Expert 9

The OECD AOP program may result in better information on the mode of action or mechanisms of toxicity for various compounds. For example, if we had a better understanding of the mechanism by which 1,3-D increased the incidence of benign lung tumors in B6C3F1 male mice, we may be better able to predict the probability that this compound could cause lung tumors in humans. The problem is that we are not there yet. What we have are empirical observations in animals that we have to attempt to extrapolate to humans. Without the benefit of mechanistic information on the observed effects of 1,3-D in mice and rats, we must still decide 1) are the observed effects real in these species and 2) to what extent can we extrapolate these effects to humans? Based on where we are today, the weight of evidence suggests that 1,3-D is unlikely to be carcinogenic to humans.

Expert 6

I think that the AOP approach proposed by OECD is interesting. I think that in this particular case of 1,3-D the AOP approach would organize results and give further information in addition to all the results obtained by in vitro and in vivo studies, MOSTLY if we consider the molecular initiating event (MIE) and the outcomes.

Expert 11

The absence of human relevance of the lung tumors could be better supported when an AOP for the response can be developed (may have been done with styrene ?) and individual steps can not be demonstrated to occur with 1,3-D. This however, may require a significant research effort that may be difficult to justify if the tumors are not treatment related .
3 votes 3 0 votes
Expert 7
04/17/2019 11:19

I agree that the AOP approach can be useful in certain situations. But before attempting mechanistic research, there should be agreement that there is a clear carcinogenic response to investigate. In this case, the benign lung response is barely outside of HCs, and thus questionable. Also, the research effort would be very challenging given that the response occurs in a genetically susceptible strain/sex with a high and variable background. If considered treatment related, this slight increase in adenomas (ie size) would likely be explained by an ncrease in growth of the spontaneous lesions (promotion).

1 vote 1 0 votes
Expert 6
04/17/2019 19:31

I agree that it is necessary to have an agreement that there is a clear carcinogenic response to investigate.

1 vote 1 0 votes
Expert 11
04/18/2019 03:04

Agree that there is no need to do AOP development if the tumor response is not treatment related. Increase in growth of spntaneous lesion may all explain the weak response in mouse lung as suggested by user-232578 [Expert 7]

2 votes 2 0 votes
Expert 8
04/18/2019 11:55

Understanding of AOP (chemically agnostic toxicity pathway) and a chemical specific MOA can contribute to the evaluation of a response as treatment-related or not.

This is not to say that one must go through the long and resource intensive process of establishing an AOP on the OECD Wiki.

3 votes 3 0 votes
Expert 9
04/18/2019 20:52

I agree with the previous comments that AOP investigations are appropriate when we have clear evidence of an increase in tumor incidence.

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