MultiCASE collaborates with the US FDA to create models using statistical and expert rule-based QSAR methodology. These models are built using our software program, CASE Ultra, to evaluate pharmaceutical impurities in accordance with ICH M7. In addition to bacterial mutagenicity, we have models used to assess other toxicological endpoints such as genotoxicity, carcinogenicity, etc. All our models follow OECD guidelines and can also be used to satisfy the information requirements listed in REACH. We use this channel to store informational and educational material related to our field of computational toxicology.
DNA-reactive, Ames-positive compounds show a reasonably high correlation to rodent carcinogenicity whereas Ames-negative compounds with positive in vitro chromosomal aberration assay results have been shown to be poorly correlated with carcinogenic potential in rodents with more than 75 % noncarcinogens giving positive clastogenicity results (therefore the emphasis is more on Ames positive compounds (DNA-reactive compounds). DNA-non reactive genotoxin is Ames negative but may be positive in chromosome damage test. While DNA-reactive chemicals bind covalently with DNA and can cause harm at very low levels (no threshold), a DNA-non reactive chemical targets components required for DNA synthesis and may cause this damage only when the dose exceeds certain threshold. Therefore limit for DNA-non reactive chemical is usually higher than for DNA-reactive
DNA-non reactive genotoxin is classified as class5 and out of scope of ICH M7. Less harmful property of the compound justifies it, I understood. Thank you for the details.
Session 2 was also fun for me. Most aldehydes are negative in QSAR, and it sometimes bothers me like Case study#3. As you mentioned(50:19), it should be handled correctly. And the ames negative compound with clastogenicity is referred as class 5 in ICH M7 Q&A(step 2b). By the way, the interim limit of DIPNA in EMA is the same as NDEA. With considering the form of diazonium ion, it looks conservative approach. What do you think about it?
In any risk assessment, the objective is to ensure safety of patients, therefore are designed to be sufficiently health protective, and as you may know, every risk assessment is associated with some uncertainty. This uncertainty will be increased when you use surrogate approach (as you do not have compound-specific data). Due to this, the risk assessor usually lean towards health protection and therefore limit derived using surrogate data is expected to be conservative than when derived using compound-specific data.
@@sebastianjoseph6279 Thank you for your kind and helpful answer. I perfectly agree with you. In other words, how to manage uncertainty is very important in risk assessment. I'll keep it in mind.
46:36 "API or related compounds to the API" may be better, because Ames test data of some related compounds to the API (e.g. process intermediate) are usually collected for manufacturing.
It's fun. I enjoyed it. Was 2-amino-1,3,4-thiazoles recognized as deactivating/ mitigating feature in GT_BMUT? I'm interested in how to review compounds with deactivating/ mitigating features. I'm looking forward to the part 2!!
Glad you enjoyed! Yes, the GT1_BMUT picks up 4 analogs which is not enough to produce an alert however GT_EXPERT picks up the alert. Part 2 next week...July 7th!
