Hello Vishwanatha,

If the inhalation bioavailability data is not available, then it is considered equal to 100%.

So, going to your queries:

1. If oral bioavailability =90%, and taking inhalation bioavailability of 100%, you will consider a TK factor of 100/90 = 1.1

2. TK factor = 100/30 = 3.3

Dear Dr. Varun Ahuja,

Thanks for the response, just need further clarity, the equation for OEL is

OEL (mg/m3): [NOAEL/ LOAEL (mg/kg/day) X BW (kg)] ¸ (UFC x TK x MF x V)

Here, TK is in the denominator, and hence inverse relation with OEL value.

As per the equation you have provided TK factor will be more for low oral bioavailable chemical (100/30=3.3, 30% oral bio-availability) and less for more bio-available compound (100/90=1.1, 90% oral bio-availability).

Further, at the overall OEL output, 30 % oral bio-available compound will have Less OEL value compare to 90% oral bio-available compound, It means 30% oral bio-available compound is more toxic than 90% bio-available compound?

I dint find correlation between what you have posted the TK factor, 100/30=3.3, and 100/90=1.1, should it be reverse as 30/100=0.3 and 90/100=0.9?

Secondly, in deriving ADE we are using body weight as 50 KG and while in OEL guideline says we have to use Body weight as 70 Kg.

Why there is such difference? is it because ADE is meant for diseased individuals (hence 50 Kg), and OEL meant for Healthy subjects (healthy subjects body weight is usually considered as 70Kg in posology calculations), or how it is please clarify.

Regards

Vishwanatha

Dear Vishwanath,

1. Compound with 30% oral bioavailability will have less OEL, as it is less toxic orally due to low bioavailability. But, when it will be given by inhalation, the bioavailability is going to shoot up to 100% (if not known by data), so the toxic effects could be anything which you don't know. So, a low OEL will help in keeping the exposed person safe.

On the other hand, if bioavailability by oral route is already 90% (almost similar to inhalation value), then you know that the drug exposure is same in both the case. So, the OEL calculated will be similar in both the cases, as other factors of toxicity have already been takne into consideration in both the cases.

2. The earlier OEL guidelines from US authorities gave 70 kg as body weight reference value (as the avergae body weight in these countries is more than ours). ADE concept came quite recently, and guideline mentions 50 kg b.wt, which could be more of a broad consideration taking the global average.

I won't accept that ADE is applicable for diseased individuals and hence 50 kg b.wt., as we take a drug for many cases where b.wt. is not reduced e.g. fever, cold etc. and not only for debilitating diseases like cancer.

To be on the conservative end, it is better to use 50 kg as the average body weight in our country is lesser. However, if you feel that you can't justify/give explanation for the same, then better to use 70 kg for which you have the reference.

Dear Dr. Varun,

Thank you so much for the detailed explanation, i got clarity on these point now.

Regards

Vishwanatha GL

Attaching a reference for you to better understand the bioavailability adjustment factor.

See Page S62, Section: Toxicokinetic Adjustment Factor

Dear Dr. Varun,

Thanks for sharing the reference, Post discussion, i got this reference through my contacts, its clearly given. Once again thanks for your timely response it was very useful.

Regards

Vishwanatha