Q:

Is nicotine toxic to humans?

More specifically, is nicotine in the concentrations that smokers receive when smoking cigarettes toxic? I know that in great enough concentrations it can be toxic (but then, so can just about anything else, including oxygen) and I know that in plants it is used as a defense against insects and can even be used as an insecticide. However, it has always been my understanding that nicotine is irrelevant as far as the harmful effects of smoking go. 
I recently had a conversation with another biologist who had just quit smoking and had done quite a bit of research on the subject. He said that nicotine itself is in fact bad for you and, therefore, that tobacco-less alternatives to cigarettes (such as electronic cigarettes) are still harmful because of the nicotine alone. 
Does anyone have any more information on this? Perhaps some references? Or, even better, a detailed explanation of the pathways involved? Again, I stress, not about nicotine's toxicity in general but about its harmful effects on vertebrates (preferably human) at the kinds of concentrations one could expect to ingest when smoking.

A:

I think its useful to say that nicotine is not very toxic to humans - cells don't die or get sick for typical smoking habits.  Secondary health effects are possible, but here is a toxicological profiles. 
Nicotine is a toxin in large enough quantities and nicotine has an LD50 (lethal dose for 50% of individuals) of 0.5-1 mg Nicotine / kg of body weight.  So even a small spill on your skin of the chemical can be life threatening, but for smokers the nicotine itself is not dangerous. 
Individuals who smoke intake about 1 mg per cigarette smoked.  So a small adult (110 lbs) can smoke 25 cigarettes in a short period of time (or all at once!) and just barely get to the bottom end of that limit.  Nicotine is water soluble and clears out through the urine at a fast rate though - half of the nicotine from a cigarette is cleared from  your system within 2 hours, which means that 4-5 pack a day smokers are not really killing themselves (from nicotine).  
That being said, children are about 5-10 times more sensitive than adults, so even 5-6 cigarettes in an hour can be toxic.  That's quite a bit of smoking though. 
Not all animals have the same relationship to the nicotinic acetylcholine receptors as humans do.  Nicotine is toxic to insects and will kill an insect in a matter of minutes or hours. Rats are about 50x less sensitive than people.  
I think its comparable to the question of whether caffeine is harmful to people.  In the amount we consume it, sometimes up to grams a day, there is no obvious common side effect, but you figure that decades later it will show up as a problem - a difficult connection to prove.

A:

Nicotine acts as a ligand for nicotinic acetycholine receptors (nAChRs), which are ligand-gated ion channels normally activated by acetylcholine. This family of receptors is expressed in every mammalian cell (Schuller, 2009). A priori, at least to me, I'd suggest that it's a bad idea to chronically introduce a foreign substance that mimics the activity of an essential signaling molecule like acetylcholine.
Directly to your question of toxicity, nicotine appears to be linked to many forms of cancer (Schuller, 2009). Cancer promoting signaling pathways are stimulated as a result of calcium entry through nAChRs. Also, interactions of nAChRs with other signalling systems, such as those based on stress hormones, GABA, and dopamine, can lead to cancer.
Nicotine also has important effects in the brain. Chronic exposure to nicotine induces a homeostatic mechanism that upregulates nAChR expression in the brain to maintain responsiveness to endogenous acetylcholine. This effect partially underlies nicotine addiction (Penton and Lester, 2009). As @Armatus notes, nicotine appears to have some neuroprotective properties against neurodegenerative diseases like Parkinson's (Quik, M., Wonnacott, S., 2011) and Alzheimer's (Mehta et al, 2012).

Schuller, H.M., 2009. Is cancer triggered by altered signalling of nicotinic acetylcholine receptors? Nature Reviews Cancer 9, 195–205.
Penton, R.E., Lester, R.A.J., 2009. Cellular events in nicotine addiction. Seminars in Cell & Developmental Biology 20, 418–431.
Quik, M., Wonnacott, S., 2011. α6β2* and α4β2* nicotinic acetylcholine receptors as drug targets for Parkinson’s disease. Pharmacol. Rev. 63, 938–966.
Mehta, M., Adem, A., Kahlon, M.S., Sabbagh, M.N., 2012. The nicotinic acetylcholine receptor: smoking and Alzheimer’s disease revisited. Front Biosci (Elite Ed) 4, 169–180.

