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A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Novel Methods in Toxicology Research".

Deadline for manuscript submissions: closed (28 February 2024) | Viewed by 11128

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Prof. Dr. Kyu-Bong Kim

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Guest Editor

College of Pharmacy, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
Interests: toxicometabolomics; toxicokinetics; risk assessment; drugs

Special Issue Information

Dear Colleagues,

The importance of applying toxicokinetic information for toxicity testing and chemical safety assessment has been increasing. In this Special Issue, we would like to invite manuscripts describing not only the toxicokinetics and toxicodynamics of chemicals for safety assessment but also research that contributes to such investigations.

The specific scope of this Special Issue includes but is not limited to:

Analytical methods of toxic chemicals;
In vitro, ex vivo, and/or in vivo research that contributes to characterize toxicokinetics and toxicodynamics for safety assessment;
Modeling approaches, including to predict human toxicokinetics and toxicodynamics;
New toxicokinetic/toxicodynamic experimental methodology or modeling approaches that contribute to a future safety assessment.

The Special Issue will give insight into the toxicokinetics and toxicodynamics that identify chemicals in consumer products, and it is expected to stimulate discussion on the way forward in developing new risk assessment strategies for capturing complex target system toxicity.

Prof. Dr. Kyu-Bong Kim
Guest Editor

Manuscript Submission Information

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Keywords

toxicokinetics
chemicals
metabolism
safety assessment

Published Papers (7 papers)

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Research

10 pages, 1611 KiB

Open AccessArticle

Analytical Method Development and Dermal Absorption of 4-Amino-3-Nitrophenol (4A3NP), a Hair Dye Ingredient under the Oxidative or Non-Oxidative Condition

by Hyang Yeon Kim, Yu Jin Kim, Jung Dae Lee, Hak Rim Kim and Dong-Wan Seo

Toxics 2024, 12(5), 340; https://doi.org/10.3390/toxics12050340 - 7 May 2024

Viewed by 213

Abstract

The chemical 4-amino-3-nitrophenol (4A3NP) is classified as an amino nitrophenol and is primarily utilized as an ingredient in hair dye colorants. In Korea and Europe, it is exclusively used in non-oxidative or oxidative hair dye formulations, with maximum allowable concentrations of 1% and 1.5%, respectively. Despite this widespread use, risk assessment of 4A3NP has not been completed due to the lack of proper dermal absorption data. Therefore, in this study, both the analytical method validation and in vitro dermal absorption study of 4A3NP were conducted following the guidelines provided by the Korea Ministry of Food and Drug Safety (MFDS). Before proceeding with the dermal absorption study, analytical methods were developed for the quantitation of 4A3NP through multiple reaction monitoring (MRM) via liquid chromatography-mass spectrometry (LC-MS) in various matrices, including swab wash (WASH), stratum corneum (SC), skin (SKIN, comprising the dermis and epidermis), and receptor fluid (RF). These developed methods demonstrated excellent linearity (R² = 0.9962–0.9993), accuracy (93.5–111.73%), and precision (1.7–14.46%) in accordance with the validation guidelines.The dermal absorption of 4A3NP was determined using Franz diffusion cells with mini-pig skin as the barrier. Under both non-oxidative and oxidative (6% hydrogen peroxide (H₂O₂): water, 1:1) hair dye conditions, 1% and 1.5% concentrations of 4A3NP were applied to the skin at a rate of 10 μL/cm², respectively. The total dermal absorption rates of 4A3NP under non-oxidative (1%) and oxidative (1.5%) conditions were determined to be 5.62 ± 2.19% (5.62 ± 2.19 μg/cm²) and 2.83 ± 1.48% (4.24 ± 2.21 μg/cm²), respectively. Full article

(This article belongs to the Special Issue Toxicokinetics of Chemicals in Consumer Products)

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12 pages, 1251 KiB

Open AccessArticle

Development of an LC–MS/MS Assay and Toxicokinetic Characterization of Hexamethylenetetramine in Rats

by Woojin Kim, Eunbin Kim, Jaewoong Lee, Chang Ho Song, Woohyung Jung, Soyoung Shin, Kyu-Bong Kim, Beom Soo Shin and Tae Hwan Kim

Toxics 2023, 11(4), 337; https://doi.org/10.3390/toxics11040337 - 31 Mar 2023

Viewed by 1380

Abstract

Hexamethylenetetramine, an aldehyde-releasing agent, is used as a preservative in various food, cosmetics, and medical treatments, such as a treatment for urinary tract infections. It has been reported to be allergenic on contact with the skin, with the additional possibility of causing toxicity once absorbed systemically. Despite its potential toxicity, there are no reports on the in vivo bioavailability of hexamethylenetetramine following oral or dermal administration. In this study, we developed a new simple and sensitive LC–MS/MS method for the determination of hexamethylenetetramine in plasma and applied this method to characterize the toxicokinetics. The developed assay had a sufficient specificity and sensitivity for toxicokinetic characterization, and its accuracy and precision were verified. Following iv injection, the plasma concentration of hexamethylenetetramine showed mono exponential decay, with an elimination half-life of about 1.3 h. Following oral administration, the T_max reached an average of 0.47 h and bioavailability was estimated as 89.93%. After percutaneous administration, it reached C_max on average at 2.9–3.6 h. Although the absorption rate was relatively slow, its average bioavailability was calculated as 77.19–78.91%. Overall, most of the orally and percutaneously administered hexamethylenetetramine was absorbed into systemic circulation. The derived results in this study are expected to be utilized as the scientific evidence for further toxicokinetic study and risk assessment. Full article

(This article belongs to the Special Issue Toxicokinetics of Chemicals in Consumer Products)

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10 pages, 1032 KiB

Open AccessArticle

Negligible Toxicokinetic Differences of Glyphosate by Different Vehicles in Rats

by Yu-Jin Kim, Nitin Nitin and Kyu-Bong Kim

Toxics 2023, 11(1), 67; https://doi.org/10.3390/toxics11010067 - 11 Jan 2023

Cited by 1 | Viewed by 1508

Abstract

Glyphosate is a non-selective herbicide. Although glyphosate is not acutely toxic, the intake of glyphosate-based herbicides has caused many accidents. Some studies have suggested that surfactants might be the cause. The purpose of this study was to compare the toxicokinetic (TK) properties of glyphosate according to different vehicles in rats. Glyphosate (1%) was dissolved in distilled water (DW), polyoxyethylene tallow amine (POEA), and Tween 20. After a single oral treatment of glyphosate (50 mg/kg), blood was collected at time intervals, and glyphosate concentrations in the target organ (liver and kidney) were determined 24 h after final blood collection. All samples were analyzed using LC-MS/MS. The TK parameters of glyphosate were similar in the DW and Tween 20 groups. However, there were significant differences in T_max and volume of distribution (V_d) between the DW and POEA group (p < 0.05). Glyphosate was absorbed about 10 times faster in POEA group rather than DW, and exhibited a higher distribution. However, other important TK parameters of T_1/2, AUC, and C_max were not statistically different among the different vehicle groups. Although glyphosate concentration in the liver was significantly higher in the POEA group than in the DW group, there was no significant difference in the kidney. These results indicate that the toxicokinetics of glyphosate are not significantly affected by POEA. It can be concluded that POEA toxicity itself can be attributed to the acute toxicity of glyphosate-containing products. Full article

(This article belongs to the Special Issue Toxicokinetics of Chemicals in Consumer Products)

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9 pages, 630 KiB

Open AccessArticle

Toxicokinetics, Percutaneous Absorption and Tissue Distribution of Benzophenone-3, an UV Filtering Agent, in Rats

by Woohyung Jung, Su Hyun Seok, Soyoung Shin, Sung Ha Ryu, Kyu-Bong Kim, Beom Soo Shin and Tae Hwan Kim

Toxics 2022, 10(11), 672; https://doi.org/10.3390/toxics10110672 - 7 Nov 2022

Cited by 1 | Viewed by 1474

Abstract

The aim of this study was to evaluate in vitro skin permeation and deposition, in vivo toxicokinetics, percutaneous absorption and tissue distribution of benzophenone-3 (BP-3) in rats. Four transdermal formulations containing BP-3 were prepared and evaluated for in vitro skin permeation and deposition of BP-3 using Franz diffusion cells. A gel formulation was used in subsequent in vivo percutaneous absorption due to its high in vitro skin permeation and deposition. Compared to intravenous (i.v.) injection, the prolonged terminal t_1/2 (3.1 ± 1.6 h for i.v. injection and 18.3 ± 5.8 h for topical application) was observed indicating occurrence of flip-flop kinetics after topical application. The bioavailability of BP-3 after topical application was 6.9 ± 1.8%. The tissue-to-plasma partition coefficient (kp) for testis, considered a toxic target for BP-3, was less than 1. Overall, findings of this study may be useful for risk assessment of BP-3. Full article

(This article belongs to the Special Issue Toxicokinetics of Chemicals in Consumer Products)

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18 pages, 2171 KiB

Open AccessArticle

Simultaneous Analysis of a Combination of Anti-Hypertensive Drugs, Fimasartan, Amlodipine, and Hydrochlorothiazide, in Rats Using LC-MS/MS and Subsequent Application to Pharmacokinetic Drug Interaction with Red Ginseng Extract

by So-Yeon Jeon, Ji-Hyeon Jeon, Jin-Hyang Park, Jihoon Lee, Minyeong Pang, Min-Koo Choi and Im-Sook Song

Toxics 2022, 10(10), 576; https://doi.org/10.3390/toxics10100576 - 30 Sep 2022

Viewed by 2083

Abstract

Fimasartan, amlodipine, and hydrochlorothiazide are commonly used in combination therapies as antihypertensive drugs. This study aimed to develop and validate an analytical method for fimasartan, its active and major metabolite fimasartan-amide, amlodipine, and hydrochlorothiazide in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The standard calibration curves for fimasartan (1–500 ng/mL), its active and major metabolite fimasartan-amide (0.3–100 ng/mL), amlodipine (0.5–200 ng/mL), and hydrochlorothiazide (5–5000 ng/mL) were linear with R² > 0.9964, and the inter- and intra-day accuracy and precision and stability were within the acceptable criteria. Using this validated analytical method, the pharmacokinetic interaction of these triple combination drugs between single administration and concomitant administration of the triple combination was investigated; the results did not reveal a significant difference in any of the pharmacokinetic parameters. Based on these results, we investigated the effects of red ginseng extract (RGE) on the pharmacokinetics of fimasartan, fimasartan-amide, amlodipine, and hydrochlorothiazide after oral administration of the combination in rats. No significant difference was observed in the pharmacokinetic parameters of fimasartan, fimasartan-amide, amlodipine, and hydrochlorothiazide, except for the T_max values of amlodipine. The delayed T_max value of amlodipine was attributed to its decreased intestinal permeability after repeated RGE treatments. In conclusion, using a combination of antihypertensive drugs and simultaneous analytical methods, we established efficient drug interaction and toxicokinetic studies using a small number of animals. Full article

(This article belongs to the Special Issue Toxicokinetics of Chemicals in Consumer Products)

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8 pages, 2115 KiB

Open AccessArticle

Analytical Method Development and Dermal Absorption of Pyrogallol, a Hair Dye Ingredient

by Yu-Jin Kim, Hyang-Yeon Kim, Jung-Dae Lee, Hong-Yoon Kim, Jueng-Eun Im and Kyu-Bong Kim

Toxics 2022, 10(10), 570; https://doi.org/10.3390/toxics10100570 - 29 Sep 2022

Cited by 1 | Viewed by 1631

Abstract

Pyrogallol is an ingredient in hair dye. Its concentration in hair dye is managed at less than 2.0% in Korea. There have been no reports on the dermal absorption rate of pyrogallol. The two purposes of this study were to develop an analytical method and determine the dermal absorption rate of pyrogallol. An analytical method was developed and validated by high-performance liquid chromatography (HPLC) analysis of various matrices including swabs (SWAB), skin (SKIN, dermis + epidermis), stratum corneum (SC), and receptor fluid (RF). Linearity (r² = 0.9993–0.9998), accuracy (92.1–108.2%), and precision (0.5–9.5%) met the validation criteria in guidelines. A Franz diffusion cell was used to determine the dermal absorption of pyrogallol using the skin of mini pigs. Pyrogallol (2.0%) was applied to the skin (10 μL/cm²). For the actual hair dye conditions, the skin was wiped with a swab 30 min after application. Twenty-four hours later, it was wiped with a swab again and the SC was collected using tape stripping. All samples were extracted with water and analyzed. RF was recovered at 0, 1, 2, 4, 8, 12, and 24 h. The total dermal absorption rate of pyrogallol was determined to be 26.0 ± 3.9%. Full article

(This article belongs to the Special Issue Toxicokinetics of Chemicals in Consumer Products)

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12 pages, 977 KiB

Open AccessArticle

Pharmacokinetics and the Dermal Absorption of Bromochlorophene, a Cosmetic Preservative Ingredient, in Rats

by Yong-Jae Lee, Hyang-Yeon Kim, Quynh-Lien Pham, Jung-Dae Lee and Kyu-Bong Kim

Toxics 2022, 10(6), 329; https://doi.org/10.3390/toxics10060329 - 16 Jun 2022

Cited by 4 | Viewed by 2107

Abstract

The cosmetic industry has flourished in recent years. Accordingly, the safety of cosmetic ingredients is increasing. Bromochlorophene (BCP) is a commonly used cosmetic preservative. To evaluate the effects of BCP exposure, in vitro dermal absorption and in vivo pharmacokinetic (PK) studies were conducted using gel and cream formulations. The Franz diffusion cell system and rat dorsal skin were used for tests according to the Korea Ministry of Food and Drug Safety guidelines for in vitro skin absorption methods. After the dermal application (1.13 mg/cm²) of BCP in the gel and cream formulations, liquid chromatography–mass spectrometry (LC–MS/MS) was used to evaluate the amount of BCP that remained unabsorbed on the skin (WASH), and that was present in the receptor fluid (RF), stratum corneum (SC), and (epi)dermis (SKIN). The total dermal absorption rate of BCP was 7.42 ± 0.74% for the gel formulation and 1.5 ± 0.9% for the cream formulation. Total recovery in an in vitro dermal absorption study was 109.12 ± 8.79% and 105.43 ± 11.07% for the gel and cream formulations, respectively. In vivo PK and dermal absorption studies of BCP were performed following the Organization for Economic Cooperation and Development guidelines 417 and 427, respectively. When intravenous (i.v.) pharmacokinetics was performed, BCP was dissolved in glycerol formal and injected into the tail vein (n = 3) of the rats at doses of 1 and 0.2 mg/kg. Dermal PK parameters were estimated by the application of the gel and cream formulations (2.34 mg/kg of BCP as an active ingredient) to the dorsal skin of the rats. Intravenous and dermal PK parameters were analyzed using a non-compartmental method. The dermal bioavailability of BCP was determined as 12.20 ± 2.63% and 4.65 ± 0.60% for the gel and cream formulations, respectively. The representative dermal absorption of BCP was evaluated to be 12.20 ± 2.63% based on the results of the in vivo PK study. Full article

(This article belongs to the Special Issue Toxicokinetics of Chemicals in Consumer Products)

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