Non-cancer endpoints

Transfluthrin induced a low frequency of urinary bladder adenomas carcinomas in rats at high doses - the NOEL for non-cancer endpoints was 20 ppm, for cancer, 200 ppm, and the urinary tumors were observed at a level of 2,000 ppm in diet. It also induced adenomas in female mice at a high dose level. Transfluthrin had no initiating activity, but was... 

The U.S. Environmental Protection Agency (EPA) has slightly modified the ADI approach and it calculates a reference dose (RfD) as the acceptable safety level for chronic non-carcinogenic and developmental effects. Similarly the ATSDR (Agency for Toxic Substances and Disease Registry) calculates minimal risk levels (MRLs) for non-cancer endpoints. 

The relatively orderly Issue of extrapolation of cancer from laboratory to man, although very complex, is nevertheless probably closer than other non-cancer endpoints to providing underlying concepts upon which to develop this "synthetic" risk assessment the full development of this strategy to other endpoints may be well in the future. 

The toxicity of cadmium has been known for more than 150 years, as summarized recently by Nordberg [1] nevertheless, there is stiU an ongoing discussion on cadmium-induced toxicity at comparatively low exposure conditions. With respect to non-cancer endpoints, the European Food Safety Authority (EFSA) has lowered the Provisional Tolerable Weekly Intake (PTWI) of 7 pg/kg bw established previously by the Joint FAOAVHO Expert Committee on Food Additives to a TWI of 2.5 pg/kg bw based on cadmium-induced nephrotoxicity [2]. One other endpoint of toxicological concern on low exposure conditions of the general population... 

MRLs and Cancer Endpoints. One panelist wondered if ATSDR will derive an MRL or some other advisory limit that reflects carcinogenic endpoints. Other panelists and ATSDR scientists explained that the MRLs, by definition, are based strictly on non-carcinogenic effects and that ATSDR, as per policy, does not derive advisory limits for cancer effects. Rather, the Agency simply defers to EPA s cancer slope factors for such limits, if appropriate. 

Erlotinib (Tarceva) took a differenf approach to a pivotal trial. In the study of Tarceva for patients with advanced, previously treated non-small cell lung cancer, where survival was the primary endpoint, patients were randomized to receive either Tarceva or placebo. Tarceva clearly prolonged overall survival (6.7 vs. 4-7 months, p = 0.001). In addition, Tarceva improved progression-free survival, and improved fime-fo-deferiora-tion of patients reported symptoms (cough, dyspnea, and pain). Obviously, this was a definitive trial (drug vs. placebo) however, it could be a controversial trial as it was a survival trial with no provisions to crossover to the active Tarceva. It is doubtful fhaf many trials with this noncrossover design (with a survival endpoint) will be done in the future. 

NCI H23 human Non-Small Cell Lung tumor cell line is measured as a screen for anti-cancer activity. Cells are grown in 96 well plates and exposed to the test compound for 48 hours. Compounds are tested at 5 different concentrations and three endpoints are estimated from this dose response curve GI50, concentration required for 50% inhibition of growth TGI, the concentration required for complete inhibition of growth and LC50, the concentration required for 50% reduction in cell number. These estimates are done by simple linear interpolation between the concentrations that surround the appropriate level. If a compound doesn t cause inhibition to the appropriate level, the endpoint is set to the highest concentration tested. ... 

Karrison TG, Maitland ML, Stadler WM, Ratain MJ. Design of phase II cancer trials using a continuous endpoint of change in tumor size apphcation to a study of sorafenib and erlotinib in non small-cell lung cancer. J Natl Cancer Inst 2007 99 1455-1461. 

GJIC inhibition is involved in non-genotoxic cancer induction, and is a candidate endpoint in screening assays for identification of non-genotoxic carcinogens and tumour promoters, which is not detected by conventional genetic toxicology tests. 

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