Thresholds in genotoxicity responses.
It has been commonly accepted that risk assessments of genotoxic chemicals are based on linear extrapolation methods. However, there is substantial evidence that some chemicals may be genotoxic only at high doses by mechanisms that do not occur at low doses, or only under specific conditions in genotoxicity assays, but are inactive at concentrations within the range of human exposure levels. There are a variety of possible mechanisms of thresholded genotoxicity, including disruption of cell division and chromosome segregation, inhibition of DNA synthesis, overloading of oxidative defence mechanisms, metabolism or plasma binding capacity, disturbances of metal homeostasis, cytotoxicity and physiological perturbations in in vivo assays. The degrees of evidence supporting the proposed mechanisms are variable and not all are sufficiently robust to be universally accepted as yet by the scientific community. However, a survey of industrial companies indicated that data have been accepted by some regulatory authorities indicating thresholds contributing to genotoxicity responses.
Henderson
L
L
SEAC Toxicology, Unilever Research Port Sunlight, Quarry Road East, Bebington, Wirral LCH63 3JW, UK. leigh.henderson@unilever.com
Albertini
S
S
Aardema
M
M
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005060:Europe; D006801:Humans; D007753:Laboratories; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000633:toxicity*; D018570:Risk Assessment; D011795:Surveys and Questionnaires; D014481:United States
D009153:Mutagens