Mechanisms of Carcinogenesis: Dose Response

Our plain-English summary of Mechanisms of Carcinogenesis: Dose Response, by P.J. Gehring, G.E. Blau (1977).

The study

• Authors: P.J. Gehring, G.E. Blau
• Published: Journal of Environmental Pathology and Toxicology (1977)
• Type of article: Journal article
• Our copy: from Johns-Manville's own medical library. The article is still under copyright, so we describe it here rather than post it.

In plain English

This 1977 theoretical paper, by two Dow Chemical Company authors, concerned chemical carcinogens in general and does not mention asbestos. It first reviewed arguments for and against a 'threshold', a dose below which a chemical would not cause cancer. The authors built a hypothetical model of how a cancer-causing chemical might be activated, detoxified, excreted, bound to DNA and other molecules, and repaired. They ran it by computer using rate values chosen for illustration, noting bias in choosing them; no people or animals were studied. In the model, above 10 to the minus 4 moles per kilogram, disproportionately more bound to critical genetic targets. In this illustrative model, raising the dose 100-fold, from 10 to the minus 4 to 10 to the minus 2, raised what the authors called the real carcinogenic dose 10,000-fold. The model predicted some cancer, albeit negligible, at any dose, provided the exposed population was large enough or lived long enough. The authors concluded that large doses may overestimate low-dose hazard. They stated the model had many flaws and covered one mechanism only, alkylation of genetic material.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of arguments about carcinogen dose-response and thresholds, followed by a hypothetical mathematical (pharmacokinetic) model solved by computer simulation
• Who was studied: No human or animal subjects; a computer simulation of a hypothetical chemical carcinogen using illustrative rate constants
• Exposure: A hypothetical chemical carcinogen that must be activated to a reactive metabolite that binds to genetic material, given as single doses expressed as initial tissue concentration in moles per kilogram; asbestos is not discussed
• Main results:
  • In the model, when the dose of the hypothetical carcinogen exceeded 10 to the minus 4 moles/kg, a disproportionately larger amount was bound to critical receptors
  • In the illustrative model, increasing the dose 100-fold (from 10 to the minus 4 to 10 to the minus 2) increased what the authors called the real carcinogenic dose 10,000-fold rather than 100-fold
  • From the model, the authors stated that currently used extrapolation techniques are likely to overestimate risk
  • No threshold was built into the model; it always predicted some incidence of cancer, albeit negligible, however low the dose, if the exposed population is sufficiently large and/or survives until cancer occurs (no competing causes of death)
• The authors' conclusion: The authors concluded that using large doses may give a fictitious overestimate of hazard for low doses, and that measuring the critical parameters identified by the model would aid judgment
• Limitations the authors state:
  • The rate constants were chosen by the authors for illustration, with acknowledged bias
  • Cell replication was treated in a simplified (first-order) way that the authors called naive
  • The authors stated the model has many flaws and was not intended to be complete
  • The model considers only one mechanism of carcinogenesis, alkylation of genetic material

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Carcinogenic.

Browse return to medical research.