In the previous video we have explained that the less than lifetime approach is a way of adjusting the acceptable intake of a mutagenic impurity, whenever the exposure is for less than a lifetime. ICH M7 describes how the TTC is adjusted for class 2 and 3 impurities, and the same applies for class 1 impurities as well. All these include safety factors which prevent us from exceeding the repair capacity of DNA or saturating detoxification pathways.
Now what about nitrosamines?
These compounds are considered to be in the cohort of concern, because they are more potent than the majority of the carcinogens, so the TTC described in ICH M7 is not applicable for this class and they generally need to be controlled at lower limits. But can the less than lifetime durational factors be applied when deriving such limits, the same way that we do for class 1 impurities?
In theory, there would be no reason why not, since the underlying principle behind the less than lifetime approach is that cancer risk increases as a function of cumulative dose, and this also applies for nitrosamines.
Some concerns have been raised as to whether a higher dose of a nitrosamine over a short duration would exceed the repair capacity of DNA enzymes.
So a paper was recently published aiming to answer this question. This study evaluated NDEA, one of the most potent nitrosamines.
The acceptable intake for NDEA proposed by health authorities is 26.5 ng/day.
This is based on the value reported in Lhasa's Carcinogenicity database ([ Ссылка ]) as the harmonic mean Gold TD50 for rats. However this value actually derives from a series of different studies, in which rats have been exposed to NDEA for different durations.
104 weeks corresponds to a lifetime of a rat, but some of these exposures were for less than their lifetime. However that final value, 26.5, corresponds to the harmonic mean lifetime TD50. but why?
When carcinogenicity studies are done, if the animals are exposed for their lifetime, we simply derive the lifetime TD50 from the study, which will be a relatively low number, because the dose that causes tumours is lower when the exposure is longer.
For shorter duration studies, a less than lifetime TD50 is obtained, which tends to be higher, because a higher dose is needed to cause that same effect, when the duration of exposure is shorter. So what is done is we apply correction factors to find a lower value that would correspond to a lifetime TD50. And the harmonic mean derives from all these different lifetime TD50s.
For NDEA this is 0.0265 mg/kg/day, and then by applying this equation we can find the acceptable intake, which was recommended by health authorities.
Well this now explains why ICH M7 proposes the less than lifetime approach. It's almost like we are correcting this back, because a lifetime TD50 does not make sense when the patient is exposed to a drug for only a short period of time.
So what would be the acceptable intake for less than lifetime if we applied the ICH M7 principles? We would be multiplying this 26.5 by 6.7, 13.3 or 80, depending on the duration of exposure, and finding our higher limits for these shorter exposures.
But are these limits conservative enough? How can we find this out?
What if we did not apply the correction factors, and found the AI corresponding to each study which lasted less than a lifetime directly?
This is what the authors did in that paper.
The ICH M7 ranges of exposure correspond to a human life, but each of these ranges represent percentages of a lifetime.
Less than a year is less than 1%, from 1 to 10 years, is from 1 to 15%, and more than 10 years is more than 15%.
And then the studies performed with rats were fit into these categories, based on what the exposure represented for the life of the rat.
If the duration of exposure was 104 weeks, this is 100% of a lifetime, but if it was 30 weeks for example, this corresponds to 29% of a lifetime.
And this way, we can evaluate what was seen experimentally and compare with what we obtain from ICH M7.
This table describes the main results, reporting what was the TD50 for each different durations of exposure.
What we see is that when animals are exposed for a lifetime, the TD50 is lower, that is, NDEA caused a 50% increase in tumour incidence at a lower dose. When the exposure was for shorter durations, the TD50 was higher, showing that higher doses were required to lead to tumours, which confirms the lower risk when the exposure is for less than a lifetime.
But how does this compare with ICH M7 limits?
The acceptable intakes obtained from these short duration studies were calculated, and the lowest value will be presented here as a conservative approach.
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