Has it ever been explained?

Uh, because I guess since stuff from Krypton affects him like stuff from Earth affects us, and that if you stood next to some unbelievably radioactive chunks of rock you'd get pretty weak too.

Superman's physiology has always had a strong connection to radiations, as do all Kryptonians. Cosmic radiations, such as solar rays from a yellow sun, blue sun or even red sun, as well as neutron stars. Dark energy and radiation from black holes like quasars, as described in the New 52 and Earth One, also affect his powers and physiology. Post-Flashpoint, he was even able to absorb, albeit in strenuous effort over a long period of time, geo-thermal radiation.

In most of these cases, Superman's ability to absorb radiation has been beneficial - his body absorbs it, processes it, metabolizes it, and then burns it, much like the way the human body stores fat and sugars for energy usage and physical exertion. But just like how some things are toxic to the human body, some frequencies are harmful to the Kryptonian physiology once absorbed, likely in the processing stage, since - while he seemingly can metabolize it - he can't "burn it" (at least one time before, he'd experienced radiation poisoning from Kryptonite after it had saturated his cells, meaning he probably can "store" the stuff). Kryptonite, and whatever non-terrain composition its minerals and elements are made of, are supremely toxic to Kryptonians once rendered into an unstable radioactive isotope.

Now the exact nature of what Kryptonite does it up to the author. Sometimes it's been portrayed as making him sweat profusely, with strained veins protruding from his body, almost as if he is fighting off an infection. At other times, it can make his powers weaken or fail completely. And still at other times, it simply causes him extreme pain and exhausts him, but doesn't otherwise impair him. In the end, all that really matters is that it is exceptionally harmful and toxic to his body chemistry, so much so that extended exposure will indeed kill him.

There was some book I found at the library called "The Science of Superman", and it was DC sanctioned and everything. Went into better detail, really good read.

There's never been a theory that exactly explains why to kriptonians its lethal and to humans even in massive amounts it does very little damage, and in some rare cases even gives humans powers.

We can only theorize why it affects kriptonians has it does. In the New 52 and even in previous versions, but more now in the new 52, I believe that kriptonite or some non-radioactive isotope of kriptonite might actually be part of kriptonian physiology. It fact having such strange rare type of matter part of their physiology could explain why they have powers under certain types of star and cosmic energies. At least it would be a better explanation than the whole immense gravity and red sun stuff.

And kriptonite is poisonous to kriptonians if they have their powers on or off. While they're on it affects them even more in extreme ways, with their powers off, its only poisonous if they get exposed in the same way that a normal human got exposed to, for example, to large doses of uranium-235.

When their powers are active their bodies absorve and metabolize enormous amounts of energy, making them even at a distance much more vulnerable to kriptonite than if they had their powers off.

@reactor:

What doesn't make sense to me is how were they able to live on Krypton, if kryptonite is toxic to them? I always assumed the kryptonite takes the powers he's gained from our yellow sun, or that the amount of krypton on Kryptonite was relatively small so it didn't effect the Kryptonians. Like how we have radioactive materials in the earth, but humans aren't all dying from radiation poisoning.

@roaris87: kryptonite was made when the planet exploded and turned the minerals of the planet radioactive.

Pretty much this below

Kryptonite didn't exist before the planet's implosion; in some way, it was very likely to be related to some element found in the planet's deep core (thus, not something exposed prior to the planet's death). Radioactive frequencies are damaging to all DNA, so it's not as if Kryptonians were immune to the effects before. It simple didn't exist at the time.

That makes more sense, I had always assumed it was a naturally occurring mineral in Krypton

pink kyptonite anyone??

also it kyptonion a rainbow planet?

Because the writers want him to be weak to kryptonite.