Statistical Issues in the Design, Analysis and Interpretation of Animal Carcinogenicity Studies

Abstract

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Risk assessment׳s insensitive toxicity testing may cause it to fail

“…(3) Data from concurrent negative controls in a TG-GLP experiment are allowed (OECD, 2012b) to be diluted, even overridden, by historical control data drawn from experiments carried out in a wide range of different conditions (accordingly, they are used in many risk assessments). Some of the variables not well controlled when using the often secret historical controls include strain and origin of animals, laboratory in which the experiment was carried out, dietary factors; environmental contaminants in air, bedding, food, and water; differences in diagnostic criteria among pathologists, and the year in which the experiment was performed; all which can produce very different results (Haseman, 1984;Hardisty, 1985). (4) Positive controls (when feasible) limit false negative results (Myers et al, 2009), but are never mentioned in the TGs or in guidance.…”

Toxicity and Carcinogenicity of T-Butyl a Lcohol in Rats and Mice Following Chronic Exposure in Drinking Water

“…For the analysis of tumor incidence data, survival-adjusted procedures were used to assess dose-reponse trends and to make pairwise comparisons between dosed groups and controls (Haseman, 1984). Fisher exact tests and Cochran-Armitage trend tests were also utilized to assess tumor : incidence data.…”

Are tumor incidence rates from chronic bioassays telling us what we need to know about carcinogens?

“…Haseman (1983) acknowledges that although his paper deals primarily with false positives, examination of the statistical properties of the standard bioassay would be incomplete without consideration of the false negative rate. Haseman (1984) provides a table that shows the false negative rate to be 30% for a chemical that induces a rare tumor in 13% of animals at the high dose. For a chemical that doubles the tumor incidence for a common tumor from 30% in the controls to 60% at the high dose, the false negative rate is also 30%.…”