Comparison of chronic toxicity and carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 2-year bioassays in female Sprague-Dawley rats.

The cancer bioassay for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) conducted by the Dow Chemical company in the mid 70s has been used extensively for conducting quantitative cancer risk assessments for human exposure to TCDD. More recently the National Toxicology Program (NTP) conducted a cancer bioassay of similar design as part of its evaluation of the dioxin toxic equivalency factor methodology. This report compares the design and the results of these two cancer bioassays. This comparison confirms, in most cases, previously published and widely used carcinogenic response characteristics with respect to dose, time course, organ selectivity, tumor type and maximum intensity of TCDD-induced carcinogenicity and toxicity in the Sprague-Dawley rat. Specifically, increases in the incidences of neoplasms were seen in both studies in the liver, lung and oral mucosa. The most notable difference was the significant increase in the incidence of cholangiocarcinoma of the liver seen in the NTP study but not in the Dow study. The experimental designs for the two studies are similar but some protocol parameters differed, such as vehicle, dosing schedule, diet and rat sub-strain utilized. Differences in the shapes of the dose response curves for several neoplasms were noted between the studies, with the NTP study showing non-linearity for all neoplasms. This may result from differences in the experimental protocols as well as divergence in the biological behavior of the different stocks of Sprague-Dawley rat strains used.

Inhibition of insulin synthesis by cyproheptadine: effects on translation.

The antihistaminic, antiserotonergic drug cyproheptadine (CPH) is known to inhibit insulin synthesis in vivo and in vitro. This inhibition of insulin synthesis occurs without a commensurate decrease in preproinsulin mRNA (PPImRNA) levels, suggesting a post-transcriptional mechanism of action. The goal of the present study was to investigate the direct effects of CPH on translation of PPImRNA in RINm5F cells. Results produced using a subcellular fractionation technique followed by real-time RT-PCR indicated that a 2-h 10 microM CPH treatment resulted in a decrease in the percentage of cellular PPImRNA associated with endoplasmic reticulum (ER) bound polysomes and increases in the percentages of translationally uninitiated and monoribosome-associated PPImRNA. These alterations in PPImRNA distribution were found to be concentration-dependent, chemical structure-specific, and reversible with a time course consistent with a previously reported CPH-induced inhibition of insulin synthesis. Further investigations to examine the possible effect of CPH on translation initiation were then undertaken by examining the phosphorylation state of the translation initiation factors eIF2alpha, eIF4E, and 4E-BP1 after CPH treatment. CPH (10 microM) treatment resulted in increased phosphorylation of eIF2alpha, and decreased phosphorylation of both eIF4E and 4E-BP1. These changes are all consistent with decreased initiation of translation. Taken together, these results suggest that the inhibition of insulin synthesis known to be elicited by CPH treatment of RINm5F cells and intact animals involves alterations of initiation factor phosphorylation leading to a decrease in insulin synthesis and of stored insulin in insulin-producing cells.