Remember, the dose makes the poison — but the scaling makes the IND. Go break some eggs.
👀 The Read
The NOAEL Is Not Your Starting Dose.
But it is where you start.
Ask ten founders how the first-in-human dose gets set, and nine will say the NOAEL.
The NOAEL is where the number starts. It is not where it ends — and treating it as the answer is how programs walk into a pre-IND meeting with a starting dose they can't defend.
Here's the actual sequence. Your NOAEL is a dose in an animal — say 50 mg/kg in the rat. You don't give a human 50 mg/kg. First you convert it to a human-equivalent dose, and you do that by body surface area, not body weight, because that's what scales toxicity across species — divide by roughly 6.2 for the rat. That 50 becomes about 8 mg/kg human-equivalent.
Then the safety factor. You divide again, default by 10 — not because 10 is magic, but because it's the standard allowance for the ways humans may be more sensitive than your animals and the variability among humans themselves. If your molecule has a specific reason for concern — a steep dose-response, a hard-to-monitor toxicity, an irreversible effect — that factor goes up, and you have to be ready to say why.
And the step everyone skips: which species do you even anchor to? You don't get to pick the convenient one. You anchor to the most sensitive appropriate species — the one that gives the lowest human-equivalent dose — unless you can justify why it isn't relevant to humans. Choose wrong and your starting dose is either indefensibly high or needlessly low, and either one is a conversation you lose at pre-IND.
Run it properly and every digit of your number has a rationale behind it — not just a study report with a NOAEL circled.
The Misconception: The NOAEL is your first-in-human starting dose.
The Correction: You start with the NOAEL, then convert it to an HED, divide by a safety factor, anchor it to the most sensitive species.
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