Precautionary principle: biological basis Paolo Vineis University of Torino and Imperial College Lon

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Precautionary principle biological basisPaolo
VineisUniversity of Torinoand Imperial College
London
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HOW IS THE PRECAUTIONARY PRINCIPLE JUSTIFIED-
IMPOSSIBLE TO SET A THRESHOLD FOR CARCINOGENIC
SUBSTANCES- LONG INDUCTION-LATENCY PERIODS (E.G.
BSE E CREUTZFELDT-JACOB)- UNCERTAINTIES ON
MECHANISMS OF ACTION- EFFECTS ON A LARGE SCALE
(CHERNOBYL, BSE)
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LIMITATIONS- WHAT IS THE MINIMUM LEVEL OF
SUSPICION THAT LEADS TO PRECAUTION?- CAN BE
PARALIZING (E.G. ARTIFICIAL ICE IN US IN EARLY
20th CENTURY)- RISKS EVALUATED INDEPENDENTLY OF
BENEFITS
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False positives and false negatives Late
lessons - Early warnings PP
a b PP - c d
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The true discussion (ethical and scientific) is
how far we want to tolerate false positives vs.
false negativesAnother important problem is the
difference between proof (e.g. mechanistic,
scientifically sound), vs. indirect and
incomplete evidence
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Table comparing the date of discovery
of a preventive measure (based on early
warnings) and the date of discovery of the
causal agent (late lessons)(from Wynder, 1994,
modified).Many of these early warnings were
originally classifed as false positives but
they were not!
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An excellent recent case of lack of PP in the US
is the case of a chemical called diacetyl used in
flavorings for example microwave popcorn. Early
toxicological tests showed it caused massive lung
damage in rats. However, no action was taken and
now a cluster of workers are suffering from
debilitating lung disease and requiring
transplants.
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A different scientific viewToxicological
approach- developed historically from acute
poisoning - generated risk assessment and the
idea of thresholdsEpidemiological approach-
developed historically from the study of chronic
diseases - developed the idea of precautionary
principle based on uncertainty
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New biological approach, based on
Evolutionary Medicine- developed historically
from the study of ecologic problems- generated
the idea that different organisms, and the
biological and physical environments, are
mutually dependent- overcomes both toxicology
with its model of chemical damage with a
threshold, and epidemiology with its model of
multifactorial probabilistic causal networks-
suggests that the scientific basis of the PP is
larger than simple prudence derived from
uncertainty
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Example of carcinogenesis role of
cell selection and selection of mutator
phenotypethe Two-Step Clonal Expansion Model
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SELECTION IN CANCER usual view

• It is commonly recognized that somatic MUTATION
  (irreversible change in DNA information content)
  initiates the process of carcinogenesis
• The mutated cell(s) are selected in vivo because
  of their growth advantage, loss of contact
  inhibition, loss of apoptotic pathway(s), etc.
  This is selection after mutation, i.e. SELECTION
  FOR THE MUTANT PHENOTYPE.
• (R Albertini)

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SELECTION FOR MUTANT PHENOTYPES IS ALSO
SELECTION FOR MUTATOR PHENOTYPES(current view)
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Proliferation of Mutators in a Cell
PopulationMao EF, Lane L, Lee J Miller
JHJournal of Bacteriology (1997)Vol 179 (2)
417-422
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IN HUMANS, AS IN BACTERIA, SELECTION FOR
MUTANT PHENOTYPES IS ALSO SELECTION FOR MUTATOR
PHENOTYPES(WHICH ARE PRESENT AT LOW FREQUENCIES
IN MOST INDIVIDUALS)(R. Albertini)
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Example



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NON-CANCER MODEL OF DARWINIAN MECHANISM
PNH Paroxysmal nocturnal hemoglobinuria
(PNH) is an acquired stem cell disorder
characterized by intravascular hemolysis,
hypercoagulability, and bone marrowe
failure. The characteristic defect in
paroxysmal nocturnal hemoglobinuria is the
somatic mutation of the PIG-A gene in
hematopoietic cells.
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The current hypothesis explaining the disorder
suggests that there are two components (1)
hematopoietic stem cells with the characteristic
defect are present in the marrow of many if not
all normal individuals in very small numbers (2)
some aplastogenic influence (e.g. an adverse
reaction to a drug) suppresses the normal stem
cells but does not suppress the defective stem
cells, thus allowing the proportion of these
cells to increase. (darwinian interpretation)
Bessler M, Mason P, Hillmen P, Luzzatto L.
Somatic mutations and cellular selection in
paroxysmal nocturnal haemoglobinuria.Lancet 1994
Apr 16343(8903)951-3
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The PNH model is interesting for the darwinian
intrepretation and because of the association
between a mutational early event and an immune
late event
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Second exampleA striking recent observation was
the finding of a very high proportion in healthy
newborns of mutations in a gene associated with
lymphocytic leukemia (the mutation rate was about
100 times higher than the cumulative incidence of
leukemia)(Mori et al, 2002). While the origin
of such mutations is not known but could
express exposure to in utero stressors it is
clear that mutations per se are insufficient to
explain the onset of leukemia, which is probably
due to further hits that select cells with a
selective advantage (the PNH model).
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Third exampleChronic exposure of yeast to
environmentally relevant concentrations of
cadmium results in extreme hypermutability.This
is due to a reduced capacity for MMR of small
misalignments and base-base mismatches.Figure
The impact of CdCl2 on mutation rates and
viability in yeast(Jin et al, Nature Genetics
2003 14 326-329)
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The importance of a darwinian approach for the
Precautionary Principle- it suggests that
long-term changes and not only short-term
exposures should be considered and monitored-
that consequences can be unpredictable on the
basis of traditional toxicology(e.g. Cadmium)-
that it is not only gross damage of
macromolecules that causes disease, but also
changes in the delicate balance between
environmental stress and response to it It
is true that an unmodifiable natural state does
not exist, but it is also true that human
physiology has constraints that are not only
those discovered by classical toxicology.