Evaluating the toxicokinetics of some metabolites of a C6 polyfluorinated compound, 6:2 fluorotelomer alcohol in pregnant and nonpregnant rats after oral exposure to the parent compound.

The 6:2 fluorotelomer alcohol (6:2 FTOH) is a common impurity in per- and polyfluoroalkyl substances (PFASs) used in many applications. Our previous toxicokinetic (TK) evaluation of 6:2 FTOH calculated times to steady state (tss) of one of its metabolites, 5:3 fluorotelomer carboxylic acid (5:3A), in the plasma and tissues of up to a year after oral exposure to rats. Our current work further elucidated the TK of 5:3A and other metabolites of 6:2 FTOH in pregnant and nonpregnant rats after repeated oral exposure and examined the role of renal transporters in the biopersistence of 5:3A.

Isoliquiritigenin Decreases Bone Resorption and Osteoclast Differentiation.

Scope: A dose-ranging study is performed using young estrogen-depleted rats to determine whether dietary isoliquiritigenin (ILQ) alters bone metabolism and if the effects are associated with estrogen receptor signaling.

Methods And Results: Six-week-old rats (ovariectomized at 4 weeks of age) are fed diets containing 0, 100, 250, or 750 ppm ILQ (n = 5/treatment) for 7 days. Gene expression in femur and uterus, blood markers of bone turnover, body composition, and uterine weight and epithelial cell height are determined.

Advancing human health risk assessment.

The current/traditional human health risk assessment paradigm is challenged by recent scientific and technical advances, and ethical demands. The current approach is considered too resource intensive, is not always reliable, can raise issues of reproducibility, is mostly animal based and does not necessarily provide an understanding of the underlying mechanisms of toxicity. From an ethical and scientific viewpoint, a paradigm shift is required to deliver testing strategies that enable reliable, animal-free hazard and risk assessments, which are based on a mechanistic understanding of chemical toxicity and make use of exposure science and epidemiological data.

A Summary Report of FSCJ Workshop "Future Challenges and Opportunities in Developing Methodologies for Improved Human Risk Assessments".

This is a summary report of FSCJ (Food Safety Commission of Japan) workshop entitled "Future Challenges and Opportunities in Developing Methodologies for Improved Human Risk Assessments, which held in November 2018. Scientific advancements have facilitated the development of new methods for chemical risk assessments with the expansion of toxicological databases. They are promising tools to overcome challenges, such as situations of data insufficiency, estimation of internal exposure and prediction of hazard, and enable us to improve our human health risk assessment in food safety.

Characterizing biopersistence potential of the metabolite 5:3 fluorotelomer carboxylic acid after repeated oral exposure to the 6:2 fluorotelomer alcohol.

Our previous report on pharmacokinetic (PK) evaluation of 6:2 fluorotelomer alcohol (6:2 FTOH) examined the biopersistence potential of its metabolites based on data published from single inhalation and occupational 6:2 FTOH exposure studies. We calculated internal exposure estimates of three key metabolites of 6:2 FTOH, of which 5:3 fluorotelomer carboxylic acid (5:3 acid) had the highest internal exposure and the slowest clearance. No oral repeated 6:2 FTOH exposure data were available at the time to fully characterize the biopersistence potential of the metabolite 5:3 acid.

(±)-Equol does not interact with genistein on estrogen-dependent breast tumor growth.

Equol (EQ) is a prominent microbial metabolite of the soy isoflavone, daidzein, with estrogen-like properties. The major soy isoflavone, genistein (GEN), stimulated growth of estrogen-dependent breast cancer (EDBC) cells in vitro and tumor growth in vivo but EQ did not. To understand possible interactions of EQ and GEN on EDBC, EQ was used with GEN in combination in vitro and in vivo.

Metabolism and disposition of arsenic species from controlled dosing with sodium arsenite in adult and neonatal rhesus monkeys. VI. Toxicokinetic studies following oral administration.

Arsenic is a common toxic contaminant in food and drinking water. Metabolic activation of arsenic species produces reactive trivalent intermediates that can disrupt cellular regulatory systems by covalent binding to thiol groups. Arsenic exposures have been associated with human diseases including cancer, diabetes, lung and cardiovascular disorders and there is accumulating evidence that early life exposures are important in the etiology.

A two-year toxicology study of bisphenol A (BPA) in Sprague-Dawley rats: CLARITY-BPA core study results.

We report the data from the guideline-compliant two-year toxicology study conducted as part of the Consortium Linking Academic and Regulatory Insights on Bisphenol A Toxicity (CLARITY-BPA). BPA (0, 2.5, 25, 250, 2,500, and 25,000 μg/kg body weight (bw)/day) was administered daily by gavage in 0.

A single or short time repeated arsenic oral exposure in mice impacts mRNA expression for signaling and immunity related genes in the gut.

Arsenic is prevalent in contaminated drinking water and affects more than 140 million people in 50 countries. While the wide-ranging effects of arsenic on neurological development and cancer draw the majority of concern, arsenic's effects on the gut mucosa-associated immune system are often overlooked. In this study, we show that 24 h after a single dose [low dose (50 μg/kg bw), medium dose (100 μg/kg bw) or high dose (200 μg/kg bw)] of arsenic by oral gavage, mice show significantly reduced gut mucosa-associated mRNA expression for the key genes involved in the signaling pathways central to immune responses, such as Nuclear factor κB (NFκB), Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), p38 and Myeloid differentiation protein 88-dependent (Myd88) pathways.

Metabolism and disposition of arsenic species from controlled dosing with dimethylarsinic acid (DMA) in adult female CD-1 mice. V. Toxicokinetic studies following oral and intravenous administration.

Arsenic species contaminate food and water, with typical dietary intake below 1 μg/kg bw/d. Exposure to arsenic in heavily contaminated drinking water is associated with human diseases, including cardiovascular and respiratory disorders, diabetes, and cancer. Dietary intake assessments show that rice and seafood are the primary contributors to intake of both inorganic arsenic and dimethylarsinic acid (DMA) and at similar magnitudes.

Comparative estrogenicity of endogenous, environmental and dietary estrogens in pregnant women II: Total estrogenicity calculations accounting for competitive protein and receptor binding and potency.

Evaluating the biological significance of human-relevant exposures to environmental estrogens involves assessing the individual and total estrogenicity of endogenous and exogenous estrogens found in serum, for example from biomonitoring studies. We developed a method for this assessment by integrating approaches for (i) measuring total hormone concentrations by mass spectrometry (Fleck et al., 2018), (ii) calculating hormone bioavailable concentrations in serum and, (iii) solving multiple equilibria between estrogenic ligands and receptors, and (iv) quantitatively describing key elements of estrogen potency.

Acrylamide Production in Autoclaved Rodent Feed.

Sterilization of rodent feed by steam autoclaving is a common practice in many research institutions. Often we only consider the beneficial effects of this process-the reduction of microbial contamination-and forget that the high temperatures and pressures can have negative effects on diet quality. The purpose of our study was to assess both the physical and chemical changes to a standard rodent feed autoclaved at multiple sterilization temperatures and the effects of the treated diets on mice.

Metabolism and disposition of arsenic species from oral dosing with sodium arsenite in neonatal CD-1 mice. IV. Toxicokinetics following gavage administration and lactational transfer.

Arsenic is a ubiquitous contaminant, with typical human dietary intake below 1 μg/kg bw/d and extreme drinking water exposures up to ∼50 μg/kg bw/d. The formation and binding of trivalent metabolites are central to arsenic toxicity and strong human evidence suggests special concern for early life exposures in the etiology of adult diseases, especially cancer. This study measured the metabolism and disposition of arsenite in neonatal mice to understand the role of maturation in metabolic activation and detoxification of arsenic.

Metabolism and disposition of arsenic species from controlled dosing with sodium arsenite in adult female CD-1 mice. III. Toxicokinetic studies following oral and intravenous administration.

Arsenic is a ubiquitous contaminant, with typical dietary intake below 1 μg/kg bw/d and drinking water exposures up to 50 μg/kg bw/d. Arsenic exposures are associated with human diseases and doses of toxicological concern are similar to typical dietary intake. Metabolism of arsenite to dimethylarsinate (DMA) by arsenite-3-methyltransferase (As3MT) promotes clearance, but also generates reactive trivalent intermediates that bind extensively to cellular thiols.

Exposure to Arsenite in CD-1 Mice during Juvenile and Adult Stages: Effects on Intestinal Microbiota and Gut-Associated Immune Status.

Intestinal microbiota composition and gut-associated immune response can contribute to the toxicity of arsenic. We investigated the potential toxicity of short-term arsenic exposure on gut microbiome composition, intestinal immune status, microbial arsenic resistance gene, and arsenic metabolic profiles in adult and developmental stages of CD-1 mice. The potential toxicity of arsenite [As(III)] was determined for two life stages: (i) adult animals at 24 or 48 h after single gavage (0.

Licorice root components mimic estrogens in an object location task but not an object recognition task.

This study investigated the efficacy of components of licorice root to alter performance on two different recognition tasks, a hippocampus-sensitive metric change in object location (MCOL) task and a striatum-sensitive double object recognition (DOR) task. Isoliquiritigenin (ISL), licorice root extract (LRE), and whole licorice root powder (LRP) were assessed. Young adult female rats were ovariectomized (OVX) and exposed to ISL, LRE or LRP at 0.

Comparative estrogenicity of endogenous, environmental and dietary estrogens in pregnant women I: Serum levels, variability and the basis for urinary biomonitoring of serum estrogenicity.

Biomonitoring of human exposure to estrogens most frequently focuses on environmental and dietary estrogens, and infrequently includes measures of exposure to potent endogenous estrogens present in serum. Pregnancy is a developmentally sensitive period during which "added" serum estrogenicity exceeding normal intra-individual daily variability may be of particular relevance. We made repeated measurements of serum concentrations of estrone (E1), estradiol (E2), estriol (E3), estetrol (E4), daidzein (DDZ), genistein (GEN) and bisphenol A (BPA) in thirty pregnant women using ultra-performance liquid chromatography coupled with tandem mass spectrometry detection (UPLC-MS/MS) and electrospray ionization (ESI).

Metabolism and disposition of arsenic species after repeated oral dosing with sodium arsenite in drinking water. II. Measurements in pregnant and fetal CD-1 mice.

Arsenic is ubiquitous in the earth's crust, and human diseases are linked with exposures that are similar to dietary intake estimates. Metabolic methylation of inorganic arsenic facilitates excretion of pentavalent metabolites and decreases acute toxicity; however, tissue binding of trivalent arsenic intermediates is evidence for concomitant metabolic activation. Pregnant and fetal CD-1 mice comprise a key animal model for arsenic carcinogenesis since adult-only exposures have minimal effects.

The effects of the botanical estrogen, isoliquiritigenin on delayed spatial alternation.

Age-related declines in cognitive function can impair working memory, reduce speed of processing, and alter attentional resources. In particular, menopausal women may show an acceleration in the rate of cognitive decline as well as an increased vulnerability to brain diseases as estrogens may play a neuroprotective and neurotrophic role in the brain. To treat menopausal symptoms, many women turn to botanical estrogens that are promoted as a safe and natural alternative to traditional hormone replacement therapy.

Cellular and Molecular Effects of Prolonged Low-Level Sodium Arsenite Exposure on Human Hepatic HepaRG Cells.

Inorganic arsenic is a human carcinogen associated with several types of cancers, including liver cancer. Inorganic arsenic has been postulated to target stem cells, causing their oncogenic transformation. This is proposed to be one of the key events in arsenic-associated carcinogenesis; however, the underlying mechanisms for this process remain largely unknown.

Metabolism and disposition of arsenic species from controlled oral dosing with sodium arsenite in adult female CD-1 mice. I. Pilot study to determine dosing, analytical measurements, and sampling strategies.

Arsenic (As) is ubiquitous in the earth's crust, with typical dietary intake in developed countries <1 μg/kg bw/d, and atypical groundwater exposures in developing countries approaching 50 μg/kg bw/d. Arsenic exposures are linked with human diseases and doses of toxicological concern are similar to typical dietary intake estimates. The methylation of arsenite by arsenite-3-methyltransferase (As3MT) promotes the clearance of arsenic as pentavalent species, but also generates reactive trivalent intermediates.

Metabolism and pharmacokinetics of zearalenone following oral and intravenous administration in juvenile female pigs.

Zearalenone (ZEN) is a well-studied mycotoxin whose potent estrogenic properties have been used by international regulatory bodies to set health-based guidance values for ZEN exposure in grain-based foods from changes in hormonally responsive tissues of juvenile female pigs. The role of metabolism in determining estrogenic responses in vivo is a major uncertainty in inter-species extrapolation to humans and in assessing the potential for added susceptibility in sensitive subpopulations. This study evaluated the metabolism of ZEN and pharmacokinetics in ∼2 month-old female pigs using oral and intravenous dosing.

Lifetime Genistein Intake Increases the Response of Mammary Tumors to Tamoxifen in Rats.

Purpose: Whether it is safe for estrogen receptor-positive (ER+) patients with breast cancer to consume soy isoflavone genistein remains controversial. We compared the effects of genistein intake mimicking either Asian (lifetime) or Caucasian (adulthood) intake patterns to that of starting its intake during tamoxifen therapy using a preclinical model.

Experimental Design: Female Sprague-Dawley rats were fed an AIN93G diet supplemented with 0 (control diet) or 500 ppm genistein from postnatal day 15 onward (lifetime genistein).

Low dose assessment of the carcinogenicity of furan in male F344/N Nctr rats in a 2-year gavage study.

Furan is a volatile organic chemical that is a contaminant in many common foods. Furan is hepatocarcinogenic in mice and rats; however, the risk to humans from dietary exposure to furan cannot be estimated accurately because the lowest tested dose of furan in a 2-year bioassay in rats gave nearly a 100% incidence of cholangiocarcinoma. To provide bioassay data that can be used in preparing risk assessments, the carcinogenicity of furan was determined in male F344/N Nctr rats administered 0, 0.