A Clash of Old and New Scientific Concepts in Toxicity, with Important Implications for Public Health

Environmental Health Sciences, Charlottesville, Virginia 22902, USA.
Environmental Health Perspectives (Impact Factor: 7.98). 11/2009; 117(11):1652-5. DOI: 10.1289/ehp.0900887
Source: PubMed


A core assumption of current toxicologic procedures used to establish health standards for chemical exposures is that testing the safety of chemicals at high doses can be used to predict the effects of low-dose exposures, such as those common in the general population. This assumption is based on the precept that "the dose makes the poison": higher doses will cause greater effects.
We challenge the validity of assuming that high-dose testing can be used to predict low-dose effects for contaminants that behave like hormones. We review data from endocrinology and toxicology that falsify this assumption and summarize current mechanistic understanding of how low doses can lead to effects unpredictable from high-dose experiments.
Falsification of this assumption raises profound issues for regulatory toxicology. Many exposure standards are based on this assumption. Rejecting the assumption will require that these standards be reevaluated and that procedures employed to set health standards be changed. The consequences of these changes may be significant for public health because of the range of health conditions now plausibly linked to exposure to endocrine-disrupting contaminants.
We recommend that procedures to establish acceptable exposure levels for endocrine-disrupting compounds incorporate the inability for high-dose tests to predict low-dose results. Setting acceptable levels of exposure must include testing for health consequences at prevalent levels of human exposure, not extrapolations from the effects observed in high-dose experiments. Scientists trained in endocrinology must be engaged systematically in standard setting for endocrine-disrupting compounds.

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Available from: Tom Zoeller, Nov 04, 2014
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    • "All of them are released to the environment via different sources and are presented simultaneously instead of separately . Thus, these chemicals not only have adverse effects on organisms at very low-level exposure (Myers et al., 2009), but also have the potential of additive or even synergistic effects when acting in combination (Kunz and Fent, 2006; Sun et al., 2009). Estrogenic chemicals have been the focus of many studies for a long time. "
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    ABSTRACT: The increasing amounts of various estrogenic chemicals coexisting in the aquatic environment may pose environmental risks. While the concept of estradiol equivalent (EEQ) has been frequently applied in studying estrogenic mixtures, few experiments have been done to prove its reliability. In this study, the reliability of EEQ and the related model concentration addition (CA) was verified based on the two-hybrid recombinant yeast bioassay when all mixture components had the same mode of action and target of action. Our results showed that the measured estrogenic effects could be well predicted by CA and EEQ for all laboratory-made mixtures using two designs, despite the varying estrogenic activity, concentration levels and ratios of the test chemicals. This suggests that when an appropriate endpoint and its relevant bioassay are chosen, CA should be valid and the application of EEQ in predicting the effect of non-equi-effect mixtures is feasible.
    Environmental Toxicology and Pharmacology 11/2014; 38(3). DOI:10.1016/j.etap.2014.10.001 · 2.08 Impact Factor
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    • "Most of these applications used the threshold model which was based on the monotonic CRCs (Myers et al., 2009; Billionnet et al., 2012). However, the threshold model is unsuitable to assess the risk of chemicals with non-monotonic CRCs, where the effects of some chemicals were not simply increase or decrease over concentrations (Myers et al., 2009). For example, non-monotonic J-shaped CRCs represent hormesis, where the stimulatory effects firstly increased and then decreased over time, and even changed into inhibitory effects (Calabrese, 2008). "
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    ABSTRACT: The threshold model based on monotonic concentration-response curves (CRCs) is unsuitable to assess the risk of chemicals with non-monotonic CRCs. The non-monotonic CRCs of mixtures may relate to the characteristics of some individual component. To reveal the cause of the mixtures resulting in the non-monotonic CRCs, we used the microplate toxicity analysis to determine the toxicity effects of six 1-alkyl-3-methyl-imidazolium ([amim]X) salts and their mixtures on Vibrio qinghaiensis sp.-Q67 (Q67). It was shown that the CRCs of six [amim]X salts are monotonic S-shaped while those of the senary mixtures designed by the uniform design ray (UD-ray) are all non-monotonic. The mixtures were further split into two ternary mixtures, one containing 1-ethyl-3-methyl-imidazolium ([emim]X) salts (noted as UTE) and the other one containing 1-butyl-3-methyl-imidazolium ([bmim]X) salts (noted as UTB). It was found that the CRCs of UTE mixtures are all non-monotonically J-shaped, while only one (UTB-R3) among UTB mixtures has a little stimulating effect and the CRCs of the other three mixtures (UTB-R1, UTB-R2 and UTB-R4) are monotonic. The CRCs of the binary mixtures designed by the direct equipartition ray design (EquRay) procedure were further examined. The CRCs of the mixtures containing [emim]Cl are non-monotonic J-shaped while those of the mixtures without [emim]Cl are still monotonic. Thus, it can conclude that it is [emim]Cl that causes the non-monotonic CRCs in [amim]X mixtures, even though the CRC of individual [emim]Cl is monotonic.
    Chemosphere 10/2014; 112C:420-426. DOI:10.1016/j.chemosphere.2014.05.007 · 3.34 Impact Factor
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    • "The impact of environmental endocrine-disrupting chemicals (EDCs) on human health is widely discussed but remains poorly understood. By definition, EDCs, usually binding to nuclear receptors (NRs), act by interfering with any aspect of hormone action (e.g., synthesis, activity, and degradation), thus altering hormone-responsive cells and tissues (Zoeller et al., 2012; Myers et al., 2009). NRs are a large class of transcription factors that play significant roles in the pathophysiology of virtually every organ (Nuclear Receptors Nomenclature Committee, 1999). "
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    ABSTRACT: Environmental exposures to chemically heterogeneous endocrine-disrupting chemicals (EDCs) mimic or interfere with hormone actions and negatively affect human health. Despite public interest and the prevalence of EDCs in the environment, methods to mechanistically classify these diverse chemicals in a high throughput (HT) manner have not been actively explored. Here, we describe the use of multiparametric, HT microscopy-based platforms to examine how a prototypical EDC, bisphenol A (BPA), and 18 poorly studied BPA analogs (BPXs), affect estrogen receptor (ER). We show that short exposure to BPA and most BPXs induces ERα and/or ERβ loading to DNA changing target gene transcription. Many BPXs exhibit higher affinity for ERβ and act as ERβ antagonists, while they act largely as agonists or mixed agonists and antagonists on ERα. Finally, despite binding to ERs, some BPXs exhibit lower levels of activity. Our comprehensive view of BPXs activities allows their classification and the evaluation of potential harmful effects. The strategy described here used on a large-scale basis likely offers a faster, more cost-effective way to identify safer BPA alternatives.
    Chemistry & Biology 05/2014; DOI:10.1016/j.chembiol.2014.03.013 · 6.65 Impact Factor
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