Problems Associated with the Recognition and Confirmation of Low-Dose Endocrine Toxicities

Abstract

Our attempts to confirm reports oflow-dose/hormetic effects in rodent endocrine toxicity studies are reviewed. It is concluded that our present failure to confirm any such effects is due, in large part, to a general lack of understanding of confounding influences and the failure of most investigators to confirm their findings before publication. The major potential confounding factor is suggested to be variability of the parameters under study within control groups, a factor that assumes increased importance when attempting to demonstrate weak low-dose effects. This is illustrated by our studies with bisphenol A in the mouse uterotrophic assay and of finasteride in the Hershberger antiandrogenicity assav. In both of these cases our ability to demonstrate a low-dose effect is dependent on whether concurrent or recent control values are used.Key Words: low dose, control variability, endocrine disruption, hormesis, antiandrogen, estrogen DISCUSSIONThe available literature on hormetic dose-response effects for chemicals has been reviewed (Calabrese, 2002). These usuallv involve a stimulatory effect at low doses and an inhibitory effect at high doses, albeit the reverse can sometimes be observed. Few of these reports relate to classical. toxicologv, but the prospect that effects may been seen for a chemical below its classicallv derived "no adverse effect level" (NOAEL) is of obvious interest. Our experiences over the past 6 years when attempting to confirm examples of effects reported for chemicals in rodents exposed at doses below the previously accepted 1'\O/\EL value (low-dose effects) are reviewed in the following text.

Protective role of Ficus deltoidea against BPA-induced impairments of the follicular development, estrous cycle, gonadotropin and sex steroid hormones level of prepubertal rats

“…Based to this result, it appears that BPA has some influence on the weight of ovary, without having significant effects on the body weight. This finding supports a previous report by Ashby et al [ 45 ]. In fact, any changes of 10% or greater in the organ weight is a strong indicator of toxic effects, particularly when it is associated with morphological changes.…”

Bisphenol-A: Epigenetic Reprogramming and Effects on Reproduction and Behavior

“…However, these studies found no effect of low dose BPA and DES on prostate size and sexual maturation in both rats and mice [ 173 , 174 , 175 ]. The methodology employed by these early studies to look at low-dose effects of BPA has been highly scrutinized, potentially invalidating studies which found effects and those which did not [ 176 ]. Since then, the methodology used to measure BPA has been standardized by multiple researchers from different institutes.…”

A novel amphibian tier 2 testing protocol: A 30‐week exposure of Xenopus tropicalis to the antiandrogen flutamide

“…From work done in our laboratory during the collection of baseline histology data, we have rarely encountered NRGT animals (authors' unpublished data), which raises the question as to why control tank 1 had 5.5% NRGT animals. Ashby [29] asserts that low-dose endocrine toxicities are particularly difficult to detect because of the inherent variability within control groups of the parameters being studied. This variability within control animals may be influenced by a variety of factors, such as stress from overcrowding and naturally occurring endocrine-active compounds in food.…”