[Medicinal]

Is there a way, based on the molecular structure of a molecule, to predict the chances that a chemical will be toxic? As well as the degree of the toxicity?

Methanol is toxic to humans because the body converts it to formaldehyde in the liver.

But from a chemical perspective, what makes formaldehyde so nasty when compared to ethanols acetaldehye?

My best guess (based on what very little I know about methanol/ethanol => aldehyde) is that molecules with a highly electropositive atom (like formaldehye) will have a high degree of toxicity towards humans.

This would explain why HF is so toxic - fluorine has a strong pull on hydrogens electrons making it very electropositive.

I assume molecular size and physical state would also play a role...

Any thoughts?

[fledarmus]

There are far too many different mechanisms of toxicity to be able to predict in general whether any structure might be toxic, in the absence of other information. There are some general principles and some calculations that can help predict whether a structure might be toxic by a particular pathway.

It is very hard to predict, for example, that benzene would cause cancer while toluene doesn't - the only difference is a methyl group on a benzene ring. However, that methyl group provides a site for metabolism that allows the body to get rid of the toluene, before a second mechanism which makes the benzene ring into a toxic metabolite can take place.

It is hard to predict that drinking methanol can cause blindness and death, but that drinking isopropanol doesn't - because drinking isopropanol causes you to throw up so rapidly that it is almost impossible for toxic amounts to be absorbed.

It is fairly easy to predict, knowing what we now know of enzyme structure, that compounds which can rapidly alkylate other compounds will show toxicities. In fact, almost any compound that is chemically very reactive is also toxic, because chemical reactions in the body must be very carefully controlled to keep the body alive.

It is fairly easy to predict that any material which binds very tightly to iron will be toxic, because it will bind with the iron in the blood and prevent it from carrying oxygen. Unless, of course, that material is rapidly removed from the body by some other transport mechanism.

Certain basic structural motifs are known to interact with the functional groups in RNA and DNA. It is fairly easy to predict that these will cause genetic toxicity if they can reach the nucleus of the cells.

And finally, almost any compound, including water, will show toxicity if it is taken in a high enough dose - "the dose makes the poison". Again, the body functions on a very precarious balance, and too much of any material can disrupt that balance. That is one reason we have so many redundant mechanisms for removing materials that don't belong in the body, and for balancing the ones that do.

[Medicinal]

Thank you for your reply.

There are some general principles and some calculations that can help predict whether a structure might be toxic by a particular pathway.

Can you give me some specific examples of this? What type of calculations?

Where would I find out more about this?

I have already got a toxicology textbook. However, it is based to much on biology to be of much interest to me. The textbook is Casarett & Doull's Toxicology (1300 pages long).

The information I am after is stuff that is not too indepth. I just want to be able to look at a molecular structure and have a general idea of its toxicity.

You have already given me some good stuff:

It is fairly easy to predict, knowing what we now know of enzyme structure, that compounds which can rapidly alkylate other compounds will show toxicities. In fact, almost any compound that is chemically very reactive is also toxic, because chemical reactions in the body must be very carefully controlled to keep the body alive.

It is fairly easy to predict that any material which binds very tightly to iron will be toxic, because it will bind with the iron in the blood and prevent it from carrying oxygen. Unless, of course, that material is rapidly removed from the body by some other transport mechanism.

Out of interest, how do you know this stuff? I am still a chemistry undergraduate, is it likely I will learn any of this as part of a standard chemistry education?

Do you know why aniline is so toxic?

If, as part of a chemistry course, two weeks were devoted to toxicology, what would be they key things taught to the students?

[Borek]

The information I am after is stuff that is not too indepth. I just want to be able to look at a molecular structure and have a general idea of its toxicity.

This is a contradiction. There are zillion ways that can make a substance toxic, you can't predict anything without having a really deep knowledge about the cell biochemistry. And even then many substances will surprise you.

What you are asking for is a rule that will let you say if the car is a diesel, or a hybrid, or has a gas engine just by knowing the paint color. It won't work.

[fledarmus]

Out of interest, how do you know this stuff?

Heh - I've been a medicinal chemist for over twenty years, my job is synthesizing brand new molecules in the hopes of inventing drugs. There are two parts to testing the compounds I make - the first is to see whether they are active in the mechanism for which they were designed, and the second is to see whether they are toxic - or rather, how toxic they are. As I said before, everything, even water, is toxic in the wrong place or the wrong dose. It is absolutely astonishing the number of unexpected toxicities that you find when you are working with new compounds in biological systems.

I am still a chemistry undergraduate, is it likely I will learn any of this as part of a standard chemistry education?

I doubt it. Chemical toxicity is rarely included in undergraduate coursework, and as far as I know, never in the chemistry department. Usually toxicology is part of graduate biology, medicinal chemistry, or pharmacy courses. It is possible that a few historically important toxic compounds might be discussed in a laboratory safety or environmental hazards course.

Do you know why aniline is so toxic?

http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+62-53-3

In short, aniline damages the red blood cells. Short term in high concentrations, the blood loses its ability to carry oxygen, which can be fatal; long term, in lower concentrations, the spleen is damaged from collecting and storing all of the broken pieces of the erythrocytes and cancers of the spleen are increased.

If, as part of a chemistry course, two weeks were devoted to toxicology, what would be they key things taught to the students?

Wow, two weeks would barely be enough to start. I think you would have to confine yourself to discussing a few very broad principles of toxicology and try to provide some practice looking up and understanding the toxic properties of known compounds.

Just my off-hand opinions - YMMV!

[Medicinal]

Wow, a medicinal chemist, that's cool!

I'm really struggling here. I've just started reading my Organic textbooks chapter on glycolysis. Then i'm going try to figure out what kind of properties would increase the chances of a chemical interfering with the pathway.

What i'm really interested in, is how the properties of a chemical affect its chances of having high toxicity.

For example, maybe a chemical that has the following attributes: highly soluble in water; extremely electronegative atoms close to an electropositive atom etc - would mean that it is highly likely that this substance will interfere with pathway X.

What are some important pathways I should learn?

Another example:

Pathway Y:
If substance A (which is highly electronegative) dissolves in water and is transported to substance B, where it combines (due to electronegativities) to make AB (a substance that is absolutely necessary for the human body), then this process could interrupted by a water soluble molecule that is more electronegative than substance A.

In which case, a good guideline to watch out for is a substance that is water soluble and has electronegativity X or higher. Not perfect I know, but that is what i'm interested in knowing about at the moment.

Obviously, electronegativity would be affected by the overall molecule...

Do you know of a good book for someone who doesn't specifically want to be a toxicologist? If you have more than one suggestion, then that would be a great help.

Thanks