Thresholds in Chemical Carcinogenesis: What Are Animal Experiments Telling Us?

Abstract

It appears that the controversy over whether animal experiments demonstrate a threshold for carcinogenicity from chemicals was due to an error in plotting dose response. A linear (arithmetic) scale for the dose of chemicals obscures effects at doses below those used in the experiment and distorts the effect seen over the range of doses used. Gaddum (Nature 156: 463, 1946) pointed out that, empirically, dose should be on a logarithmic scale to effect a linear quantal response. It now is proposed that this logarithmic relationship of dose to effect has a sound basis in chemical thermodynamics (Waddell, Toxicol Sci 68: 275-279, 2002). When the results of major studies (e.g., ED01, etc.) done in the past were reanalyzed with this in mind using the Rozman et al scale (Drug Metab Rev 28: 29-52, 1996), which has a logarithmic scale down to one molecule (10 0 ), unequivocal thresholds were demonstrated. Many animal studies now have been reanalyzed by this procedure (e.g., Waddell, Toxicol Sci 72: 158-163, 2003; Waddell, Food Chem Toxicol, in press; Waddell, Hum Exp Toxicol, in press); these studies show thresholds for carcinogenicity at doses ranging from 10 17.1 to 10 21.92 molecules/kg/day. These results require a complete reevaluation of human risk assessment for carcinogenesis from chemicals and a redirection of basic research to discover the system, or systems, that are overwhelmed at these thresholds.

Lack of large intestinal carcinogenicity of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine at low doses in rats initiated with azoxymethane

“…8,9 Moreover, thresholds for chemical carcinogenesis were concluded in a recent article. 10 In practice, the many factors active in vivo, from intake of carcinogens through to lesion development, mean that the processes are highly complicated, so that if the DNA-damaging potency of a carcinogen is low, the linear part of the low dose-cancer incidence curve might be hidden within the background variability, and issues of true threshold and practical threshold have therefore been discussed. 11 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) is an environmentally abundant HCA, produced by pyrolysis of amino acids and proteins during cooking of meat and fish.…”

An Alternative Perspective: A Critical Evaluation of the Waddell Threshold Extrapolation Model in Chemical Carcinogenesis

“…However, he (i) apparently has the mistaken belief that if a model fits the data well in the observed range, it can be extrapolated to much lower doses to "unequivocally demonstrate" a threshold; (ii) apparently does not realize that his model is structured in a manner that essentially forces, rather than demonstrates, a threshold; and (iii) erroneously believes that by rescaling the dose and using a log linear model, he has achieved an important scientific breakthrough that once and for all resolves the threshold issue in chemical carcinogenesis. Waddell asserts that "the controversy over whether animal experiments demonstrate a threshold for carcinogenicity from chemicals" is due to nothing more than "an error in plotting dose-response" (8). This is a rather simplistic view of the extrapolation issue.…”

“…Waddell justifies his approach by citing impressivesounding concepts like the "thermodynamic concept of chemical potential and the law of mass action" (8) and "Avogadro's constant" (4). However, he never explains how these "laws of nature" justify his view that a log linear model reflects the underlying mechanisms of carcinogenesis for all tumor sites, all chemicals, and all animal models.…”

“…First, he expresses dose in terms of molecules of carcinogen/kg/day. Despite Waddell's claims that this rescaling, which he attributes to Rozman et al (3), is a "brilliant concept" (5) and one that is "enormously important" (8), it is simply a conversion of dose from one scale of measure to another. Nothing more.…”

“…In a series of papers (4)(5)(6)(7)(8), including a Perspective article in this journal (8), William Waddell presents and discusses one particular threshold-based extrapolation model. However, he (i) apparently has the mistaken belief that if a model fits the data well in the observed range, it can be extrapolated to much lower doses to "unequivocally demonstrate" a threshold; (ii) apparently does not realize that his model is structured in a manner that essentially forces, rather than demonstrates, a threshold; and (iii) erroneously believes that by rescaling the dose and using a log linear model, he has achieved an important scientific breakthrough that once and for all resolves the threshold issue in chemical carcinogenesis.…”