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Scurvy

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

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Scurvy

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  1. Precautionary principle: biological basisPaolo VineisUniversity of Torinoand Imperial College London

  2. 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)

  3. 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

  4. False positives and false negatives“Late lessons” + - “Early warnings”PP + a b PP - c d

  5. 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

  6. 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!

  7. Scurvy Lind, 1753 1928 Ascorbic acid defic. Pellagra Casal 1755 1924 Niacin deficiency Cancer of the scrotum Pott, 1775 1933 Benzopyrene Smallpox Jenner, 1798 1958 Orthopox virus Puerperal fever Semmelweiss, 1847 1879 Streptococcus

  8. Cholera Snow, 1849 1893 Vibrio Cholerae Professional bladder cancer Rehn, 1895 1938 2-naphthyl amine Yellow fever Finlay, 1881 1928 Flavivirus Mouth cancer, tobacco chew Abbe, 1915 1974 N-nitrosonornicotine

  9. 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.

  10. 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

  11. 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”

  12. Example of carcinogenesis: role of cell selection and selection of mutator phenotypethe Two-Step Clonal Expansion Model

  13. 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)

  14. SELECTION FOR MUTANT PHENOTYPES IS ALSO SELECTION FOR MUTATOR PHENOTYPES(current view)

  15. Proliferation of Mutators in a Cell PopulationMao EF, Lane L, Lee J & Miller JHJournal of Bacteriology (1997)Vol 179 (2): 417-422

  16. 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)

  17. 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.

  18. 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

  19. The PNH model is interesting for the “darwinian” intrepretation and because of the association between a mutational early event and an immune late event

  20. 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).

  21. 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)

  22. 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.

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