Non-genotoxic

Purchase, l.P.H. (1994). Current knowledge of mechanisms of carcinogenicity genotoxic vs. non-genotoxic. Human and Experimental Toxicology 13, 17-28. 

Nie AY, McMillian MK, Leone AM, Parker JB, Piechta L-A, Bryant S, et al. A gene signature for non-genotoxic carcinogens. Society of Toxicology, 2005. 

This study, like that of Fisher and Allen (1993), incorporated a linear multistage model. However, the mechanism of trichloroethylene carcinogenicity appears to be non-genotoxic, and a non-linear model (as opposed to the linearized multistage model) has been proposed for use along with PBPK modeling for cancer risk assessment. The use of this non-linear model has resulted in a 100-fold increase in the virtually safe lifetime exposure estimates (Clewell et al. 1995). 

Compared to animal assays, CTA is faster and cheaper. In vitro CTAs have been shown to involve a multistage process that closely resembles some stages of in vivo carcinogenesis and have the potential to detect both genotoxic and non-genotoxic carcinogens. 

Pyrethrins (I) Pyrethrins induce the formation of liver and thyroid tumors by mechanisms that appear to be similar to those of other non-genotoxic, mitogenic substances, e.g., phenobarbital, which produce tumors in rodents, and these tumors are not predictive of hazard in humans at relevant exposures [99]... 

Mutagenicity and carcinogenicity are generally considered to be non-threshold effects, unless a non-genotoxic mechanism can be established with a NOEL (or NOAEL or LOAEL). Risk assessment is based on establishing whether exposure is prevented. A similar process of preventing exposure also applies for skin and respiratory sensitisers, since there is no means of identifying a dose or concentration below which adverse effects will not occur in someone already sensitised to a particular substance. 

Clay son, D.B. (1989). ICPEMC publication No. 17 Can a mechanistic rationale be provided for non-genotoxic carcinogens identified in rodent hioassays Mutation Res. 221 53-67. 

Telang S, Tony C, Williams GM. 1982. Epigenetic membrane effects of a possible tumor promoting type on cultured liver cells by the non-genotoxic organochlorine pesticides chlordane and heptachlor. Carcinogenesis 3 1175-1178. 

Carcinogenic substances have conventionally been divided into two categories according to the presumed mode of action genotoxic and non-genotoxic (epigenetic). 

For threshold carcinogens, it is possible to identify a NOAEL for the underlying toxicity responsible for tumor formation. The following general guidance is provided for the dose-response assessment for non-genotoxic (threshold) carcinogens (EC 2003). The dose-response assessment for the relevant tumor types is performed in a two-step process. 

Phaeochromocytoma (a tumor in the adrenal medulla) is not uncommon in rats, but rare in humans. Pheochromocytomas are induced in rats by a variety of non-genotoxic substances that may act indirectly by stimulating chromaffin cell proliferation. They are not known to be similarly inducible in other species. In the rat, a mechanism for the development may be hypercalcaemia (Tischler et al. 1999 Capen et ah, in Haschek et al. 2001). 

For most types of toxic effects (e.g., organ-specific, neurological, immunological, non-genotoxic carcinogenicity, reproductive, developmental), it is generally considered that there is a dose or... 

Gronlund (1992) has investigated methods used for quantitative risk assessment of non-genotoxic substances, with special regard to the selection of assessment factors. Gronlund found that humans, in most cases, seem to be more sensitive to the toxic effects of chemicals than experimental animals, and that the traditional 10-fold factor for interspecies differences apparently is too small in order to cover the real variation. It was also noted that a general interspecies factor to cover all types of chemicals and all types of experimental animals cannot be expected. It was concluded that a 10-fold factor for interspecies variability probably protects a majority, but not all of the population, provided that the dose correction for differences in body size between experimental animals and humans is performed by the body surface area approach (Section 5.3.2.2). If the dose correction is based on the body weight approach (Section 5.3.2.1), the 10-fold factor was considered to be too small in most cases. 

Gronlund (1992) has investigated methods used for quantitative risk assessment of non-genotoxic substances, with special regard to the selection of assessment factors. Gronlund found that the 10-fold factor suggested for interindividual variability probably protects a majority but not all of the population. 

Carcinogenicity, usually but not exclusively for non-genotoxic chemicals, the most common reason... 

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