Tumor-supporting response

The results of this study, which must be the largest of its kind ever conducted, suggest that even though two types of dose responses were observed, the nearly linear dose response for liver tumors supports the use of linear extrapolation rates at extremely low doses to assure conservative risk... 

The inflammatory response in UC is propagated by atypical type 2 helper T cells that produce proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF).7 As discussed previously, a genetic predisposition to UC may partially explain the development of excessive colonic and rectal inflammation. The finding of positive perinuclear antineutrophil cytoplasmic antibodies (pANCA) in association with the human leukocyte antigen (HLA)-DR2 allele in a large percentage of patients with UC supports this theory.4,12... 

Yet different elaboration of the same molecule affords a compound (162) that acts as an inhibitor to the pituitary peptide hormone prolactin, the factor responsible for supporting lactation. As such the drug has found use in suppressing lactation and in the treatment of prolactin-dependent breast tumors. 

Another factor responsible for regulating the levels of p53 by (3-carotene could be the dose employed. At high carotenoid concentrations, an increase in p53 expression was observed in SCC cells (Schwartz, 1993) and in HL-60 cells (Palozza et al 2002b). In HL-60 cells, the treatment with the carotenoid induced a remarkable increase in ROS production, accompanied by an enhanced expression of p21WAFl and by a concomitant arrest of cell cycle at the G0/G1 phase (Palozza et al., 2002b). An arrest of cell cycle, accompanied by apoptosis induction, was also observed following dietary supplementation with lutein (Chew et al., 2003). The inhibition of mouse mammary tumor growth by lutein was also supported by the observed increase in the expression of p53 and Bax induced by the carotenoid (Chew et al., 2003). 

A nonlinear approach should be selected when there are sufficient data to ascertain the mode of action and to conclude that it is not linear at low doses, and the agent does not demonstrate mutagenic or other activity consistent with linearity at low doses. The POD is in this case generally a BMDL when incidence data are modeled. A sufficient basis to support this nonlinear procedure is likely to include data on responses that are key events in the carcinogenic process. This means that the POD may be based on these precursor response data, for example hormone levels or mitogenic effects, rather than tumor incidence data. A nonlinear approach can be used to develop an RfD or an RfC. This approach expands such reference values, previously reserved for threshold effects, to include carcinogenic effects determined to have a nonlinear mode of action. A nonlinear approach should generally not be used in cases where the mode of action has not been ascertained. 

Where alternative approaches with signihcant biological support are available for the same tumor response and no scientihc consensus favors a single approach, an assessment may present results based on more than one approach. 

Mendel rats supports chronic renal tubule injury as the mode of action underlying the renal tumor response. Toxicol Set 53(2) 237-44, 2000... 

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