| Report for Food Standards Agency Project T01034: Risk assessment of dietary dioxins (2009) | |
Abstract | |
| These studies show conclusively that developmental exposure to TCDD during pregnancy did not cause potent effects on sperm levels in the offspring, nor cause potent effects on the weight of accessory sexual organs. These findings are reinforced by the statistical power of the data, the improved methodology (CASA, as opposed to manual, unblinded counting of sperm), and the study being performed with validated protocols to GLP. Further confidence in this conclusion comes in five additional studies that have been performed since 2000 (Fig. 8), which are concordant in that they show no effect of developmental TCDD exposure during pregnancy at doses below 300 ng/kg on F1 sperm levels [5] [6] [7] [8] [9]. It is also not possible to attribute the different results to strain differences, since attempts at replication in Holtzmann [5] [3] [6], Long-Evans [11] [9] and Wistar strain rats [37] [38] [1] have all failed to find a potent effect of TCDD on sperm levels in the repeat experiment. While there are a large number of potential variables that could confound the results of animal experiments, and it has not been possible to exclude all of these variables as a possible source of difference, the failure to reproduce the original findings of Mably [3] [12] [13] on sperm levels call into question the ability to rely upon this endpoint for the purposes of human risk assessment. The finding that TCDD caused a decrease in weight gain and delay in puberty at 2.4 ng/kg/ day in the sub-chronic study revealed that TCDD was significantly more potent after subchronic exposure, compared to acute dosing. The potency of these effects yielded a novel sensitive endpoint for the toxicity of TCDD, and together with the fetal TCDD concentration, this information was used to confirm that the current TDI for dioxins is protective [39]. The finding that TCDD may have a lactational mode of action is an important finding that has ramifications for modelling, and hence, assessing the human risk of TCDD exposure. The finding that there were two different size classes of AhR protein enabled the demonstration of two distinct genotypes of AhR present in CRL:WI(Han) rats. Molecular cloning of these genes enabled us to determine that there was no detectable effect of genotype on the potency of the AhR for binding to TCDD. Development of a robust genotyping assay enabled the examination of any linkage of the AhR genotype with developmental toxicity in our studies, and there was no significant and biologically plausible relationship observed. Thus this finding shows that AhR genotype did not affect the measured outcomes in these studies, and confirms that the conclusions from the animal studies remain unchanged. Finally, although the recombinant expression of AhR was initially problematic, it was successfully achieved, and validated against rat cytosolic AhR. The human AhR bound five different compounds 10-30 fold less avidly than the rat AhR, and this suggests that humans may be significantly less sensitive to toxicity from dioxins and related compounds. | |
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