been observed. The variations in cell
defense mechanisms are also demonstrated by several phenomena: initial cell
hypersensitivity during irradiation, rapid variations in radiosensitivity
after short and intense irradiation at a very high dose rate, adaptive
responses which cause a decrease in radiosensitivity of the cells during
hours or days following a first low dose irradiation, etc.. 

2) Moreover, it was thought that radiocarcinogenesis was initiated by a
lesion of the genome affecting at random a few specific targets
(proto-oncogenes, suppressor genes, etc.). This relatively simple model,
which provided a theoretical framework for the use of LNT, has been replaced
by a more complex process including genetic and epigenetic lesions, and in
which the relation between the initiated cells and their microenvironment
plays an essential role. This carcinogenic process is confronted by effective
defense mechanisms in the cell, tissue and the organism. With regard to
tissue, the mechanisms which govern embryogenesis and direct tissue repair
after an injury seem to play an important role in the control of cell
proliferation. This process is particularly important when a transformed cell
is surrounded by normal cells. These mechanisms could explain the lesser
efficacy of heterogeneous irradiation, i.e. local irradiations through a grid
as well as the absence of a carcinogenic effect in humans or experimental
animals contaminated by small quantities of a-emitter radionuclides. The
latter data suggest the existence of a threshold. This interaction between
cells could also help to explain the difference in the probability of
carcinogenesis according to the tissues and the dose, since the death of a
large number of cells disorganizes the tissue and favors the escape from
tissue controls of an initiated cell. 

3) Immunosurveillance systems are able to eliminate clones of transformed
cells, as is shown by tumor cell transplants. The effectiveness of
immunosurveillance is also shown by the large increase in the incidence of
several types of cancers among immunodepressed subjects (a link seems to
exist between a defect in NHEJ DNA repair and immunodeficiency).

These phenomena suggest the lesser effectiveness of low doses, or even of a
practical threshold which can be due to either a failure of a low level of
damage to sufficiently activate DNA repair mechanisms or to an association
between apoptosis + error-free repair + immunosurveillance, to determine a
threshold (between 5 and 50 mSv?). The stimulation of the cell defense
mechanisms could also cause hormesis by fighting against endogenous mutagenic
factors, in particular against reactive oxygen species. Indeed a
meta-analysis of experimental data shows that in 40% of animal experiments
there is a decrease in the incidence of spontaneous cancers after low doses.
This observation has been overlooked so far because the phenomenon was
difficult to explain.

These data show that the use of a linear no-threshold relationship is not
justified for assessing by extrapolation the risk of low doses from
observations made for doses from 0.2 to 5 Sv since this extrapolation relies
on the concept of a constant carcinologic carcinogenic effect per unit dose,
which is inconsistent with experimental and radiobiological data. This
conclusion is in contradiction with those of an article and a draft report
[43,118], which justify the use of LNT by several arguments.

1. for doses lower than 10 mGy, there is no interaction between the
different physical events initiated along the electron tracks through the DNA
or the cell;

2. the nature and the repair of lesions thus caused are not influenced by
the dose and the dose rate;

3. cancer is the direct and random consequence of a DNA lesion in a cell
apt to divide;

4. LNT model correctly fits the dose-effect relationship for the induction
of solid tumors in the Hiroshima and Nagasaki cohort;

5. the carcinogenic effect of doses of about 10 mGy is proven by results
obtained in humans in studies on irradiation in utero.

With respect to the first argument, it should be noted that the
physico-chemical events are identical but their biological consequence may
greatly vary because the cellular defense reactions differ depending on dose
and dose rate. The second argument is contradicted by recent radiobiological
studies considered in the present report. The third argument does not take
into account recent findings showing the complexity of the carcinogenic
process and overlooks experimental data. Regarding the fourth argument, it
can be noted that besides LNT, other types of dose-effect relationships are
also compatible with data concerning solid tumors in atom bomb survivors, and
can satisfactorily fit epidemiological data that are incompatible with the
LNT concept, notably the incidence of leukemia in these same A-bomb
survivors. Furthermore, taking into account the latest available data, the
dose-effect relationship for solid tumors in Hiroshima-Nagasaki survivors is
not linear but curvilinear between 0 and 2 Sv. Moreover, even if the
dose-effect relationship were demonstrated to be linear for solid tumors
between, for example, 50 mSv and 3 Sv, the biological significance of this
linearity would be open to question. Experimental and clinical data have
shown that the dose effect relationship varies widely with the type of tumor
and with the age of the individuals - some being linear or quadratic, with or
without a threshold. The composite character of a LNT relationship between
dose and all solid tumors confirms the invalidity of its use for low doses.

Finally, with regard to irradiation in utero, whatever the value of the
Oxford study, some inconsistencies should lead us to be cautious before
concluding to a causal relationship from data showing simply an association.
Moreover, it is questionable to extrapolate from the fetus to the child and
adult, since the developmental state, cellular interactions and immunological
control systems are very different.

In conclusion, this report doubts the validity of using LNT in the evaluation
of the carcinogenic risk of low doses (< 100 mSv) and even more for very low
doses (< 10 mSv). LNT can be a pragmatic tool for assessing the carcinogenic
effect of doses higher than a dozen mSv within the framework of
radioprotection. However the use of LNT in the low dose or dose rate range is
not consistent with the current radiobiological knowledge; LNT cannot be used
without challenge for assessing by extrapolation the risks of associated with
very low doses (< 10 mSv), nor be used in benefit-risk assessments imposed on
radiologists by the European directive 97-43. Biological mechanisms are
different for doses lower than a few dozen mSv and for higher doses. The
eventual risks in the dose range of radiological examinations (0.1 to 5 mSv,
up to 20mSv for some examinations) must be estimated taking into account
radiobiological and experimental data. An empirical relationship which is
valid for doses higher than 200 mSv may lead to an overestimation of risk
associated with doses one hundred fold lower and this overestimation could
discourage patients from undergoing useful examinations and introduce a bias
in radioprotection measures against very low doses (< 10 mSv).

Decision makers confronted with problems of radioactive waste or risk of
contamination, should re-examine the methodology used for the evaluation of
risks associated with these very low dose exposures delivered at a very low
dose rate. This analysis of biological data confirms the inappropriateness of
the collective dose concept to evaluate population irradiation risks.