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...

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

Human exposure to bisphenol A (BPA).

Systematic review of the chemical composition of contemporary dental adhesives

Bisphenol A (BPA) is the monomer used to manufacture polycarbonate plastic, the resin lining of cans, and other products, with global capacity in excess of 6.4 billion lb/year. Because the ester bonds in these BPA-based polymers are subject to hydrolysis, leaching of BPA has led to widespread human exposure. A recent report prepared by the Harvard Center for Risk Analysis and funded by the American Plastics Council concluded that evidence for low-dose effects of BPA is weak on the basis of a review of only 19 studies; the report was issued after a delay of 2.5 years. A current comprehensive review of the literature reveals that the opposite is true. As of December 2004, there were 115 published in vivo studies concerning low-dose effects of BPA, and 94 of these report significant effects. In 31 publications with vertebrate and invertebrate animals, significant effects occurred below the predicted “safe” or reference dose of 50 μg/kg/day BPA. An estrogenic mode of action of BPA is confirmed by in vitro experiments, which describe disruption of cell function at 10−12 M or 0.23 ppt. Nonetheless, chemical manufacturers continue to discount these published findings because no industry-funded studies have reported significant effects of low doses of BPA, although > 90% of government-funded studies have reported significant effects. Some industry-funded studies have ignored the results of positive controls, and many studies reporting no significant effects used a strain of rat that is inappropriate for the study of estrogenic responses. We propose that a new risk assessment for BPA is needed based on a) the extensive new literature reporting adverse effects in animals at doses below the current reference dose; b) the high rate of leaching of BPA from food and beverage containers, leading to widespread human exposure; c) reports that the median BPA level in human blood and tissues, including in human fetal blood, is higher than the level that causes adverse effects in mice; and d) recent epidemiologic evidence that BPA is related to disease in women.

https://endocrinedisruptors.missouri.edu/pdfarticles/vomsaalHughesEHP2005.pdf

An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment.

http://endocrinedisruptors.missouri.edu/pdfarticles/richterbpainvivoreviewrtx2007.pdf

In vivo effects of bisphenol A in laboratory rodent studies

Adult male Sprague-Dawley rats were exposed to tap water containing 0, 8,571, 17,143, or 34,286 ppm cypermethrin for 12 weeks. Based on water consumption per animal per day the rats received 13.15, 18.93, and 39.66 mg cypermethrin, respectively. Fertility was significantly reduced in male rats ingesting cypermethrin at a concentration of 13.15 and 18.93 mg in that the number of females impregnated by them was significantly reduced. The number of implantation sites was significantly reduced in females mated with males that had ingested cypermethrin at a concentration of 39.66 mg. A significant reduction in the number of viable fetuses was observed in females impregnated by the exposed males at all three doses of cypermethrin.

Evaluation of the toxic potentials of cypermethrin pesticide on some reproductive and fertility parameters in the male rats

The aim of this investigation was to evaluate the effect of bisphenol A (BPA), a contaminant of resin-based dental composites and sealants, on the fertility of male mice. Forty adult male Swiss mice were divided into four groups of 10. BPA (5, 25 and 100 micro g kg(-1) [corrected] was administered intragastrically daily to the mice in the test groups and distilled water to the control group for 28 d. Male fertility was assessed by mating each mouse with two untreated females. Females mated with male mice having ingested 25 and 100 micro g kg(-1) [corrected] BPA showed a significant reduction in pregnancy rates. Furthermore, the total number of resorptions out of the total number of implantations was significantly increased in females impregnated with males having ingested all three doses of BPA. Males having ingested 25 and 100 micro g kg(-1) [corrected] BPA showed a significant reduction in testicular sperm counts and in the efficiency of sperm production. Epididymal sperm counts were also significantly reduced in males that had ingested BPA. There were significant reductions in the absolute weights of the testes and seminal vesicles. These results suggest that male fertility and reproduction is impaired by bisphenol A.

Effects of bisphenol A on adult male mouse fertility.

Long-term exposure of male and female mice to trivalent and hexavalent chromium compounds: effect on fertility

This study investigated the effects of leached components from a resin-based dental composite (Z-100) and bisphenol A (BPA) on female mouse fertility. Leached components or BPA (5, 25 and 100 microg kg(-1)) were administered intragastrically daily to the test and distilled water to the control groups for 28 d. Female mice were then mated with sexually mature untreated males and their fertility was assessed. The results revealed a significant reduction in the number of pregnancies--54.5% vs. 100% (control)--in mice treated with the leached components from the dental composite, which also showed an increase of 142% in relative ovary weights. Exposure to 25 and 100 microg kg(-1) BPA resulted in significant increases in the total number of resorptions out of the total number of implantations and significant increases in relative uterine weights. Relative ovarian weights were significantly increased at the highest dose. High performance liquid chromatography analysis showed that tri-(ethylene glycol)-dimethacrylate (TEG-DMA) was the major leached component (total: 5945 microg ml(-1)) from the composite, followed by bisphenol A glycerolate dimethacrylate (BIS-GMA) (total: 2097 microg ml(-1)) and BPA (total: 78 microg ml(-1)). The results suggest that leached components from the dental composite used and commercially purchased BPA have adverse effects on the fertility and reproductive system of female mice.

Leached components from dental composites and their effects on fertility of female mice.

The effects of an extremely low frequency (ELF) magnetic field on the sex hormones and other fertility parameters of adult male Sprague-Dawley rats were investigated. Adult male rats were exposed to a 50 Hz sinusoidal magnetic field at approximately 25 microT (rms) for 18 consecutive weeks. There were no significant effects on the absolute body weight and the weight of the testes of the exposed rats. However, the weights of seminal vesicles and preputial glands were significantly reduced in the exposed male rats. Similarly, a significant reduction in sperm count was observed in the exposed group. Furthermore, there were no significant effects on the serum levels of male follicle stimulating hormone (FSH) during the 18 weeks of exposure period. On the other hand, there was a significant increase in the serum levels of male luteinizing hormone (LH) after 18 weeks of exposure (P < .005), while testosterone levels were significantly decreased only after 6 and 12 weeks of the exposure period. These results suggest that long term exposure to ELF could have adverse effects on mammalian fertility and reproduction.

Ahmed Elbetieha

Papers

Evaluation of the toxic potentials of cypermethrin pesticide on some reproductive and fertility parameters in the male rats

Effects of bisphenol A on adult male mouse fertility.

Long-term exposure of male and female mice to trivalent and hexavalent chromium compounds: effect on fertility

Leached components from dental composites and their effects on fertility of female mice.

Influence of 50 Hz magnetic field on sex hormones and other fertility parameters of adult male rats.