Certain substances are more toxic at lower doses than at higher doses
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Peer-reviewed literature in endocrinology and toxicology documents that certain endocrine-disrupting chemicals exhibit non-monotonic dose-response relationships, characterized by U- or inverted U-shaped curves where effects occur at lower concentrations.
In the fields of endocrinology and toxicology, there are ongoing debates about whether endocrine disrupting chemicals (EDCs) produce non-monotonic dose responses. This type of response is typically characterized by a U- or inverted U-shaped relationship between dose and effect. In a recent report, a US EPA panel concluded that non-monotonicity is observed for EDCs, but that these responses are not expected in vivo, and are not typically observed in apical endpoints, i.e. endpoints that are indicators of adverse effects. Here, we have analyzed the shapes of the dose response curves in an EPA report analyzing the effectiveness of the Endocrine Disruptor Screening Program (EDSP) Tier 1 assays. This report included the results of 11 guideline assays for each of 4 chemicals. We found indications of non-monotonic dose response curves (iNMDRCs) for 3 of the 4 coded chemicals. In total, 27% of assays with dose response data included at least one iNMDRC. When the endpoints from the 4 test chemicals with dose response data were considered together, 9% were consistent with non-monotonicity. Collectively, these results indicate that non-monotonic responses occur in guideline endpoints including the kinds of adverse outcomes that regulatory agencies use in chemical safety assessments such as circulating hormone concentrations and organ weights. These results should inform discussions about whether NMDRCs are ‘real’ and occur frequently enough to be important. Because risk assessments typically involve high dose testing, limited dose groups (often only 3) and extrapolation to lower doses that are not expected to have adverse effects, the presence of NMDRCs challenges this status quo.
Environmental endocrine-disrupting chemicals (EDCs) often exhibit nonmonotonic dose-response (NMDR) relationships, posing significant challenges to health risk assessment and regulations. Several molecular mechanisms operating locally in cells have been proposed; however, whether and how systemic negative feedback-a global structure of all homeostatic endocrine systems-may render NMDRs is poorly understood. We hypothesized that an EDC may produce nonmonotonic effects by competing with the endogenous hormone for receptors simultaneously (i) at the central site to interfere with the feedback regulation and (ii) at the peripheral site to disrupt the hormone's endocrine action. We constructed a dynamical model of a generic hypothalamic-pituitary-endocrine axis with negative feedback to evaluate the hypothesis and biological conditions that favor NMDR. Our modeling found that when an EDC interferes sufficiently with the central feedback action, the net endocrine effect at the peripheral target site can be opposite to what is expected of an agonist or antagonist at low concentrations. J/U or Bell-shaped NMDRs arise when the EDC has differential binding affinities and/or efficacies, relative to the endogenous hormone, for the peripheral and central receptors. Novel quantitative relationships between these biological parameter variabilities and associated distributions were discovered, which can distinguish J/U and Bell-shaped NMDRs from monotonic responses. In conclusion, the ubiquitous negative feedback regulation in endocrine systems may act as a universal mechanism for counterintuitive and nonmonotonic effects of EDCs. Depending on the key receptor kinetic and signaling properties of EDCs and endogenous hormones, certain individuals may be more susceptible to these complex endocrine effects.
A Gompertz age-specific mortality rate model of aging, hormesis, and toxicity: fixed-dose studies.
Based on the proposition that the logarithm of age-specific mortality rate (Gompertzian) is a linear measure of the mean intensity of injury for a homogeneous mammalian population in a uniform environment, a model was developed which characterizes mortality experience resulting from both toxic and hormetic actions. The mortality-reducing component (longevity hormesis) was assumed to be reversible; toxic effects, on the other hand, were assumed to accumulate irreversibly. Following chronic low-dose administration of selected toxic substances, it was demonstrated (in certain cases) that longevity hormesis could enhance lifespan, even in the presence of concomitant toxicity. Even when toxicity was evident, hormesis could ameliorate some of the mortality. The assumption that high-dose chronic toxicity studies can generate realistic estimates of risk at low doses is challenged.
Published in Drug metabolism reviews (1988)
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