Seul Min Choi

Toxicological Characteristics of Endocrine-Disrupting Chemicals: Developmental Toxicity, Carcinogenicity, and Mutagenicity

It is generally accepted that endocrine-disrupting chemicals (EDCs) play a role in a variety of adverse health effects in an intact organism or its progeny as a consequence of changes in the endocrine system. Primary toxic effects of EDCs were reported to be related to infertility, reduction in sperm count, and teratogenicity, but other important toxic effects of EDCs such as carcinogenicity and mutagenicity have also been demonstrated. The aim of the present study was to systematically analyze the toxicological characteristics of EDCs in pesticides, industrial chemicals, and metals. A comprehensive literature survey on the 48 EDCs classified by the Centers for Disease Control and Prevention (CDC) was conducted using a number of databases which included Medline, Toxline, and Toxnet. The survey results revealed that toxicological characteristics of EDCs were shown to produce developmental toxicity (81%), carcinogenicity (79%, when positive in at least one animal species; 48%, when classified based on IARC evaluation), mutagenicity (79%), immunotoxicity (52%), and neurotoxicity (50%). Regarding the hormone-modulating effects of the 48 EDCs, estrogenic effects were the most predominant in pesticides, while effects on thyroid hormone were found for heavy metals. EDCs showing estrogen-modulating effects were closely related to carcinogenicity or mutagenicity with a high degree of sensitivity. Systematic information on the toxicological characteristics of the EDCs will be useful for future research directions on EDCs, the development of new screening methods, legal regulation, and for investigations of their mechanism of action.

Safety Evaluation And Risk Assessment Of d-Limonene

d-Limonene, a major constituent of citrus oils, is a monoterpene widely used as a flavor/fragrance additive in cosmetics, foods, and industrial solvents as it possesses a pleasant lemon-like odor. d-Limonene has been designated as a chemical with low toxicity based upon lethal dose (LD50) and repeated-dose toxicity studies when administered orally to animals. However, skin irritation or sensitizing potential was reported following widespread use of this agent in various consumer products. In experimental animals and humans, oxidation products or metabolites of d-limonene were shown to act as skin irritants. Carcinogenic effects have also been observed in male rats, but the mode of action (MOA) is considered irrelevant for humans as the protein α2u-globulin responsible for this effect in rodents is absent in humans. Thus, the liver was identified as a critical target organ following oral administration of d-limonene. Other than the adverse dermal effects noted in humans, other notable toxic effects of d-limonene have not been reported. The reference dose (RfD), the no-observed-adverse-effect level (NOAEL), and the systemic exposure dose (SED) were determined and found to be 2.5 mg/kg/d, 250 mg/kg//d, and 1.48 mg/kg/d, respectively. Consequently, the margin of exposure (MOE = NOAEL/SED) of 169 was derived based upon the data, and the hazard index (HI = SED/RfD) for d-limonene is 0.592. Taking into consideration conservative estimation, d-limonene appears to exert no serious risk for human exposure. Based on adverse effects and risk assessments, d-limonene may be regarded as a safe ingredient. However, the potential occurrence of skin irritation necessitates regulation of this chemical as an ingredient in cosmetics. In conclusion, the use of d-limonene in cosmetics is safe under the current regulatory guidelines for cosmetics.

AN ALTERNATIVE MODE OF ACTION OF ENDOCRINE-DISRUPTING CHEMICALS AND CHEMOPREVENTION

Endocrine-disrupting chemicals (EDCs) produce a wide variety of endocrine-disruption effects, including developmental disorders, carcinogenicity, and mutagenicity. Our recent study demonstrated that about 94% of the 48 EDCs classified by Centers for Disease Control and Prevention (CDC) generated free radicals and that this free radical generation induced by EDCs might represent a common toxic mechanism of action of EDCs. The chemoprevention of endocrine-disrupting effects, such as employed in the control of caner by interfering with common toxic mechanisms of action of EDCs, represents a promising approach to this problem. In this context, it is proposed that EDCs may produce endocrine-disrupting effects including carcinogenicity via the generation of free radicals, and thus the effects may be modulated or prevented by scavenging free radicals with antioxidants, such as vitamins, curcumin, isoflavonoids, resveratrol, and plant polysaccharides. Here, an alternative mode of action of EDCs and their possible chemoprevention are proposed.

Safety Evaluation of GX-12, a New HIV Therapeutic Vaccine: Investigation of Integration into the Host Genome and Expression in the Reproductive Organs

AIDS is one of the greatest infectious disease threats to human health despite the extensive efforts made since the discovery of HIV in 1983. The use of plasmid DNA vaccination to elicit humoral and cell-mediated immune responses against HIV infection has produced promising results in animal and in human trials. However, there are several safety concerns about the use of a DNA vaccine, which include the possibility of integration into the host genome, adverse immunopathology, and anti-DNA autoantibody induction. In this study, we examined the potential integration and distribution of GX-12, a new therapeutic vaccine for HIV infection, at various times in muscles and reproductive organs of rats. Animals of both sexes were injected with GX-12 at the dose of 400 µg/animal i.m. once a week for 4 weeks, and host genome integration and tissue distribution were examined on day 1, 5, 15, 30 and 45 days after the final injection. A PCR-based assay revealed that GX-12 was not integrated into the host genome, nor expressed in reproductive organs at any time. These findings suggest that the risk of mutation or germline transmission due to GX-12 injection is negligible.

Risk Assessment of Volatile Organic Compounds Benzene, Toluene, Ethylbenzene, and Xylene (BTEX) in Consumer Products

Exposure and risk assessment was performed by evaluating levels of volatile organic compounds (VOC) benzene, toluene, ethylbenzene, and xylene (BTEX) in 207 consumer products. The products were categorized into 30 different items, consisting of products of different brands. Samples were analyzed for BTEX by headspace-gas chromatography/mass spectrometry (headspace-GC/MS) with limit of detection (LOD) of 1 ppm. BTEX were detected in 59 consumer products from 18 item types. Benzene was detected in whiteout (ranging from not detected [ND] to 3170 ppm), glue (1486 ppm), oil-based ballpoint pens (47 ppm), and permanent (marking) pens (2 ppm). Toluene was detected in a leather cleaning product (6071 ppm), glue (5078 ppm), whiteout (1130 ppm), self-adhesive wallpaper (15–1012 ppm), shoe polish (806 ppm), permanent pen (609 ppm), wig adhesive (372 ppm), tapes (2–360 ppm), oil-based ballpoint pen (201 ppm), duplex wallpaper (12–52 ppm), shoes (27 ppm), and air freshener (13 ppm). High levels of ethylbenzene were detected in permanent pen (ND–345,065 ppm), shoe polish (ND–277,928 ppm), leather cleaner (42,223 ppm), whiteout (ND–2,770 ppm), and glue (ND–792 ppm). Xylene was detected in permanent pen (ND–285,132 ppm), shoe polish (ND–87,298 ppm), leather cleaner (12,266 ppm), glue (ND–3,124 ppm), and whiteout (ND–1,400 ppm). Exposure assessment showed that the exposure to ethylbenzene from permanent pens ranged from 0 to 3.11 mg/kg/d (men) and 0 to 3.75 mg/kg/d (women), while for xylene, the exposure ranges were 0–2.57 mg/kg/d and 0–3.1 mg/kg/d in men and women, respectively. The exposure of women to benzene from whiteout ranged from 0 to 0.00059 mg/kg/d. Hazard index (HI), defined as a ratio of exposure to reference dose (RfD), for ethylbenzene was 31.1 (3.11 mg/kg/d/0.1 mg/kg/d) and for xylene (2.57 mg/kg/d/0.2 mg/kg/d) was 12.85, exceeding 1 for both compounds. Cancer risk for benzene was calculated to be 3.2 × 10−5 based on (0.00059 mg/kg/d × 0.055 mg/kg-d−1, cancer potency factor), assuming that 100% of detected levels in some products such as permanent pens and whiteouts were exposed in a worst-case scenario. These data suggest that exposure to VOC via some consumer products exceeded the safe limits and needs to be reduced.

5,7-Dihydroxy-3,4,6-trimethoxyflavone inhibits intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 via the Akt and nuclear factor-κB-dependent pathway, leading to suppression of adhesion of monocytes and eosinophils to bronchial epithelial cells

5,7‐Dihydroxy‐3′,4′,6′‐trimethoxyflavone (eupatilin), the active pharmacological ingredient from Artemisia asiatica Nakai (Asteraceae), is reported to have a variety of anti‐inflammatory properties in intestinal epithelial cells. However, little information is known about the molecular mechanism of eupatilin‐induced attenuation of bronchial epithelial inflammation. This study investigates the role of eupatilin in the adhesion of inflammatory cells such as monocytes and eosinophils to bronchial epithelial cells. Stimulation of a human bronchial epithelial cell line (BEAS‐2B) with tumour necrosis factor‐α (TNF‐α) increased the expression of surface adhesion molecules, including intercellular adhesion molecule 1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1), in which eupatilin significantly inhibited the expression of those adhesion molecules in a dose‐dependent manner. Eupatilin suppressed the TNF‐α‐induced activation of IκBα and nuclear factor‐κB (NF‐κB) signals in BEAS‐2B cells. The IκB kinase (IKK) activation was also significantly reduced in eupatilin‐pre‐treated BEAS‐2B and primary normal human bronchial epithelial (NHBE) cells. However, eupatilin did not influence AP‐1 activity in TNF‐α‐stimulated cells. Suppression of NF‐κB signalling induced by eupatilin resulted in the inhibition of the expression of adhesion molecules and the adhesion of monocytes and eosinophils to BEAS‐2B cells. Furthermore, eupatilin suppressed the phosphorylation of Akt in TNF‐α‐stimulated BEAS‐2B and NHBE cells, leading to down‐regulation of NF‐κB activation and adhesion molecule expression and finally to suppression of the inflammatory cell adhesion to epithelial cells. These results suggest that eupatilin can inhibit the adhesion of inflammatory cells to bronchial epithelial cells via a signalling pathway, including activation of Akt and NF‐κB, as well as expression of adhesion molecules.

DA6034 promotes gastric epithelial cell migration and wound-healing through the mTOR pathway

Background and Aim:  7‐Carboxymethyloxy‐3′,4′,5‐trimethoxy flavone (DA6034), a synthetic derivative of eupatilin, has a protective effect on gastric mucosa against various ulcerogens, and is currently in the phase III clinical trial in the treatment of peptic ulcer disease. Cell migration and/or growth plays a role in the repair process of gastric ulcer, so this study investigated the effect of DA6034 on the movement and proliferation of gastric epithelial cells and its associated signaling pathway.

Comparative safety evaluation of selective androgen receptor modulators and anabolic androgenic steroids.

Introduction: Anabolic androgenic steroids (AASs) have been in use for decades for the treatment of short stature, severe burns, HIV wasting syndrome, osteoporosis, and anemia. However, their lack of selective effects on certain symptoms and unfavorable pharmacokinetic properties has limited their long-term usage in clinics. Areas covered: Selective androgen receptor modulators (SARMs) have some advantages over AASs; they are highly specific for androgen receptors, are orally available, and, most importantly, act as strong receptor agonists in skeletal muscle and bone, and as weak agonists or antagonists in androgen-responsive tissues such as the prostate and sebaceous glands. The exact molecular mechanism, however, has not been fully elucidated. This article includes a toxicological review of major AASs, and a comparative safety analysis of major AASs and SARMs in clinical trials to evaluate the therapeutic potential of SARMs. Expert opinion: Based on the robust tissue selectivity of SARMs over AASs, they are worth considering as a promising therapeutic option for the treatment of various muscle-wasting diseases.

Risk assessment of zinc oxide, a cosmetic ingredient used as a UV filter of sunscreens

ABSTRACT Zinc oxide (ZnO), an inorganic compound that appears as a white powder, is used frequently as an ingredient in sunscreens. The aim of this review was to examine the toxicology and risk assessment of ZnO based upon available published data. Recent studies on acute, sub-acute, and chronic toxicities of ZnO indicated that this compound is virtually non-toxic in animal models. However, it was reported that ZnO nanoparticles (NP) (particle size, 40 nm) induced significant changes in anemia-related hematologic parameters and mild to moderate pancreatitis in male and female Sprague-Dawley rats at 536.8 mg/kg/day in a 13-week oral toxicity study. ZnO displayed no carcinogenic potential, and skin penetration is low. No-observed-adverse-effect level (NOAEL) ZnO was determined to be 268.4 mg/kg/day in a 13-week oral toxicity study, and a maximum systemic exposure dose (SED) of ZnO was estimated to be 0.6 mg/kg/day based on topical application of sunscreen containing ZnO. Subsequently, the lowest margin of safety (MOS) was estimated to be 448.2, which indicates that the use of ZnO in sunscreen is safe. A risk assessment was undertaken considering other routes of exposure (inhalation or oral) and major product types (cream, lotion, spray, and propellant). Human data revealed that MOS values (7.37 for skin exposure from cream and lotion type; 8.64 for skin exposure of spray type; 12.87 for inhalation exposure of propellant type; 3.32 for oral exposure of sunscreen) are all within the safe range (MOS > 1). Risk assessment of ZnO indicates that this compound may be used safely in cosmetic products within the current regulatory limits of 25% in Korea.

Potential metabolomic biomarkers for evaluation of adriamycin efficacy using a urinary 1H-NMR spectroscopy.

A metabolomics approach using proton nuclear magnetic resonance (NMR) was applied to investigate metabolic alterations following adriamycin (ADR) treatment for gastric adenocarcinoma. After BALB/c‐nu/nu mice were implanted with human gastric adenocarcinoma, ADR (1 or 3 mg kg−1 per day) was intraperitoneally administered for 5 days. Urine was collected on days 2 and 5 and analyzed by NMR. The levels of trimethylamine oxide (TMAO, ×0.3), hippurate (×0.3) and taurine (×0.6) decreased significantly (P < 0.05), whereas the levels of 3‐indoxylsulfate (×12.6), trigonelline (×1.5), citrate (×2.5), trimethylamine (TMA, ×2.0) and 2‐oxoglutarate (×2.3) increased significantly (P < 0.05) in the tumor model. After ADR treatment, TMAO, hippuarte and taurine were increased significantly on day 5 compared with those of the tumor model. The levels of 2‐oxoglutarate, 3‐indoxylsulfate, trigonelline, TMA and citrate, which increased in the tumor model, significantly decreased to those of normal control by ADR treatment. Furthermore, the ratio between TMA and TMAO was dramatically altered in both tumor and ADR‐treated groups. Overall, metabolites such as TMAO, TMA, 3‐indoxylsulfate, hippurate, trigonelline, citrate and 2‐oxoglutarate related to the tricarboxylic acid (TCA) cycle might be considered as therapeutic targets to potentiate the efficacy of ADR. Thus, these results suggest that the metabolomics analysis of tumor response to ADR treatment may be applicable for demonstrating the efficacy of anticancer agent, ADR and treatment adaptation. Copyright