The shape of a carcinogen dose- @entity5 incidence curve is discussed as the result of a superposition of dose-response relationships for various effects of the carcinogen on the process of @entity105 . Effects include direct DNA damage, e.g., by covalent binding, indirect DNA damage, e.g., by increased formation of reactive @entity26 species or interaction with DNA replication or chromosome integrity. The 'fixation' of a DNA adduct as a heritable mutation depends on its pro-mutagenic potency and on the rates of DNA repair and DNA replication. Endogenous and unavoidable DNA damage is responsible for a background rate of the process of mutagenesis and @entity105 and forms the basis of spontaneous @entity5 incidence. For DNA-reactive carcinogens, linearity of the dose response at the low-dose end is expected. With increasing dose, saturation of DNA repair can introduce a sublinearity (example: @entity1232 ). Stimulation of cell division as a result of high-dose @entity137 and regenerative proliferation also results in a sublinear deviation from low-dose linearity. If the DNA-damaging potency of the carcinogen is low in comparison with the high-dose effects, the linear part of the low dose- @entity5 incidence curve might be hidden within the background variability. Under such conditions, 'practical thresholds' could be discussed ( @entity406 ). If a carcinogen increases the rate of cell division or the level of oxidative stress at high dose but has an antimitogenic or antioxidative effect at low dose, a J-shaped (or: U-shaped) curve with a decrease of the spontaneous @entity5 incidence at low dose could result ( @entity14627 ; @entity1300 ). This phenomenon has been observed even under conditions of a genotoxic contribution (ionizing radiation; diesel exhaust particles). For a mechanism-based assessment of a low-dose @entity5 risk, information on the various modes of action and modulations should be available over the full dose range, and models should be refined to incorporate the respective information.

Dose-response relationships in XXXX : superposition of different mechanisms of action, resulting in linear-nonlinear curves, practical thresholds, J-shapes.

@entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'cancer'] @entity26 :: ('MESH:D010100', 'Chemical') :: ['oxygen'] @entity406 :: ('MESH:D005557', 'Chemical') :: ['formaldehyde'] @entity14627 :: ('MESH:C040048', 'Chemical') :: ['caffeic acid'] @entity1300 :: ('MESH:D013749', 'Chemical') :: ['TCDD'] @entity1232 :: ('MESH:D004128', 'Chemical') :: ['dimethylnitrosamine'] @entity105 :: ('MESH:D063646', 'Disease') :: ['carcinogenesis']
@entity105 :: (MESH:D063646,Disease) :: ['chemical carcinogenesis']
