For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

/pdf/hormones-and-endocrine-disrupting-chemicals-low-dose-effects-2vn32zoqc8.pdf

Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

Information concerning the fundamental mechanisms of action of both natural and environmental hormones, combined with information concerning endogenous hormone concentrations, reveals how endocrine-disrupting chemicals with estrogenic activity (EEDCs) can be active at concentrations far below those currently being tested in toxicological studies. Using only very high doses in toxicological studies of EEDCs thus can dramatically underestimate bioactivity. Specifically: a) The hormonal action mechanisms and the physiology of delivery of EEDCs predict with accuracy the low-dose ranges of biological activity, which have been missed by traditional toxicological testing. b) Toxicology assumes that it is valid to extrapolate linearly from high doses over a very wide dose range to predict responses at doses within the physiological range of receptor occupancy for an EEDC; however, because receptor-mediated responses saturate, this assumption is invalid. c) Furthermore, receptor-mediated responses can first increase and then decrease as dose increases, contradicting the assumption that dose-response relationships are monotonic. d) Exogenous estrogens modulate a system that is physiologically active and thus is already above threshold, contradicting the traditional toxicological assumption of thresholds for endocrine responses to EEDCs. These four fundamental issues are problematic for risk assessment methods used by regulatory agencies, because they challenge the traditional use of extrapolation from high-dose testing to predict responses at the much lower environmentally relevant doses. These doses are within the range of current exposures to numerous chemicals in wildlife and humans. These problems are exacerbated by the fact that the type of positive and negative controls appropriate to the study of endocrine responses are not part of traditional toxicological testing and are frequently omitted, or when present, have been misinterpreted.

Large Effects from Small Exposures. I. Mechanisms for Endocrine-Disrupting Chemicals with Estrogenic Activity

(1976). Survival Distributions: Reliability Applications in the Biomedical Sciences. Technometrics: Vol. 18, No. 4, pp. 501-501.

Survival Distributions: Reliability Applications in the Biomedical Sciences

Cancer is the second leading cause of death in the United States. Despite the estimated 565,650 deaths in 2008 of Americans as a result of cancer, it is mostly a preventable disease. Simply by modification of diet, maintenance of optimum body weight, and regular physical activity, 30% to 40% of all instances of cancer could be prevented. Modification of diet alone by increasing vegetable and fruit intake could prevent 20% or more of all cases of cancer and may potentially prevent approximately 200,000 cancer-related deaths annually. Because of their safety, low toxicity, antioxidant properties, and general acceptance as dietary supplements, fruits, vegetables, and other dietary elements (phytochemicals and minerals) are being investigated for the prevention of cancer. Extensive research over the past several decades has identified numerous dietary and botanical natural compounds that have chemopreventive potential. In this review, we discuss promising natural chemopreventive compounds, their molecular targets, and their mechanisms, which may help the further design and conduct of preclinical and clinical trials.

/pdf/perspectives-for-cancer-prevention-with-natural-compounds-3v6n76iq8x.pdf

Perspectives for Cancer Prevention With Natural Compounds

Flavonoids are a family of polyphenolic compounds which are widespread in nature (vegetables) and are consumed as part of the human diet in significant amounts. There are other types of polyphenols, including, for example, tannins and resveratrol. Flavonoids and related polyphenolic compounds have significant antiinflammatory activity, among others. This short review summarizes the current knowledge on the effects of flavonoids and related polyphenolic compounds on inflammation, with a focus on structural requirements, the mechanisms involved, and pharmacokinetic considerations. Different molecular (cyclooxygenase, lipoxygenase) and cellular targets (macrophages, lymphocytes, epithelial cells, endothelium) have been identified. In addition, many flavonoids display significant antioxidant/radical scavenging properties. There is substantial structural variation in these compounds, which is bound to have an impact on their biological profile, and specifically on their effects on inflammatory conditions. However, in general terms there is substantial consistency in the effects of these compounds despite considerable structural variations. The mechanisms have been studied mainly in myeloid cells, where the predominant effect is an inhibition of NF-κB signaling and the downregulation of the expression of proinflammatory markers. At present there is a gap in knowledge of in vitro and in vivo effects, although the pharmacokinetics of flavonoids has advanced considerably in the last decade. Many flavonoids have been studied for their intestinal antiinflammatory activity which is only logical, since the gastrointestinal tract is naturally exposed to them. However, their potential therapeutic application in inflammation is not restricted to this organ and extends to other sites and conditions, including arthritis, asthma, encephalomyelitis, and atherosclerosis, among others.

Effects of Flavonoids and other Polyphenols on Inflammation

The isoflavone genistein (4,7,4'-trihydroxyisoflavone) is a phytoestrogen found in high levels in soy products that has been associated with decreased incidences of breast and prostate cancers. The potential effects of genistein on the immune system were evaluated in adult female B6C3F1 mice. Groups of mice were exposed to vehicle or genistein by gavage for 28 d. The doses of genistein used were 2, 6 and 20 mg/kg body. Consistent with the chemopreventive effect of genistein, exposure to this compound significantly increased host resistance to B16F10 tumor as reflected by a decrease in the number of lung tumor nodules after tumor cell injection at the middle and high dose levels. Inhibition of B16F10 tumor formation was not due to a direct effect of serum genistein and/or its metabolites on the proliferation of B16F10 tumor cells. When innate and acquired immune responses were evaluated, a dose-related increase of cytotoxic T-cell activity was observed in genistein-treated mice with significant changes observed at the middle and high dose levels. Furthermore, in vitro interleukin (IL)-2-stimulated natural killer (NK) cell activity was significantly enhanced in the high genistein dose group, although the basal NK cell activity was not affected. Although no affect on the mixed lymphocyte responses and anti-CD3 antibody-mediated splenocyte proliferation was observed, exposure to genistein significantly increased basal splenocyte proliferation. Exposure to genistein did not alter the activity of the mononuclear phagocyte system and the cytotoxic/cytostatic function of thioglycollate-recruited peritoneal cells on B16F10 tumor cells. Finally, exposure to genistein did not produce biologically meaningful changes in spleen immunoglobulin (Ig)M and IgG antibody-forming cell responses. In conclusion, genistein enhanced host resistance as evaluated in the B16F10 tumor model, which may be related to the increases in the activities of cytotoxic T cells and NK cells.

Genistein modulates immune responses and increases host resistance to B16F10 tumor in adult female B6C3F1 mice.

Bisphenol A (BPA), used in polycarbonate plastics and epoxy resins, has a widespread exposure to humans. BPA is of concern for developmental exposure resulting in immunomodulation and disease development due to its ability to cross the placental barrier and presence in breast milk. BPA can use various mechanisms to modulate the immune system and affect diseases, including agonistic and antagonistic effects on many receptors (e.g., estrogen receptors), epigenetic modifications, acting on cell signaling pathways and, likely, the gut microbiome. Immune cell populations and function from the innate and adaptive immune system are altered by developmental BPA exposure, including decreased T regulatory (Treg) cells and upregulated pro- and anti-inflammatory cytokines and chemokines. Developmental BPA exposure can also contribute to the development of type 2 diabetes mellitus, allergy, asthma and mammary cancer disease by altering immune function. Multiple sclerosis and type 1 diabetes mellitus may also be exacerbated by BPA, although more research is needed. Additionally, BPA analogs, such as bisphenol S (BPS), have been increasing in use, and currently, little is known about their immune effects. Therefore, more studies should be conducted to determine if developmental exposure BPA and its analogs modulate immune responses and lead to immune-related diseases.

/pdf/developmental-bisphenol-a-exposure-modulates-immune-related-2ghy2rc4p4.pdf

Developmental Bisphenol A Exposure Modulates Immune-Related Diseases.

Genistein modulates splenic natural killer cell activity, antibody-forming cell response, and phenotypic marker expression in F0 and F1 generations of Sprague-Dawley rats

Tai L. Guo

Papers

Genistein modulates immune responses and increases host resistance to B16F10 tumor in adult female B6C3F1 mice.

Developmental Bisphenol A Exposure Modulates Immune-Related Diseases.

Genistein modulates splenic natural killer cell activity, antibody-forming cell response, and phenotypic marker expression in F0 and F1 generations of Sprague-Dawley rats

Oral exposure to atrazine modulates cell-mediated immune function and decreases host resistance to the B16F10 tumor model in female B6C3F1 mice.

TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice.