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I know that some chemical compounds have been known to be carcinogenic in humans.

But can we make a reliable prediction of how likely a substance is to be carcinogenic based on the chemical and physical properties of the substance ? How good will the prediction be ?

It would be good if the following methods were compared

  1. Computational chemistry
  2. Crystallography
  3. Bacteria models such as the Ames test
  4. Animal models such as rats and mice
  5. Chemical kinetics experiments
  6. Predictions based on the fact that a substance is from the same class as a known carcinogen or non carcinogen
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    $\begingroup$ The biological interactions that create cancer are very complex. It seems unlikely that any simple prediction exists. As an indication of how big and complicated this question could be, this old question and answer of mine on skeptics.SE is worth a look . $\endgroup$ – matt_black Jul 18 '18 at 23:58
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    $\begingroup$ I would suggest we take the question off hold, I think that while a universal predictor of carcinogenic potential for all classes of compound is not possible. It is possible for some classes of compound to make a good prediction of how strong a genotoxic carcinogen it is. $\endgroup$ – Nuclear Chemist Jul 19 '18 at 14:21
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    $\begingroup$ sciencedirect.com/science/article/pii/B9780128046678000055 For toxicity, this kind of studies are being done and have also successful results. I guess prediction part is way more difficult than toxicity due to the longevity of the carcinogenicity experiments. That may very well change. And I also think that this question should be off hold. omictools.com/qsar-toxicity-predictions-category This is another good source for similar topics. $\endgroup$ – Güray Hatipoğlu Jul 19 '18 at 15:01
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    $\begingroup$ If the question is taken off hold, I am willing to have a go at giving an answer which relates to alkylation agents. I am sure that some simple kinetics experiments can be used to make a reasonable judgement as to the potential of an alkylation agent to induce the mutations needed to induce cancer. $\endgroup$ – Nuclear Chemist Jul 19 '18 at 16:53
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    $\begingroup$ I really do feel that this is too broad - I have several entire books dedicated to this on my bookshelf, and none of them come close to providing an answer that will neatly fit into an answer on StackExchange. That said, I think the question is an interesting one. I'd favour splitting it into more specific issues ("can computational chemistry be used to predict whether a compound is likely to alkylate and cause cancer") which individuals might actually have the expertise to answer $\endgroup$ – NotEvans. Jul 20 '18 at 22:43
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One of the great problems is that there is no single mechanism by which a chemical carcinogen causes the damage which leads to cancer. There are a range of different mechanisms, I will mention some of them.

One mechanism is alkylation of DNA, the attachment of alkyl groups to DNA will prevent it being read correctly. In some cases the damage can be repared while in other cased the damage will cause the body to misread one base pair as another. There is an interesting problem with electrophilic alkylation agents, if they are too reactive towards water then they will not survive to reach the DNA.

There is an interesting paper in which this idea is discussed E.W. Vogel and M.J.M. Nivard, Mutation Research, 1994, volume 305, pages 13-32 considers it at length. If we consider the ratio of the rate constant for the reaction of an alkylation agent with thiosulfate and acetate, then as the ratio of these reaction rates changes in favour of the thiosulfate reaction something known as the Swain Scott constant (s) also increases. The Swain Scott constant is the ratio between reaction at two different sites (7-alkylguanine/O6-alkylguanine) in DNA. In general the higher the value of the s constant the stronger a carcinogen is. In the paper by A. Barbin and H. Bartsch in Mutation Research, 1989, volume 215, page 95 to 106 a series of directly alkylating carcinogens a good but not perfect relatioship is seen between the s constant and how carconogenic they are in rodents.

So it appears for one class of carcinogen that it is possible by doing some simple chemical kinetics experiments that it is possible to make an assessment of how carcinogenic a substance.

One of the great problems is that many "carcinogens" are in fact "precarcinogens" which require metabolic activation to make them carcinogenic. For example hydrazine reacts with formaldehyde in the liver before being oxidized to form diazomethane which then methylates the liver. This is why acute large hydrazine exposures in humans can cause liver failure.

This brings us to the Ames test, this is a test using bacteria which measures how able a substance is to alter DNA. The idea is that cancer is caused by altering the DNA of normal cells. So something which is able to randomly alter the DNA of cells is able to induce cancer. The great problem with the Ames test is that while it is a good test. There are both false positives and false negatives if it is used as a test for carcinogenic potential.

The normal Ames test protocol includes some sterile extract of rat liver to provide some metabolic activation. This will increase the ability of things like polycyclic aromatic hydrocarbons to alter the DNA of the bacteria.

If we consider an inorganic example, the chromate anion is known to be carcinogenic while chromium(III) is not carcinogenic. To understand this we need to know something about chromium biochemistry.

It is true that chromium(III) can form some very stable complexes which are very slow to react with DNA. But the chromium(III) is unable to reach the DNA in the cell. However chromate is able to pass through the sulfate transport channels in both the cell and nuclear membranes to allow it to reach the nucloplasm. There it is reduced to chromium(III) which then damages the DNA. As a result we can make a judegment about chromate and sulfate.

Sulfate is unable to react in the nucloplasm to form something which will form long lasting complexes with DNA, so even while sulfate is able to reach the DNA by the same route as chromate it is clear that sulfate is unable to act as a carcinogen by the same mechanism as chromate.

Also permanganate or magnanate is a stronger oxidant than chromate, I suspect that as it would be less able to survive the journey through the body to the DNA it is less able to incude cancer. This is likely to be one of the the reasons why permanganate is far less carcinogenic than chromate. Plenty of evidence exists for chromate being carcinogenic but little if any evidence exists for permanaganate.

Also the complexes of manganese with DNA are likely to be shorter lived than those of chromium. This is becuase chromium(III) complexes are slow to exchange ligands while manganese(II) are rather quick to exchange ligands. This is due to the fact that chromium(III) complexes are d3 while manganese(II) are d4.

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