• Toxicological Research
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• 제35권4호
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• pp.319-330
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• 2019

Adverse drug reactions (ADRs) constitute key factors in determining successful medication therapy in clinical situations. Integrative analysis of electronic medical record (EMR) data and use of proper analytical tools are requisite to conduct retrospective surveillance of clinical decisions on medications. Thus, we suggest that electronic medical recording and human genetic databases are considered together in future directions of pharmacovigilance. We analyzed EMR-based ADR studies indexed on PubMed during the period from 2005 to 2017 and retrospectively acquired 1161 (29.6%) articles describing drug-induced adverse reactions (e.g., liver, kidney, nervous system, immune system, and inflammatory responses). Of them, only 102 (8.79%) articles contained useful information to detect or predict ADRs in the context of clinical medication alerts. Since insufficiency of EMR datasets and their improper analyses may provide false warnings on clinical decision, efforts should be made to overcome possible problems on data-mining, analysis, statistics, and standardization. Thus, we address the characteristics and limitations on retrospective EMR database studies in hospital settings. Since gene expression and genetic variations among individuals impact ADRs, pharmacokinetics, and pharmacodynamics, appropriate paths for pharmacovigilance may be optimized using suitable databases available in public domain (e.g., genome-wide association studies (GWAS), non-coding RNAs, microRNAs, proteomics, and genetic variations), novel targets, and biomarkers. These efforts with new validated biomarker analyses would be of help to repurpose clinical and translational research infrastructure and ultimately future personalized therapy considering ADRs.

• Safety and Health at Work
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• 제10권1호
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• pp.114-121
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• 2019

Background: The photolithography process in the semiconductor industry uses various chemicals with little information on their constitution. This study aimed to identify the chemical constituents of photoresist (PR) products and their by-products and to compare these constituents with material safety data sheets (MSDSs) and analytical results. Methods: A total of 51 PRs with 48 MSDSs were collected. Analysis consisted of two parts: First, the constituents of the chemical products were identified and analyzed using MSDS data; second, for verification of the by-products of PR, volatile organic compounds were analyzed. The chemical constituents were categorized according to hazards. Results: Forty-five of 48 products contained trade secrets in amounts ranging from 1 to 65%. A total of 238 ingredients with multiple counting (35 ingredients without multiple counting) were identified in the MSDS data, and 48.7% of ingredients were labeled as trade secrets under the Korea Occupational Safety and Health Act. The concordance rate between the MSDS data and the analytical result was 41.7%. The by-product analysis identified 129 chemicals classified according to Chemical Abstracts Service No., with 17 chemicals that are carcinogenic, mutagenic, and reprotoxic substances. Formaldehyde was found to be released from 12 of 21 products that use novolak resin. Conclusion: We confirmed that several PRs contain carcinogens, and some were not specified in the toxicological information in the MSDS. Hazardous chemicals, including benzene and formaldehyde, are released from PRs products as by-products. Therefore, it is necessary to establish a systematic management system for chemical compounds and the working environment.

• 한국산업보건학회지
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• 제10권1호
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• pp.147-159
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• 2000

The NIOSH health hazard evaluation program (HHE program) was created in response to the mandate to determine the toxic effect and potential health hazard of workplace exposure, which is found in Occupational Safety and Health Act of 1970 and the Federal Mine Safety and Health Act of 1977, A primary benefit of HHE program is its ability to provide current health hazard data to employers and employees, which assists them in identifying solutions to occupational health and safety problems in their workplaces, The HHE program also stimulates research in the development and review of sampling methods and diagnostic tests and may prompt additional exposure assesment efforts and toxicological and epidemiological studies. HHE projects also provide human exposure-toxicity data that are used to asses the validity of existing occupational health standards and to support criteria for new standards of recommendation, The HHE request is classified into four categories: 1) category 1: As a administratively invalid, 2) category 2: These are valid requests for which a site visit is not essential to an appropriate response, 3) Category 3 : These are valid requests for which a site visit is necessary for an adequate evaluation, 4) These are valid request which present a complex problem or an opportunity for research, To carry out HHE program one or methods of investigation might be used: 1) direct observation and evaluation of production processes and employee work practices 2) employees exposure level and air contamination level 3) medical test or physical examinations of employees 4) private, confidential interviews with employees 5) review of employer's record of injuries and illness, employee exposure data, medical tests and job histories. After investigation and analysing the data, NIOSH issues a final report, giving finding and recommendation.

• Toxicological Research
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• 제26권3호
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• pp.203-208
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• 2010

Bronchoalveolar lavage (BAL) is a useful tool in researches and in clinical medicine of lung diseases because the BAL fluid contains biochemical and cytological indicators of the cellular response to infection, drugs, or toxicants. However, the variability among laboratories regarding the technique and the processing of the BAL material limits clinical research. The aim of this study was to determine the suction frequency and lavage fraction number necessary to reduce the variability in lavage using male Sprague-Dawley rats. We compared the total cell number and protein level of each lavage fraction and concluded that more cells and protein can be obtained by repetitive lavage with a suction frequency of 2 or 3 than by lavage with a single suction. On the basis of total cell recovery, approximately 70% of cells were obtained from fractions 1~3. The first lavage fraction should be used for evaluation of protein concentration because fractions 2~5 of lavage fluid were diluted in manifolds. These observations were confirmed in bleomycin-induced inflamed lungs of rats. We further compared the BAL data from the whole lobes with data from the right lobes and concluded that BAL data of the right lobes represented data of the whole lobes. However, this conclusion can only be applied to general lung diseases. At the end, this study provides an insight into the technical or analytical problems of lavage study in vivo.

• Environmental Analysis Health and Toxicology
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• 제30권sup호
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• pp.7.1-7.10
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• 2015

Objectives For successful adoption of legislation controlling registration and assessment of chemical substances, it is important to obtain sufficient toxicological experimental evidence and other related information. It is also essential to obtain a sufficient number of predicted risk and toxicity results. Particularly, methods used in predicting toxicities of chemical substances during acquisition of required data, ultimately become an economic method for future dealings with new substances. Although the need for such methods is gradually increasing, the-required information about reliability and applicability range has not been systematically provided. Methods There are various representative environmental and human toxicity models based on quantitative structure-activity relationships (QSAR). Here, we secured the 10 representative QSAR-based prediction models and its information that can make predictions about substances that are expected to be regulated. We used models that predict and confirm usability of the information expected to be collected and submitted according to the legislation. After collecting and evaluating each predictive model and relevant data, we prepared methods quantifying the scientific validity and reliability, which are essential conditions for using predictive models. Results We calculated predicted values for the models. Furthermore, we deduced and compared adequacies of the models using the Alternative non-testing method assessed for Registration, Evaluation, Authorization, and Restriction of Chemicals Substances scoring system, and deduced the applicability domains for each model. Additionally, we calculated and compared inclusion rates of substances expected to be regulated, to confirm the applicability. Conclusions We evaluated and compared the data, adequacy, and applicability of our selected QSAR-based toxicity prediction models, and included them in a database. Based on this data, we aimed to construct a system that can be used with predicted toxicity results. Furthermore, by presenting the suitability of individual predicted results, we aimed to provide a foundation that could be used in actual assessments and regulations.

• Biomolecules & Therapeutics
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• 제25권6호
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• pp.648-658
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• 2017

7-O-Succinyl macrolactin A (SMA) exerts several pharmacological effects including anti-bacterial, anti-inflammation, and anti-cancer activities. Recently, SMA has been extensively evaluated as an anti-cancer drug. Thus, the objectives of the present study were to characterise the pharmacokinetics of SMA via both non-compartmental and compartmental analysis in mice, rats, and dogs, and to derive an appropriate first-in-man dose based on allometric scaling of the animal data. The time courses of plasma SMA concentrations after intravenous administration to rats and dogs were analysed retrospectively, as were data collected after intraperitoneal SMA injection in mice. Pharmacokinetic parameters were estimated via both noncompartmental and compartmental analysis, and were correlated with body weight and/or the potential maximum life-span. The clearance and distribution volume of SMA in humans were predicted, and a first-in-man dose proposed. A two-compartment model best described the time courses of SMA plasma concentrations after a saturation elimination process was applied to fit the dataset obtained from rats. Incorporation of the maximum potential life-span during allometric scaling was required to improve the estimation of human clearance. The SMA clearance and the distribution volume in the steady state, in a 70-kg adult male, were estimated to be 30.6 L/h and 19.5 L, respectively. To meet the area under the curve (AUC) required for anti-tumour activity, a dose of 100 mg (~1.5 mg/kg) was finally proposed as the first dose for a 70-kg human. Although toxicological profiles derived from non-clinical studies must be considered before any final decision is made, our work will facilitate clinical studies on SMA.

• Safety and Health at Work
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• 제11권2호
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• pp.235-240
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• 2020

Background: Cadmium exposure may induce chronic intoxication with renal damage. Silver soldering may be a source of cadmium exposure. Methods: We analyzed working environment measurement data and periodic health screening data from a small-scale silver soldering company with ten workers. Concentrations of cadmium in air from working environment measurement data were obtained. Concentrations of blood and urinary cadmium, urine protein, and urine β2-microglobulin (β2M) were obtained. The generalized linear model was used to identify the association between blood and urine cadmium and urine β2M concentrations. Clinical features of chronic cadmium intoxication focused with toxicological renal effects were described. Results: The mean duration of work was 8.5 years (standard deviation [SD] = 6.9, range = 3-20 years). Cadmium concentrations in air were ranged from 0.006 to 0.015 mg/㎥. Blood cadmium concentration was elevated in all ten workers, with a highest level of 34.6 ㎍/L (mean = 21.288 ㎍/L, SD = 11.304, range = 9.641-34.630 ㎍/L). Urinary cadmium concentration was elevated in nine workers, with a highest level of 62.9 ㎍/g Cr (mean = 22.151 ㎍/g creatinine, SD = 19.889, range = 3.228-62.971 ㎍/g creatinine). Urine β2M concentration was elevated in three workers. Urinary cadmium concentration was positively associated with urine protein concentration (beta coefficient = 10.27, 95% confidence interval = [4.36, 16.18]). Other clinical parameters were compatible with renal tubular damage. Conclusion: Cadmium intoxication may occur at quite low air concentrations. Exposure limit may be needed to be lowered.

• Toxicological Research
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• 제18권1호
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• pp.99-106
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• 2002

The United States Environmental Protection Agency (EPA) characterized the cancer hazard of di(2-ethylhexyl)-phthalate (DEHP) as a B2 group (probable human carcinogen) and proposed "Guide-lines for Carcinogen Risk Assessment". This guidelines proposed alternative methods for analyzing carcinogen dose-response data and for extrapolating the effects of observed at high dose to predict that might occur at lower doses relevant to human exposure. This proposed guidelines state that "If in a particular case, the evidence indicated a threshold, as in the case of carcinogenicity being secondary to another toxicity that has a threshold, the margin of exposure analysis for toxicity is the same as is done for a non-cancer endpoint". DEHP is excellent candidate for reconideration under the new guidelines for carcinogen risk assessment (John Doull et al., 1998). This study is conducted about risk assessment for infant exposure on DEHP in powdered milk wing methodology in EPA's new guideline on carcinogenic risk assessment. Estimated cancer risk of DEHP in powdered milk and cow milk is 2.83$\times$$10^5$ (using cancer potency: 1.4$\times$$10^2$/ (mg/kg/day)) as mean and MOE is 12075 (using selected NOEL 20 mg/kg/day) as mean. mg/kg/day) as mean.

• Toxicological Research
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• 제13권1_2호
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• pp.103-110
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• 1997

This study was performed to investigate the effects of cadmium chloride on the acute and chronic toxicity on rats. Several toxic effects of cadmium has been shown following short-term and longterm pretreatment with cadmium and zinc. Four groups of rats (A, B, C, D), each consisting of 16 rats, were studied and each group was divided into four subgroups (1, 2, 3, 4), 4 rats for each subgroup. Rats were subcutaneously pretreated with $CdCl_2$ (0.5 mg/kg, A & C), and $ZnCl_2$ (13.0 mg/kg, B & D) during time periods of 1 weeks (group A & B) and 6 weeks (group C & D). At the end of the period, rats were challenged with $CdCl_2$ (3.0, 6.0 and 9.0 mg/kg, i.p.). After giving the challenge dose, cadmium and metallothionein(MT) concentrations were determined. The concentrations of cadmium were higher in the liver than the kidney irrelevantly to cadmium and zinc pretreatment and increased dose-dependently to the challenge dosage. The metallothioneins showed higher concentrations in the liver than the kidney following cadmium pretreatment and were higher in the long-term pretreatment groups than the short-term pretreatment groups in the liver and the kidney of rats. These data suggest that metallothioneins are induced preferentially in the liver by pretreatment of cadmium and then, formed in the form of Cd-MT, may play an important role in the nephrotoxicity.

• Toxicological Research
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• 제13권1_2호
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• pp.71-78
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• 1997

The mutational effects of pentachlorophenol (PCP) on the hypoxanthine phosphoribosyl transf erase (hprt) locus in human T-cell were analysed by T-cell clonal assay in vitro. Cells were exposed for 24 hours at primary culture to 0~100 ppm (W/V) PCP in dimethyl sulfoxide. Treated cells were allowed at the same time to stimulate by phytohemagglutinin (PHA) and T-cell growth factor (TCGF) and then seeded in medium containing 6-thioguanine to select for hprt-negative routants. We have also defined the optimal condition for the determination of mutant frequency. The parameters investigated include survival counting, first and second subculture for clonal efficiency plating and mutant plating. Under the optimal conditions, mutant frequencies of high dose-treated cells were significantly higher than those of non-treated or low dose cells. The results indicated a clear dose-effect relationship and showed that mutant frequency in 50 ppm PCP treated cell was 4.31$\times$$10^{-5}$ (background, 8.32$\times$$10^{-6}$). Above data strongly suggest that hprt mutation assay can be used as a biomarker for the environmental risk assessment.