Threshold cytotoxic

Safrole has been found to be a weak hepatocarcinogen, which is linked to the formation of safrole-DNA adducts. Safrole treatment will induce oxidative damage in rat hepatic tissue (331) and is a genotoxic carcinogen in rat liver in vivo (332). These cytogenetic effects may result from covalent DNA modification in the rat liver. The threshold cytotoxic concentration found for safrole is 0.10 mug/ml safrole (333). 

APA derivatives (R89439) [67], inhibit HIV-1 replication at a concentration of approximately 1 ng/mL, that is, 100,000-fold below the cytotoxicity threshold. 

Neutropenias may also arise as a side effect or deliberate consequence of therapy. For example, some drugs used in the treatment of inflammatory disorders are immunosuppressive, and if these decrease the number of circulating neutrophils to below the critical threshold level, then susceptibility to infection may result. During chemotherapy for the treatment of solid tumours, an inevitable consequence of cytotoxic therapy is that the bone marrow will be destroyed by the drugs thus, patients will have a considerable risk of infection during this induction period. Similarly, during the treatment of haematological disorders (e.g. leukemias and myelodysplastic syndromes), the aim of therapy is to attack the bone marrow so as to destroy... 

On the other hand, several ROS are highly cytotoxic. Consequently, eukaryotic cells have developed an elaborate arsenal of antioxidant mechanisms to neutrahze their deleterious effects (enzymes such as superoxide dismutases, catalases, glutathione peroxidases, thioredoxin inhibitors of free-radical chain reaction such as tocopherol, carotenoids, ascorbic acid chelating proteins such as lactoferrin and transferrin). It can be postulated that ROS may induce an oxidative stress leading to cell death when the level of intracellular ROS exceeds an undefined threshold. Indeed, numerous observations have shown that ROS are mediators of cell death, particularly apoptosis (Maziere et al., 2000 Girotti, 1998 Kinscherf et al., 1998 Suzuki et al., 1997 Buttke and Sanstrom, 1994 Albina et al., 1993). 

Until recently, their major concern had to do with taste and odor problems in drinking water (due to a low threshold concentration of medicinal tastes and odors in drinking water - as low as 0.02-5 pg/L) [30]. It was not until 2008 that they were investigated for genotoxicity and cytotoxicity [21]. One iodo-THM (chlorodiiodomethane) is highly genotoxic in mammalian cells, and all six iodo-THMs are... 

The principle of the human skin model test is that the test material is apphed topically for up to 4h to a three-dimensional human skin model, comprising at least a reconstructed epidermis with a functional stratum comeum (outermost layer of the skin). The human skin models can come from various sources, but they must meet certain criteria. Corrosive materials are identified by their abdity to produce a decrease in cell viabdity (as determined, e.g., by using a dye reduction assay) below defined threshold levels at specified exposure periods. The principle of the test is in accordance with the hypothesis that corrosive chemicals are able to penetrate the stratum comeum (by diffusion or erosion) and are sufficiently cytotoxic to cause cell death in the underlying cell layers. 

For systemic effects, ECETOC (2003) recommended a default assessment factor of 6 for extrapolation from subacute (28 days) to chronic exposure, and a factor of 2 from subchronic (90 days) to chronic exposure. For local effects, no additional assessment factor is needed for duration of exposure extrapolation for substances with a local effect below the threshold of cytotoxicity. 

WHO/IPCS (1994, 1996, 1999) did not consider an extrapolation factor for duration of exposure specifically, but the uncertainty related to this element is included in a broader defined additional factor addressing the adequacy of the overall database (Section 5.9). The US-EPA (1993) has adopted the 10-fold factor to account for the uncertainty involved in extrapolating from less than chronic NOAELs to chronic NOAELs. This default value has later on been reconfirmed (US-EPA 2002) when only a subchronic duration smdy is available to develop a chronic reference value no chronic reference value is derived if neither a subchronic nor a chronic smdy is available. For systemic effects, ECETOC (2001) recommended a default assessment factor of 6 for extrapolation from subacute (28 days) to chronic exposure, and a factor of 2 from subchronic (90 days) to chronic exposure. For local effects, no additional assessment factor is needed for duration of exposure extrapolation for substances with a local effect below the threshold of cytotoxicity. KEMl (2003) suggested that extrapolation from subchronic to chronic exposure should be based on the distribution of NOAEL ratios reported by Vermeire et al. (2001) with an assessment factor of 16 covering 95% of the substances compared and for extrapolation from subacute to chronic exposure, with an assessment factor of 39 covering 95% of the substances. 

However, this reaction is expected to be endothermic due to a more negative potential for the NO, H+/HNO couple (147, 164). Dehydrative dimerization of HNO to N20 [Eq. 6 8 x 106M 1s 1 (106)] is substantially faster then deprotonation to 3NO- [Eq. 10 5 x 104M l s OH ] (106)]. These kinetic constraints indicate that 3NO and subsequent ONOO- formation (Eq. 9) does not occur until the HNO concentration drops to the low nanomolar range, which is below the current observation threshold. Furthermore, the oxidative chemistry from Angeli s salt was found to be pH-independent (167), suggesting that HNO not NO- reacts with O2 to form the oxidant and cytotoxic species. Although the nature of the oxidative intermediate has not been determined, it is apparent that the HNO/O2 reaction is fundamentally different than that of the NO/O2 (and the NO /02) reaction in resultant reactive intermediates and product formation. 

The effect of variability on drug cytotoxicity markedly depends on the temporal pattern of 5-FU delivery. When the peak in the circadian delivery of 5-FU occurs at 4 p.m., i.e. when the circadian schedule of 5-FU administration is most toxic to the cells, whether in the absence or presence of entrainment by the circadian clock, cytotoxicity increases as the degree of variability decreases. The effect is more marked in the conditions of entrainment a threshold in cytotoxicity then exists between... 

The biological significance has to be taken into consideration for positive evaluation (i.e. cytotoxicity can artefactually lead to an increase in the value of net nuclear grain count). The positive control should induce a clear increase in the mean net nuclear grain count higher than the threshold value of five. 

Bmstein NL. Preservative cytotoxic threshold for benzalkonium chloride and chlorhexidine digluconate in cat and rabbit corneas. Invest Ophthalmol Vis Sci 1980 19 308-313. 

Epigenetic Promotors (phenobarbital) Cytotoxic/mitogenic agents (d-limonene, saccharin) Hormone-modifiers (estrogen) Immunosuppressors (cyclophoshamide) Peroxisome proliferators (clofibrate) Receptor-mediated (dioxins) Miscellaneous mechanisms (sodium nitrilotriacetic acid) Mostly in one species, strain or sex At high dose levels (MTD) Long latency period Threshold considerable for extrapolation to humans... 

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