Tobacco Documents Online

Critical approach of mathematical extrapolation Prof. Etienne Fournier (free translatiion not checked by the author.)

A critical study of inethods of assessment of the effects of low doses P. Etienne Fournier (1993) This paper sets out to be a consideration of the positions taken by experimental toxicologists and regulatory bodies for more than 40 years and on their necessary confrontation with the facts from hutnan observation conducted by clinical physicians and, preferably, by clinical toxicologists. One objective is apparent, in any case part of all the legislation - that of suppressing - in theory completely (objective 0), in praetice.in such a way as to become indiscernible, and at worst to reduce substantially - ailmeats connected with.the absorption of chemical products howeverr absorbed and the clinical course of cancer.. Let us admit that in the usual constitution of discussion panels, clinical toxicologists (representing internal medicine or working mediciae) although the only qualified observers, are practically excluded from the final report in favour off experimental toxicologists or analysts. This is not a paradox, since each of their contributions stresses actual facts including a strong probability of correlation N . Q between a known exposure and the too premature, too frequent jV and excessively atypical incidence of certain cancers. W From these comes the set of agreed procedures which are

t transcribed and quantified to achieve national and interAational regulation. Calculations in this matter are those of epidemiologists and biostatisticians and evaluation.of doses those of-analysts: A first logical., quasi-mathematical, relationship will be established: For one exposure to xl ppm in the air or for oral absorption of x2 mg/Kg/day, n cancers appear (in the context of the study: target population, - exposure tirae, time before appearance, & -). A second relationship, no less classical, normally follovs. it is defined in accordance with methods which avoid the essential bias of the number of these cancers observed in a reference population suffering no exposure to the target chemical hazard. In general, it results in a mortality coefficient implying excess mortality for a defined exposure . From the moment when the set of. interpretations begins, the most frequent being a major increase through a purely formal movement to sufficiently large numbers: For example, if Xhas observed.tWo fatal cancers in the target population and only one in the control population, Y can say that the SHII2 ratio is 200%. Whilst recognizing ~ immediately that this simple cutline is not only ~ unacceptable but is far from representing the reality of the ~ cancerous condition. ~ ~ ~ 0

a) Most common hormone-sensitive cancers currently treated are cured or benefit from a prolonged remission. Indeed the morbidity of cancer is exceptionally well-documented. b) The relative importance of cancers subject to hormonal influence has not ceased to grow and this group does not alvays have an obvious connection with toxic impregnation, with the exception of thyroid cancers, although an associated effect should be observed. c) Conversely, cancers appear in subjects. treated and cured by the use of radiation.or drugs primarily acting on DNA. d) Other pathological phenomena certainly recognized apart from the transmission of transplacental products, individual predispositions in individuals who are carriers of inherited cancers, identify genetic criteria in families where.;the _ preponderance of cancer amongst the causes of morbidity is important. This notion is particularly useful in the study of childhood cancers. This is found in an exaggerated manner -in subjects who are carriers of inherited abnormalities relating to the DNA and its repair, and who present a greater prevalence of cancers of the skin or blood ( leukaeatias and lytaphomas ). There are too few such families to identify from them response criteria to chemi.cal.products. And caffeine, the classical inhibitor of DNA repair, has no demonstrated in experimental carcinogenesis.

el The jtvout cotamon cancers of c2iemi.cal origjn are cancers of the lun$ due to chronic addiction to smoking uith constant e:.poeure to several grams of carcinogenic substanoes over the bronchial anicous Meatbr+sne, phot:oeensitive Skin cancors susceDtiblE to activation by cheia.ical products and oL the bladder atter excessively prolonged iatpregnation (aromatic amines). In all thrco cases cellular expoaura is massive and. prolonged_ AcbestoE cancers in the form of MPsothelivcna arc consparable with them becau.Se of a considerable accumulation of asbcetos fibrilla irreversibly accWaul•ated in the serous nteabra,ie. In fact, human cancPrs due to chemical produets (the "may cause human cancer" categoty) appeac after long periods of close and significant contact betveen a cellular type and t.he product itsplt or its sattabolites. The "one bit - one canc:er' hypothesis should therefore be quesLioned. This slogan is suspect because it is a Sloqan. It cannot simply be accepted. Clinicians have urv+x taken eteps to observe a cancer occurring after one single minimal contact, which certainly dv"s not mean that this method of occurrence cannot be suggested as one possible hypothesis. F.ach individu&l is free to express his views. But this firet attitude, an extreme one, is also one v2xic.ti prevents all subsequent 4

, ' discussion, since no individual has been totally protected from the sun or fumes. In advance we are all cancerous - which will perhaps be confirmed but in different vays. A better quantitative approach to the initial mutation phenomenon might be assessment involving tests on procarocytes of the 'mini.mctm concentration effective. In the usual literature, the biologist looks for an obvious effect which he calls positive and which he contrasts with doubtful or negative results. It vould•be interesting to test the molecules by specifying the threshold-concentration from observation of a rise in mutations compared with the spontaneous mutations of the original preparation_ Even if we do not know the cause'of-spontaneous mutations we may assume that they relate to a random process on the scale of a micro-organism vhich becomes a measurable constant for the population, and the deviation from'the constant may be a good experimental index for the effect of loW dose- concentrations (less thaan 1--9M). The same reasoning is proposed for organs and their cellular population_ Proaposed extrapolations . a) an3.ma1 references conditions, the logical stance would be to take experimentan Since no cancer due to a chemical product can have been observed in man in the purest imaginable environmental data supported by control animals reared under rigorous

conditions- water, food, air, accommodation and free of viral immunological reactions. Even If all is not yet perfect in the field of good laboratory practice, experimenters are nearing perfection. They also note that the spontaneous mortality, apparently inescapable, of such animals is largely of cancerous origin, and that the date of appearance of cancers depends on the species and the breed. N.B. 1 Epidemiologists, for their part, give us to understand that the prevalence of human cancers is a function of age: kA5, but this proposition has only modest consequences if the average lifespan varies little from one population to ano.ther.'Thus the variation from 70 to 75 years (considerable average variation) only increases the probability caused by 41.%. N.B.2 An extrapolation by linear or even semi-Zogarithmic function towards doses - or concentrations - considerably lower than those for which cancers have been observed in man or animals, leads to non observable rates of effect still comparable with the initial doses, generally very high (n mq/Kg/day)- over some forty years an abstract approach has developed based on hypotheses which at first were the interpretation of extremely simplistic elementary principles but which have evolved through the introduction of the biological knowledge accumulated during recent-years and the biology of DNA. W

Let us briefly recall them: First h_vnothCs.is: only one particular shock - production of a single radical OR* - causes DNA to explode (cellular death) or deforms it sufficiently for the cell to become uncontrollable (one hit one cancer). Apart from its fundamental drawbacks, the hypothesis ill applies to the absorption of chemical substances or to the effect of their metabolites. Avogadro's constant 6.02 1023 implies that the nanogram supports an average of 3 10 12 reactive poles. This is considerably more than can be supported by an organism if each cell absorbing a single reactive molecule were to become cancerous . Secp~hypo hesic: It refers to the most generally accepted knowledge of cancerisation, the current theory 'making to succeed' an initial stage which remains latent in successive phases of advancement. If the same molecule is initiator and promoter, the hypothesis of a multiple stage reaction is acceptable. Unfortunately our knowledge about promoters is still very hazy compared with what we know about initiators and complete carcinogens. If we admit that a very large number of molecules such as some phenols are promoters and that the human being always carries them, we are brought back to the previous stage. For initiators the current theory.would be that of

incomplete repairs leaving adduits???-mutations in place, becoming more and more numerous. For promoters a consensus without formal reason agrees somewhat shamefacedly to consider that they only act above a certain threshold. ThjXd hvoothesis: This results from knowledge of anticancerous genes - emerogenes. These can equally FTell be stimulated by both chemical products and pro-oncogenes. Similarly, damaged DNA excision-repair phenomena unite to predict the appearance of immortal cells with carcinogenic potential. The theory seeks a differential function between. the initiator effect and the-repairer effect. h hvflathesis: Coming finally to the in situ control of frQur,t formed cancer and its own evolution by metastases, attacks and phases of stabilization. The simple theory holds that once formed, the i.nitiated and promoted cell divides in an inescapable way. In this case, whatever the duration of a pathological division, the carrier of the cancerous mass should die within a few days or months, Which is effectively observed in acute forms. The actual phenomenon becomes at least doubly random - uncertainty about the progress uncertainty about regression - in so far as we are of gauging the different factors and measuring the cytokines which regulate the complete process_

Matbematical analysis of sequential and contradictory cellular phenomena calls on models of physio-pathological regulation. In respect of mathematical carcinogenesis, we are unfortunately at the point where the ancient Egyptian surveyors of a random expanse - the silt of the Nile - were, before fundamental data about plane geometry. But additional data is gradually appearing. Evaluation of resistance to a cancer has barely begun. For we already knflw that not all asbes-tos workers die of inesothelioma even if exposed to the maximum amount of dust. oa a simpler mode, not all the bacteria of the Ames systemm mutate when they divide in a milieu containing a reference carcinogen, but.it is clear that the random nature of the mutation is located at a level other than that of the non exposed population. The deregulation is explained by a coefficient of ntutageaesis: It is in hotnolog.ous terms that the coeff icients of morbidity (rarely recognized) and mortality (which are only valid for cancers which are often fatal) appear_ Uncertainty increases in the proximity of the coefficient 1 in as much as the first serious observation was that of the "healthy worker effect" which brings the coefficient to 0_8 during adult life. Hence faced the extraordinary by biologists conf us ion of demands and doctors who admit for nil risk, N that this N ~