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Elisabete Silva, Martin Scholze, and Andreas Kortenkamp

The School of Pharmacy, University of London, London, United Kingdom

Abstract
Background: Certain effects induced by endocrine-disrupting chemicals (EDCs) may occur at dose levels lower than those normally tested in toxicology, but few systematic dose–response studies have been carried out in the low-dose range.

Objectives: The high statistical power afforded by a high-throughput in vitro assay such as the E-Screen assay was exploited with the aim of producing low-dose estimates for 24 estrogenic chemicals, including endogenous hormones and xenoestrogens.

Results: Unusual dose–response curves with inverted U-shapes were not observed in the low-dose range. Instead, many chemicals exhibited curves with very small gradients at low doses, and this complicated the reliable estimation of low effects. Systematic comparisons between the outcomes of hypothesis-testing procedures (lowest observed effect concentrations—LOECs, no observed effect concentrations—NOECs) and regression modeling approaches (EC₀₁—effective concentration causing a 1% effect, EC₀₅—effective concentration causing a 5% effect) produced estimates that agreed reasonably well. In many cases, NOECs were shown to be associated with proliferative responses of 1–2%. This is in contrast with the widespread perception of NOECs as values that signal complete absence of effects. For many of the tested xenoestrogens, the NOECs, EC₀₁, and EC₀₅ were in the nanomolar range, and comparisons with measured serum and adipose tissue levels in Europe revealed considerable overlaps in some cases.

Conclusions: Our studies illustrate the difficulties that may be encountered during the estimation of low doses in vivo. High statistical power is required when the underlying dose–response curves are shallow. Through the use of large sample sizes and numerous repeats, the experimental power of the E-Screen assay was sufficiently high to measure effect magnitudes of around 1–2% with reliability. However, such resources are usually not available for in vivo testing, with the consequence that the statistical detection limits are considerably higher. If this coincides with shallow dose–response curves in the low-effect range (which is normally not measurable in vivo) , the limited resolving power of in vivo assays may seriously constrain low-dose testing.

Key words: endocrine disruption, exposure assessment, low dose, NOEC, regression modeling. Environ Health Perspect 115(suppl 1) :91–97 (2007) . doi:10.1289/ehp.9363 available via http://dx.doi.org/ [Online 8 June 2007]

Address correspondence to A. Kortenkamp, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom. Telephone: 44 20 77535908. Fax: 44 7753 5811. E-mail: andreas.kortenkamp@pharmacy.ac.uk

This article is part of the monograph "Endocrine Disruptors—Exposure Assessment, Novel End Points, and Low-Dose and Mixture Effects."

The MCF-7 BOS cells were a kind gift from Ana Soto (Tufts University School of Medicine, Boston, MA, USA) .

This work is part of the European Union–supported EDEN-project "Endocrine Disrupters: Exploring Novel Endpoints, Exposure, Low Dose- and Mixture-Effects in Humans, Aquatic Wildlife and Laboratory Animal" (QLK4-CT-2002-00603) , and we gratefully acknowledge financial support from the European Commission.

The author declares he has no competing financial interests.

Received 22 May 2006 ; accepted 4 December 2006.