Expert 5

This is difficult to answer as there is a broad range of nongenotoxic effects that could impact carcinogenicity. For instance, agents/conditions that increase the rate of cell proliferation can increase the mutagenicity and carcinogenicity of genotoxic agents, allowing cells to replicate before DNA repair is complete, or by promoting the growth and progression of cells that would otherwise not progress, or would progress too slowly to give rise to cancer. The whole field of tumor promotion is rife with examples of nongenotoxic agents enhancing cancer risk. Agents that lead to inflammation can increase cancer risk in initiated cells not only by increasing rates of cell proliferation, but by enhancing oxidative stress (also a source of tumor promotion). In addition agents that suppress apoptosis can increase cancer risk, by reducing the rate of elimination of cells with DNA damage. I'm not familiar with any particular examples, but in principle, agents that inhibit DNA repair would also increase cancer risk form genotoxic agents. Then of course, are cancer-pathway specific agents, that might mediate cancer risk by enhancing oncogene activation or inhibiting tumor suppression. There is a good chance that certain agents could lead to enhancement of cancer risk by overlapping more than one effect. Thus, to answer this question it depends on how many potential pathways one considers in possible nongenotoxic enhancement of carcinogenic effects and how many tests (and what type) one would run. Perhaps a starting point might be testing whether 1,3D affects the carcinogenicity or another in vivo surrogate test of carcinogenicity of different types of carcinogens.

Expert 14

Provided that the substance is non-genotoxic, additional exposure to that given substance would change the additional cancer risk only in case of tumor promoting agents, See also (Ito et al. Effects of ingestion of 20 pesticides in combination at acceptable daily intake levels on rat liver carcinogenesis. Food Chem Toxicol 1995; 33: 159-163; Ito et al.. Lack of carcinogenicity of pesticide mixtures administered in the diet at acceptable daily intake (ADI) dose levels in rats. Toxicology letters 1995; 82/83: 513-520; Ito et al. Effects of pesticide mixtures at the acceptable daily intake levels on rat carcinogenesis. Food Chem Toxicol 1996; 34: 1091-1096).

Expert 1

I am not completely clear about this question - is it addressing potential additivity of effects? To answer that question one would need to know which AOP/MoA this is addressing. generally speaking I would see additivity of effects only for substances that are hitting the same pathway or where thresholded mechanisms rely on the same defense mechanisms.
0
Expert 2
04/18/2019 09:28

I think the original question was unclear and is being misinterpreted. The question probably doesn't ask about additional exposure to 1,3D on top of previous exposures to 1,3D itself, but about the RISK of 1,3D outside of the laboratory where humans are exposed to many other carcinogens. To be more blunt, I'd ask it this way: why assume that a nongenotoxic carcinogen is any "better" (less risky) than a genotoxic one??

I think user-553126 [Expert 5] (first comment above at this date) says it well-- "it depends." So my question remains-- if we don't KNOW whether incremental exposures to 1,3D are non-harmful (as they might be if 1,3D only promoted tumors, but somehow all environmental initiators were removed), then why are we seemingly exonerating it for being "nongenotoxic"?

3 votes 3 0 votes
Expert 8
04/18/2019 10:29

The genotoxicity or lack thereof is not an exoneration, but rather a consideration in the over all process of hazard characterization.

1 vote 1 0 votes
Expert 2
04/18/2019 13:33

To user 24419 [Expert 8] : I agree that nongenotoxicity should be "a consideration in the overall process," but I don't see any coherent MOA argumentation in the white paper, other than the TACIT argument that because 1,3D "is" nongenotoxic, it "must" have a threshold dose-response function. To the contrary, there are examples (and good theory) why some nongenotoxic MOAs could have linear, or piecewise linear, or sublinear, dose-response functions, without a population threshold at all, or with one that is so low as to be "not a consideration in the overall process" of risk assessment.

1 vote 1 0 votes
Expert 1
04/21/2019 19:55

I am still unclear of what is being asked here in 6.1 which makes it also difficult to comment on the above discussion.

Comments are closed for this page.