Work on radiation has also supported the idea that both mutagenesis and mitogenesis are important in tumor induction. The defense systems against reactive electrophilic mutagens, such as the glutathione transferases, are also almost all inducible and buffer cells against increases in active forms of chemicals that can cause DNA lesions. Therefore, the effect of a particular chemical insult is dependent on the level of each defense, which in turn is dependent on the past history of exposure.Thus, a small dose of a mutagen can protect against a subsequent challenge from a large dose, as has been shown for radiation and a variety of other mutagens.Different adducts are repaired with different effectiveness.Oxidative lesions, being so common in all aerobic creatures, may be particularly well repaired.However, even though radiation is an oxidative mutagen, it still can add to the background of DNA lesions to give increased mutation and cancer.Future experimental work measuring mitogenesis will show how often chronic dosing at the MTD is like chronic wounding, which is known to increase tumor yields in rodent tests and to be a risk factor for cancer in humans for taking mitogenesis into account in animal cancer tests help to explain many of the results that have been found in analyzing these tests, as discussed below.To the extent that increases in tumor incidence in rodent studies are due to the secondary effects of administering high doses, then any chemical that increases mitogenesis may be a rodent carcinogen; thus, one would expect that a high proportion of chemicals tested at the MTD would be positive, and this is indeed what is found.It is unlikely that the high proportion of carcinogens in rodent studies is due simply to selection of suspicious chemical structures because most chemicals were selected because of their use as industrial compounds, pesticides, drugs, or food additives.Moreover, historically, our knowledge to predict carcinogenicity has been inadequate. Because mitogenesis indirectly increases mutation, one would expect that in animal tests at the MTD, nongenotoxic carcinogens are likely to be acting by this mechanism. Mitogenesis at the MTD is an important, and possibly the dominant, factor in carcinogenesis for mutagens.Mutagenic chemicals, because they directly damage DNA, are generally more effective at killing cells at high doses than nonmutagens and thus are more effective at causing mitogenesis.Mutagens, unlike nonmutagens, can damage DNA as well as increase mitogenesis at high doses, giving a multiplicative interaction for carcinogenesis.Even those mutagens that are carcinogens may not all be acting as genotoxins in animals because of detoxification and other processes.The importance of mitogenesis, even for mutagens, has been shown in experiments with pairs of mutagenic isomers. In each pair only one chemical was a carcinogen, and only the <a href="http://www.targetmol.com/compound/Pirfenidone">sell
Pirfenidone</a> carcinogen was mitogenic. Several recent analyses of dose response in animal tests are consistent with the idea that mitogenesis from cell killing and cell replacement at the high doses tested is important.In the usual experimental design of dosing at the MTD and MTD, both dose levels are high and may result in mitogenesis.Moreover, the proportion positive only at the high dose is similar for mutagens and nonmutagens.