Transcript Precautionary principle: biological basis Paolo Vineis

Precautionary principle:
biological basis
Paolo Vineis
University of Torino
and Imperial College London
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)
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
False positives and false negatives
“Late lessons”
+
-
PP +
a
b
PP -
c
d
“Early warnings”
The true discussion (ethical and scientific) is how far we
want to tolerate false positives vs. false negatives
Another important problem is the difference between
“proof” (e.g. mechanistic, scientifically sound), vs.
indirect and incomplete evidence
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!
Scurvy
Lind, 1753
1928
Ascorbic
acid defic.
Pellagra
Casal 1755
1924
Cancer
of
the scrotum
Pott, 1775
1933
Niacin
deficiency
Benzopyrene
Smallpox
Jenner,
1798
Semmelwei
ss, 1847
1958
Puerperal
fever
1879
Orthopox
virus
Streptococc
us
Cholera
Snow, 1849
1893
Vibrio
Cholerae
2-naphthyl
amine
Professional
bladder
cancer
Yellow fever
Rehn, 1895
1938
Finlay, 1881
1928
Flavivirus
Mouth cancer,
tobacco chew
Abbe, 1915
1974
Nnitrosonornic
otine
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.
A different scientific view
Toxicological approach:
- developed historically from acute poisoning
- generated risk assessment and the idea of
thresholds
Epidemiological approach:
- developed historically from the study of chronic
diseases
- developed the idea of precautionary principle
based on uncertainty
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”
Example of carcinogenesis: role of cell selection and
selection of mutator phenotype
the Two-Step Clonal Expansion Model
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)
SELECTION FOR MUTANT
PHENOTYPES IS ALSO
SELECTION FOR MUTATOR
PHENOTYPES
(current view)
Proliferation of Mutators in a Cell
Population
Mao EF, Lane L, Lee J & Miller JH
Journal of Bacteriology (1997)
Vol 179 (2): 417-422
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)
Example
A 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.
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 16;343(8903):951-3
The PNH model is interesting for the
“darwinian” intrepretation and because
of the association between a mutational
early event and an immune late event
Second example
A 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).
Third example
Chronic 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)
The importance of a “darwinian” approach for the
Precautionary Principle:
- it suggests that long-term changes and not only shortterm 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.