Quantitative Relationship Between Mutagenic and Carcinogenic Potencies A Feasibility Study (1983) / Chapter Skim
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3. Quantitative Correlation Between Mutagenicity and Carcinogenicity
3. Quantitative Correlation Between Mutagenicity and Carcinogenicity
Pages 17-26
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From page 17... ...
This chapter deals with attempts to discover quantitative relationships, with particular attention to the quality and precision of the quantitative data and to the statistical relationships that have been deduced . QUANTITATIVE POTENTIAL OF MUTAGENICITY DATA Ability to extrapolate from chemical mutagens ranked according to the ~ trength of their mutagenicity in simple tes t systems to effects in systems more relevant to man, such as mammals, would have great advantages in risk estimation.
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From page 18... ...
The Committee stated: "Extrapolation from experimental organisms to man has considerable justification as a qualitative measure, but quantitative extrapolation is uncertain. There is neither suf ficient uni formity among sys tems nor su f ficient basic knowledge for quantitative extrapolation to human mutation.
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From page 19... ...
A formal description of the Co~ittee's mutagenicity potency scheme follows: Suppose that the least potent chemical in a given test has a value of X, which is in the range lOk-lOk ~ 1 units. Each chemical examined in this test is assigned to one of the fol lowing potency groups: Group I: potency values between lok and 1ok + 1 Group 2: potency values between lok ~ 1 and lok ~ 2 Group 3: potency values between 1ok + 2 and 1ok ~ 3, and so forth until the highest observed value is reached.
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From page 20... ...
However, cancer bioassays are not simple feeding experiments, and problems of interpretation can arise in bioassays. For example, because the number of animals in an experiment is limited, the highest tolerated doses are often chosen so that the probability of inducing tumors will be as high as possible; but this increases the difficulty of extrapolating to the risk associated with low doses and interpreting the influence of high doses on metabolism of the test chemical, premature mom tality, and fitness of the animals.
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From page 21... ...
A more formal statistical evaluation of TD,o and a detailed numerical defense will soon be published.50~07 The proposed TD,o index of carcinogenic potency constitutes ~ refinement of precarious attempts, in that the incidences of spontaneous tumors and intercurrent mortality were accounted fore Crouch and Witson42 have formulated an estimate of cam cinogenic potency. At low doses, the dose~response curve is inear and de f ined by 21
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From page 22... ...
Thus, according to Squire, the most potent carcinoma yens induce primarily malignant tumors, at multiple sites, in a short period, at low doses, and in both sexes of several species. Although not explicitly designed to assess independently carcinogenic potency, the IARO criteria for evaluating 22
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From page 23... ...
Squire was cautious on the exclusive use of mathematical models to describe biologic events, particularly carcinogenesis. He stated that, "for the same animal data, different models may predict levels of risk that vary widely, indicating the potential error involved in estimating carcinogenic potency or human cancer risks by such methods." To illustrate this point, Squire referred to the controversy surrounding the testing of saccharin.83 This warning about treating in a too nearly mathematical way biologic phenomena whose mechanisms are incompletely understood underscores an uncertainty about calculations of carcinogenic potency.
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From page 24... ...
Differences in carcinogenic potency between animal species were also discussed, especially in regard to the general lack of concordance in S9 enzymatic activity and whole-animal tumor susceptibility. Ames and Hooper4 responded that linear correlation between mutagenic and carcinogenic potencies may depend on the particular chemical and its interaction with a particular organism.
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From page 25... ...
Hoel et al.5 have analyzed mathematically the relationship between DNA adduc t formation and carcinogenes i ~ . Tumor response could be linearly correlated with the concentration of DNA adducts in the target organs, and the kinetic processes ire DNA adduct formation by care inogens are implicated in the nonlinearities in the dose~esponse curve for tumor frequency when they occur.
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From page 26... ...
First, a universally accepted index of carcinogenic potency has not yet been defined. TD,o has been proposed by Ames and colleagues as a standard index and was used in the Meselson and Russell77 correlative study, but the scientific community has not yet accepted this definition.
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