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Die Risikobewertung von Kanzerogenen und die Wirkungsschwelle, Teil I

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Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz Aims and scope

Zusammenfassung

Die Wirkungsschwelle ist so ein Wort, das im Sinne von Karl Popper nicht ernst genommen werden sollte, vor allem, wenn es das Ausbleiben einer Wirkung von Krebs erzeugenden Substanzen beschreibt. Bei der Abschätzung des Risikos von Kanzerogenen müssen jedoch die Fragen, die sich aus Behauptungen und Hypothesen ergeben, deutlich gemacht werden, wenn auch damit die Probleme noch nicht gelöst sind. Ziel bei der Bewertung gesundheitlicher Gefährdung durch Chemikalien ist es u. a., die Voraussetzungen für die Aufstellung von Grenzwerten zu prüfen. Aus den unterschiedlichsten Gründen wurde gefolgert, dass es eine Wirksamkeitsgrenze gibt, an der aus einer gesundheitlich bedenklichen eine unbedenkliche Dosis wird. Wird eine solche Schwelle unterschritten, soll die Gesundheit des Menschen nicht mehr gefährdet sein. Um eine solche Schwelle zu finden, werden meist Dosis-Wirkungs-Beziehungen herangezogen. Ob die für akut toxische Effekte geläufige Beziehung für die chronische Wirkung Krebs erzeugender Stoffe überhaupt anwendbar ist, war zunächst fraglich. Anhand von Beispielen werden die Threshold/Non-threshold-Debatte der letzten 35 Jahre und die sich daraus ergebenden Argumente für oder gegen die Existenz von Wirkungsschwellen verfolgt. Auf der experimentellen Seite wurden bis zu Expositionen, die weit unterhalb der minimal Krebs erzeugenden Dosis lagen, lineare Dosis-Effekt-Beziehungen erhalten. Bei typisch gentoxischen Chemikalien wurden also keine Hinweise auf Nichtlinearität bei niedrigen Expositionen gefunden. Zusammengenommen sprechen die Argumente gegen die Existenz von Wirkungsschwellen, bei solchen Stoffen.

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Notes

  1. „After a certain point on the way to cancer produced by chemicals there should exist a threshold. There is very little biological counteraction to that unregulated growth beyond that stage, or that threshold.“

  2. „The word is used to indicate an entrance, or the beginning as, for example, the threshold of a new career. It is also referred to the lowest limit of perception of a stimulus“.

  3. „Threshold limit values refer to airborne concentrations of chemical substances and represent conditions under which it is believed that nearly all workers may be exposed, day after day over a working life time without adverse health effects, there will be considerable variation in the level of biological response to a particular chemical substance, regardless of the airborne concentration.“

  4. „The question of a no-effect level for carcinogens, i.e. the concept of threshold, is a hotly debated subject. I believe there are such thresholds in intact animals and man, both of which have DNA repair and immunological protective systems.“

  5. „When a chemical causes a defined form of toxicity, the threshold is the maximum exposure when this toxicity does not occur. It is an operational parameter and is limited in its interpretation and applicability.“

  6. NEL=No-Effect Level; NOEL=No Observed Effect Level, NOAEL=No Observed Adverse Effect Level.

  7. „A concentration of a chemical below which a cell would not notice the presence of this agent. In other words the chemical is present but does not interact with a cellular target. The lowest concentration of a chemical that induces a statistically significant increase in the endpoint being measured.“

  8. „Dose of a substance or exposure concentration below which a stated effect is not observed or expected to occur. Intake or dose below which homeostatic changes are able to reverse any adverse effects; or an intake or dose below which homeostatic changes are unable to compensate; or an intake below which a stimulus ceases to be perceptible.“

  9. „Indeed, inhibition of carcinogenesis via trapping of the ultimate carcinogen(s) with non-critical nucleophiles probably occurs to some extent with all chemical carcinogens, and may provide a natural protective mechanism, especially with the very small doses of carcinogens we are likely to face in our environment at any one time. The removal of ultimate carcinogenic forms through non-carcinogenic reactions may be an important factor in the determination of threshold doses of carcinogens or changes in the slopes of dose response curves at low doses of carcinogens.“

  10. „Stochastic determinants impose a lower limit on the dose-response relationship between cells and chemicals.“

  11. „There might be a concentration limit below which biologically significant reactions probably would not occur.“

  12. „No level of exposure to a chemical carcinogen should be considered toxicologically insignificant for man. For carcinogenic agents a ‚safe level for man‘ cannot be established by application of our present knowledge. The concept of socially acceptable risk represents a more realistic notion.“

  13. „Many toxicologists feel intuitively that no-effect levels must exist also for mutagens and carcinogens.“

  14. „In certain circumstances as the applied dose is lowered, the delivered dose may become proportionately less than at high doses so that a new linear relation of lower slope is established.“

  15. „The amendment states simply that no additive found to induce cancer in any animal species following oral ingestion shall be deemed safe.“

  16. „Interpretation and enforcement have followed lines that seem to have ignored both the well-established pharmacological principle of threshold dose (that below which no effect is detectable) and the remarkable degrees of improvement in the sensitivity and specificity of analytical methods that have now been developed.“

  17. “... there is a dose below which there is no effect. If so, then any dose below the level would be „safe“ (in the species tested).“

  18. „That no firm thresholds have been demonstrated.“

  19. „ACGIH TLVs may represent guides of levels which have been achieved are certainly not thresholds.“

  20. „that carcinogenic response at low doses and low dose rates is likely to have a non-linear component, which might result in a dose threshold at the organismal level.“

  21. „that a threshold for biological activity exists within a cell at 104 atoms“

  22. „Methods do not now exist to establish a threshold for long-delayed effects such as cancer.“

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  1. Institut für Toxikologie Universität Würzburg, Privat: Peter-Haupt-Straße 27, 97080 , Würzburg

    H.-G. Neumann

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Neumann, HG. Die Risikobewertung von Kanzerogenen und die Wirkungsschwelle, Teil I. Bundesgesundheitsbl. 49, 665–674 (2006). https://doi.org/10.1007/s00103-006-1287-7

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