Based upon your preferred MOA(s) documented in your response Question 1 for rodent liver tumors, is the MOA also applicable for human health risk assessment (please explain your answer)?

Results
(6 Answers)

Expert consensus indicates that the rodent liver tumor MOA is qualitatively relevant to humans, but with important quantitative considerations:

Agreement on biological plausibility: Most experts (5 of 6) consider the MOA at least "possibly applicable" to humans, with Experts 4 and 6 noting similar biological mechanisms exist in humans.
Disagreement on practical relevance: Expert 3 considers it "not applicable" due to the high-dose requirements, while others (Experts 1, 4, 5) acknowledge human relevance but emphasize threshold-based considerations.
Quantitative concerns: Multiple experts highlight that the high doses required for tumor formation are unlikely in human exposure scenarios, making practical risk "negligibly low."
Research needs: Expert 4 suggests developing robust PBK models to address quantitative variations, while Expert 2 emphasizes the need to study high-risk subgroups.

Summary Generated by AI

Answer Explanations

Possibly applicable

Expert 5

In the case of a cytotoxic MOA , in theory these same key events and biological processes seen in rodents would also function in humans. Thus in theory a cytotoxic DX MOA might apply to humans. However any hepatotoxicity in humans would be for short-
term since the exposure would be discountinued once liver injury was detected. Even if chronic human exposure would occur the doses as noted in the occupational exposure studies woudl not be sufficient to induce chronic hepatic toxicity needed to invoke a regenerative hepatic hyperplastic response. The epidemiological data on DX exposure to humans did not show an increae in liver tumors.
Likely applicable

Expert 6

There is no reason to believe that the MOA for hepatic effects is fundamentally different between humans and rodents. However, there remains some uncertainty as long as the molecular events leading to cytotoxicity/cell death have not been fully elucidated. It appears inadequate, however, to base the idea of a non-thresholded MOA on the lack of a full understanding of the molecular mechanism leading to cytotoxicity.
Applicable,

Expert 4

Qualitative relevance of the hypothesized mode of action in humans cannot be precluded based on evidence that humans lack some mechanistic element known to be necessary for the rodent tumourigenic response. Hepatotoxicity associated with cyp 2E1 induction in humans has been observed following exposure to high doses of other toxicants . However, there are a number of factors which may contribute to quantitative variations in response in humans for the hypothesized key events including, for example, the distribution and activity of cyp 2E1 and the relative sensitivity of tissue response to cyp 2E1 induction. If possible, the development of a sufficiently robust (verified) PBK model to address quantitative variations in the induction of cyp 2E1 by 1,4-DX would be helpful to estimate the sustained levels of human exposure anticipated to result in similar response in humans to that observed in studies in rodents. These are likely very high, with the practical implication that the probability of 1,4-DX causing cancer in humans is likely negligibly low (or zero).
Likely applicable

Expert 2

This requires careful study of high-risk subgroups, not just healthy subjects.
Possibly applicable

Expert 1

Possibly applicable as long as MOA is considered and a threshold based extrapolation is used.
Not applicable

Expert 3

Given that the MoA action is high-dose specific and requiring of metabolic saturation, and that such doses are extremely unlikely to be encountered under any reasonable human chronic exposure scenario, this tumor response can be considered as "quantitatively not relevant" to human cancer based on the application of conventional MoA framework analyses.

Debate (3 Comments)

Expert 2

05/13/2024 12:33

I agree with the nuances articulated in the above responses from multiple Experts. The hepatotoxic aspects should be common to animals and humans.

Expert 6

05/21/2024 10:35

I agree with expert 5. The fact that human exposure levels are or have been lower than in the top doses in the rodent studies most probably explains why the human epidemiology is not showing an increase in liver tumors . This observations supports the notion that there is no evidence for a fundamentally different MoA in humans.

Expert 3

05/23/2024 18:09

The existing MoA framework analyses provide for addressing an initial question that if the hypothesized MoAs could plausibly occur in humans regardless of dose conditions required to elicit the MoAs, the tumors are regarded as potentially (qualitatively) human relevant. However, and importantly, the MoA then allow for consideration of the whether or not the tumor are quantitatively relevant to human, e.g., humans have quantitatively lower metabolism to hypothesized toxic metabolite(s) driving the MoA. Saturation of metabolism, resulting in high-dose specific tissue accumulation of parent DX driving the hypothesized MoA(s), is a parallel scenario potentially lacking quantitative human relevance if the doses sufficient to saturate DX metabolism are demonstrably quantitatively implausible in humans. Human DX exposure scenarios support such a conclusion that, e.g., no humans would tolerate a lifetime of likely very high concentration nasal irritating exposures to DX, and lifetime drinking water scenarios in the high 100s to 1000s of ppm necessary to elicit metabolic saturation are a completely unrealistic human exposure scenario. Thus, although the biology associated with liver tumors in rodents theoretically exists in humans, such biology would never be stimulated given that no plausible human exposure scenarios would quantitatively sufficient to result in doses required to initiate even the first biological events hypothesized for the MoA

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SciPi 599: Rat Liver Tumor Mode of Action