• 대한약침학회지
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• 제22권3호
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• pp.192-199
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• 2019

Objectives: KCHO-1(Mecasin), also called Gamijakyakgamchobuja-tang originally, is a combination of some traditional herbal medicines in East Asia. This medicine has been used mainly for alleviating neuropathic pains for centuries in Korean traditional medicine. KCHO-1 was developed to treat pain, joint contracture and muscular weakness in patients with amyotrophic lateral sclerosis. This study was carried out to investigate the chronic toxicity of KCHO-1 oral administration in rats for 26 weeks. Methods: Sprague-Dawely rats were divided into four groups and 10 rats were placed in the control group and the high-dose group, respectively. Group 1 was the control group and the remaining groups were the experimental groups. In the oral toxicity study, 500 mg/kg, 1,000 mg/kg, and 2,000 mg/kg of KCHO-1 were administered to the experimental group, and 10 ml/kg of sterile distilled water was administered to the control group. Survival rate, body weight, feed intake, clinical signs, and visual findings were examined. Urinalysis, ophthalmologic examination, necropsy, organ weight, hematologic examination, blood chemical examination and histopathologic examination were performed. Results: Mortality and toxicological lesions associated with the administration of test substance were not observed in all groups. Conclusion: NOAEL(No observed adverse effect level) of KCHO-1 is higher than 2000 mg/kg/day. And, the above findings suggest that treatment with KCHO-1 is relatively safe.

• 생명과학회지
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• 제26권10호
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• pp.1153-1162
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• 2016

계종버섯(Thermitomyces albuminosus)의 안정성을 입증하기 위하여 사료에 계종버섯의 분말을 5%, 2.5%, 1.25%, 0%를 혼합하여 90일 동안 랫드에 자유 급이 시켜 실험동물의 일반증상, 체중변화, 혈액학적 검사, 부검소견, 임상병리, 조직병리학적 검사의 결과를 토대로 독성을 평가하였다. 독성판정기준은 독성의 정도와 양상에 따라 weight-based classification (독성 강도에 따른 분류)로 분류 하였는데 비시험물질-유래 변화인 NOEL, 시험물질-유래 경미한 변화는 NOAEL, 시험물질-유래 중요한 변화는 LOAEL을 기준으로 나누었다. 시험결과, 수컷 좌, 우측 신장 중량이 용량의존적으로 증가하여 고용량군에서는 12%, 8% 증가 하였다. 하지만 임상, 조직병리학적 결과 독성으로 판단되는 소견이 관찰되지 않아 시험물질-유래 경미한 변화로 판단으로 분류하였다. 따라서 판정기준에 따라 수컷은 NOAEL 암컷은 NOEL이 식이함량 5%로 추정되지만 식약처고시에 따라 암수 모두 NOAEL이 식이함량의 5%로 추정할 수 있다. 따라서 계종버섯은 식품 또는 기능성식품으로의 개발에 문제가 없을 것으로 사료된다.

• Journal of Dairy Science and Biotechnology
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• 제34권2호
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• pp.99-116
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• 2016

본 시험은 sialic acid가 7%를 함유하도록 제조한 유청가수분해단백분말제제(whey protein of hydrolysis)의 기능성 식품원료로 개발을 위한 동물안전성을 평가함에 연구목표를 두었다. GMP를 원료로 제조한 시험물질은 sialic acid 7%(v/v)와 원료인 GMP 가수분해 단백질이 93%로 구성되어 있었다(시험명: 7%-GNANA). 시험물질의 독성 유무는 한국식품의약안전청(KFDA, 2014)과 OECD(2008)의 의약품 등의 독성시험 기준에 따라 실시하였다. 평가방법으로서, 시험물질의 투여용량을 0, 1,250, 2,500 및 5,000 mg/kg/day로 하여 SPF Sprague-Dawley 계열 암수 랫드에 90일 동안 반복경구투여하였을 때 나타나는 독성 여부를 평가하였다. 평가항목으로서는 사망률, 일반증상관찰, 체중 변화, 사료 섭취량 측정, 안검사, 요검사, 혈액학적 및 혈액생화학적 검사, 부검 시 장기의 중량측정, 부검 시 육안적 검사 및 조직병리학적 검사 등을 평가하였다. 90일 반복경구투여 실험결과로서, 시험물질투여 및 관찰기간 동안 사망동물은 발생하지 않았다. 또한 일반증상, 체중 변화, 사료섭취량, 안과학적 검사, 요검사 그리고 혈액학적 및 혈액이화학적 이상 및 혈액응고검사에서 대조군 대비 특이한 변화는 관찰되지 않았다(p<0.05). 부검 및 병리조직학적 평가 결과, 암수 모두에서 시험물질-유래 중요한 변화 없이 시험물질-유래 경미한 변화(non-adverse effect)만인 5,000 mg/kg/day에서 확인되었다. Weight-based classification(독성 강도에 따른 분류)을 적용한 최종 독성평가 결과, 수컷의 경우 NOEL(No Observed Effect Level)은 5,000 mg/kg/day 그리고 암컷의 경우는 NOAEL(No Observed Adverse Effect Level)은 5,000 mg/kg/day로 최종 확인되었다. 따라서, 암수 모두에서 시험물질의 NOAEL은 투여최대용량인 5,000 mg/kg/day로 확인되었다. 결론적으로, GMP를 원료로 하여 제조한 7%-GNANA(유청가수분해단백분말)는 투여가능 최대용량에서도 독성이 없는 안전한 천연물이라는 것을 확인하였고, 의약품이나 기능성 식품으로서의 개발 가능성을 확인하였다.

• Toxicological Research
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• 제32권3호
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• pp.245-250
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• 2016

3-Methylpentane ($C_6H_{14}$, CAS No. 96-14-0), isomer of hexane, is a colorless liquid originating naturally from petroleum or natural gas liquids. 3-Methylpentane has been used as a solvent in organic synthesis, as a lubricant, and as a raw material for producing carbon black. There is limited information available on the inhalation toxicity of 3-methylpentane, and the aim of this study was to determine its subacute inhalation toxicity. According to OECD Test Guideline 412 (subacute inhalation toxicity: 28-day study), Sprague Dawley rats were exposed to 0, 284, 1,135, and 4,540 ppm of 3-methylpentane for 6 hr/day, 5 days/week for 4 weeks via whole-body inhalation. Mortality, clinical signs, body weights, food consumption, hematology, serum chemistry, organ weights, and gross and histopathological findings were compared between control and all exposure groups. No mortality or remarkable clinical signs were observed during the study. No gross or histopathological lesions, or adverse effects on body weight, food consumption, hematology, serum chemistry, and organ weights were observed in any male or female rats in all exposure groups, although some statistically significant changes were observed in food consumption, serum chemistry, and organ weights. In conclusion, the results of this study indicate that no observable adverse effect level (NOAEL) for 3-methylpentane above 4,540 ppm/6 hr/day, 5 days/week for rats.

• Toxicological Research
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• 제34권1호
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• pp.49-53
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• 2018

Cyclohexanone ($C_6H_{10}O$, CAS No. 108-94-1) is a colorless oily liquid obtained through the oxidation of cyclohexane or dehydrogenation of phenol. It is used in the manufacture of adhesives, sealant chemicals, agricultural chemicals, paint and coating additives, solvent, electrical and electronic products, paints and coatings, photographic supplies, film, photochemicals, and as an intermediate in nylon production. Owing to the lack of information on repeated inhalation toxicity of cyclohexaone, in this study, we aimed to characterize the subacute inhalation toxicity. B6C3F1 mice were exposed to 0, 50, 150, and 250 ppm of cyclohexanone for 6 hr/day, 5 days/week for 4 weeks via whole-body inhalation in accordance with the OECD Test Guideline 412 (subacute inhalation toxicity: 28-day study). Mortality, clinical signs, body weights, food consumption, hematology, serum biochemistry, organ weights, as well as gross and histopathological findings were evaluated between the control and exposure groups. No mortality or remarkable clinical signs were observed during the study. No adverse effects on body weight, food consumption, hematology, serum biochemistry, and organ weights, gross or histopathological lesions were observed in any male or female mice in any of the exposure groups, although some statistically significant changes were observed in organ weights. We concluded that no observable adverse effect level (NOAEL) is above 250 ppm in mice exposed to cyclohexanone for 6 hr/day for 5 days/week.

• Journal of Dairy Science and Biotechnology
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• 제34권2호
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• pp.117-135
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• 2016

본 시험은 sialic acid가 23%를 함유하도록 제조한 유청가수분해단백분말제제(whey protein of hydrolysis)의 기능성 식품원료로 개발을 위한 동물안전성을 평가에 연구목표를 두었다. 시험물질은 sialic acid 23%(v/v)와 원료인 GMP(glycomacropeptide)가수분해 단백질이 87%(v/v)로 구성되어 있었다(시험명: 23%-GNANA). 시험물질의 독성 유무는 한국식품의약안전청(KFDA, 2014)과 OECD(2008)의 의약품 등의 독성시험 기준에 따라 실시하였다. 평가방법으로서, 시험물질의 투여용량을 0, 1,250, 2,500 및 5,000 mg/kg/day하여 SPF Sprague-Dawley 계열 암수 랫드에 90일 동안 반복경구투여하였을 때 나타나는 독성 여부를 평가하였다. 평가항목으로서는 사망률, 일반증상관찰, 체중 변화, 사료섭취량 측정, 안검사, 요검사, 혈액학적 및 혈액생화학적 검사, 부검 시 장기의 중량 측정, 부검 시 육안적 및 조직병리학적 검사 등을 평가하였다. 결과로서, 시험물질로 인한 일반증상 및 사망동물은 발생하지 않았다. 또한, 안과학적 검사, 요검사 그리고 혈액학적 및 혈액이화학적 이상 여부와 부검 시 육안적 검사 및 조직병리학적 검사에서 대조군 대비 특이한 변화는 관찰되지 않았다(P<0.05). 이외의 평가 항목에서, 암컷은 사료섭취량과 증체율이 다소 감소하였고, 그리고 수컷에서는 요의 SG와 PRO 및 고환 무게가 다소 증가하는 경향을 보였지만, 시험물질-유래 경미한 변화(non-adverse effect)가 고용량군(5,000 mg/kg/day)만 확인되었다. Weight-based classification(독성 강도에 따른 분류)를 적용한 최종 독성평가 결과는 다음과 같다. 수컷의 경우, NOEL(No Observed Effect Level)은 5,000 mg/kg/day 그리고 암컷의 경우는 NOAEL(No Observed Adverse Effect Level)은 5,000 mg/kg/day로 최종 확인되었다. 따라서, 암수 모두에서 시험물질의 NOAEL은 투여최대용량인 5,000 mg/kg/day로 확인되었다. 결론적으로, 시험물질인 유청가수분해단백분말제제는 건강기능식품의 특성상 임상허용용량인 1,000 mg/kg/day의 5배 수준에서 안전함을 확인되었다.

• Biomolecules & Therapeutics
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• 제6권1호
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• pp.82-88
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• 1998

LBO0014, a new recombinant human erythropoietin, was at dose levels of 0, 120, 600, and 3,000 IU/kg/day administered intravenously to pregnant Sprague-Dawley rats during the organogenetic period. All dams were subjected to caesarean section on day 20 of pregnancy, Effects of test substance on dams and embryonic development of Fl fetuses were examined. No treatment-related changes in clinical signs, body weight, and food consumption were observed at all doses tested. At necropsy spleen enlargement was found at 3,000 lU/kg. There was an ulcrease in the spleen weight at 600 and 3,0007/kg. Developmental toxicity was evident as increased resorptions at 3,000 lU/kg. At 600 and 3,000 RJ/kg, retarded ossification of fetuses occurred at an incidence of 31.3% and 64.7%, respectively. In addition, there was a delay in ossification of sternebrae and sacrocaudal vertebrae at 600 and 3,000 lU/kg. A decrease in the number of metacarpi and metatarsi was also seen at 3,000 nJ/kg. The results show that the no observed adverse effect dose level (NOAEL) for material toxicity was over 3,000 IU/kg/day and the NOAEL for developmental toxicity was 120 IU/kg/day.

• Toxicological Research
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• 제20권3호
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• pp.273-280
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• 2004

The present study was carried out to investigate the potential toxicity of dimethyl disulfide by a 2-week inhalation in F344 rats. The test article, dimethyl disulfide, was exposed by inhalation to male and female rats at dose levels of 0, 33, 100, or 300 ppm/6 hrs/day for 2 weeks. At the end of treatment period, all males and females were sacrificed. During the test period, clinical signs, mortality, body weights, food consumption, hematology, serum biochemistry, and gross findings were examined. The mean body weights of the male 300 ppm group and the female 33 ppm or higher dose groups were significantly lower than those of the control group, respectively. The mean food consumption at male 300 ppm and female 100 and 300 ppm were significantly decreased compared with the controls. Some treatment-related serum biochemical changes, including decreased alkaline phosphatase at male 300 ppm and female 100 and 300 ppm, reduced total bilirubin at male 300 ppm, and decreased alanine aminotransferase at female 300 ppm, were observed in a dose-dependent manner, but these findings were considered to be of no toxicological significance. There were no adverse effects on mortality, clinical signs, hematology, and necropsy findings in any treatment group. Based on these results, it was concluded that the 2-week repeated dose of dimethyl disulfide by inhalation resulted in suppressed body weight gain and decreased food consumption at the dose of male 300 ppm and suppressed or reduced body weight gain and decreased food consumption at the dose of female 33 ppm or higher. In the present experimental conditions, the no-observed-adverse-effect level (NOAEL) was considered to be 100 ppm/6 hrs/day for male rats and below 33 ppm/6 hrs/day for female rats.

• 대한환경공학회지
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• 제33권1호
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• pp.60-70
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• 2011

본고에서는 현재 시행중인 해양오염퇴적물질 관리용 유해화학물질 정화지수($CI_{HC}$)를 대상으로, $CI_{HC}$은 동일하나 유해 물질별 함량이 다른 해저퇴적물들이 같은 생물위험을 보이는가를 판단하려 하였다. 이를 위해 5개의 가상 오염퇴적물을 설정하고, 퇴적물 위험평가를 위한 트로픽트레이스 모형($TrophicTrace^{(R)}$ model)을 이용하여, 이 가상 퇴적물이 쥐노래미(Hexagrammos otakii)에 대해 미치는 생물위험을 최대무작용량에 기반한 독성지수(NOAEL TQ)와 최소작용량에 기반한 독성지수(LOAEL TQ)로 평가하였다. 쥐노래미에 대한 NOAEL TQ의 합계는 5개 가상 오염퇴적물에서 0.69~1.54의 범위였고, LOAEL TQ의 합계는 0.111~0.261로 약 2배 이상의 차이가 났다. 이는 퇴적물 유해물질 환경기준이 해양저서무척추동물군집에 대한 영향만을 고려하고 사람으로 연결되는 식용의 쥐노래미에 대한 영향을 반영하지 않기 때문으로 사료된다. 인체에 대한 비발암위험지수(HI) 값은 PCB의 경우 9.8~47.1로 매우 위험한 것으로 나타났다. PCB의 발암위험도는 5개 퇴적물에서 $39{\sim}190{\times}10^{-5}$으로 높게 나타났으며 As의 경우에도 $8.1{\sim}18.0{\times}10^{-5}$으로 높게 나타났다. 유해화학물질정화지수가 8로 동일한 5개 가상 오염퇴적물에서 비발암위험지수(HI) 및 발암위험도가 서로 매우 다르게 나타난 것은 각 오염물질별로 인체에 악영향을 미치는 정도가 다르기 때문이다.

• 대한약침학회지
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• 제19권3호
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• pp.213-224
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• 2016

Objectives: Ginseng Rh2+ is enzyme-treated ginseng extract containing high amounts of converted ginsenosides, such as compound k, Rh2, Rg3, which have potent anticancer activity. We conducted general and genetic toxicity tests to evaluate the safety of ginseng Rh2+. Methods: An acute oral toxicity test was performed at a high-level dose of 4,000 mg/kg/day in Sprague-Dawley (SD) rats. A 14-day range-finding study was also conducted to set dose levels for the 90-day study. A subchronic 90-day toxicity study was performed at dose levels of 1,000 and 2,000 mg/kg/day to investigate the no-observed-adverse-effect level (NOAEL) of ginseng Rh2+ and target organs. To identify the mutagenic potential of ginseng Rh2+, we conducted a bacterial reverse mutation test (Ames test) using amino-acid-requiring strains of Salmonella typhimurium and Escherichia coli (E. coli), a chromosome aberration test with Chinese hamster lung (CHL) cells, and an in vivo micronucleus test using ICR mice bone marrow as recommended by the Korean Ministry of Food and Drug Safety. Results: According to the results of the acute oral toxicity study, the approximate lethal dose (ALD) of ginseng Rh2+ was estimated to be higher than 4,000 mg/kg. For the 90-day study, no toxicological effect of ginseng Rh2+ was observed in body-weight changes, food consumption, clinical signs, organ weights, histopathology, ophthalmology, and clinical pathology. The NOAEL of ginseng Rh2+ was established to be 2,000 mg/kg/day, and no target organ was found in this test. In addition, no evidence of mutagenicity was found either on the in vitro genotoxicity tests, including the Ames test and the chromosome aberration test, or on the in vivo in mice bone marrow micronucleus test. Conclusion: On the basis of our findings, ginseng Rh2+ is a non-toxic material with no genotoxicity. We expect that ginseng Rh2+ may be used as a novel adjuvant anticancer agent that is safe for long-term administration.