Nitrosamines crisis in pharmaceuticals-Insights on toxicological implications,root causes and risk assessment:A systematic review

The presence of N-nitroso compounds,particularly N-nitrosamines,in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects.This systematic review investigates their toxicity in active pharmaceutical ingredients(APIs),drug products,and pharmaceutical excipients,along with novel analytical strategies for detection,root cause analysis,reformulation strategies,and regulatory guidelines for nitrosamines.This review emphasizes the molecular toxicity of N-nitroso compounds,focusing on genotoxic,mutagenic,carcinogenic,and other physiological effects.Additionally,it addresses the ongoing nitrosamine crisis,the development of nitrosamine-free products,and the importance of sensitive detection methods and precise risk evaluation.This comprehensive overview will aid molecular biologists,analytical scientists,formulation scientists in research and development sector,and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.

Quantification of Structurally Alert Mutagenic Impurities in Meropenem Trihydrate Drug Substance by Liquid Chromatography with High Resolution Mass Spectrometer (LC-HRMS)

Potential mutagenic impurities in Active Pharmaceutical Ingredient, Meropenem Trihydrate were assessed and a novel analytical method for their quantification was developed and validated. This Liquid Chromatographic method using High Resolution Mass Spectrometer (LC-HRMS) technique is proved to be suitable for simultaneous quantification of all ten identified impurities with required specificity, sensitivity, resolution, precision, accuracy, and other method characteristics as per ICH Guidelines. The acceptable limit of less than 2.9 μg/g was considered for evaluations, based on drug substance dosage and duration of treatment. The method stands most sensitive with a Limit of Detection of 0.35 μg/g, considering the challenge full acceptance criteria as per current regulatory standards.

Preliminary Study on the Mutagenic Effects of Space Flight on Alfalfa Seeds

[Objective] The study aimed to understand the mutagenic effects of space flight on alfalfa seeds.[Method] Seeds of three lines of alfalfa were carried into orbit by the satellite 'Shijian-8' for space fight,the indices including seed germination rate,plant height and growth rate,were measured after the seeds been retrieved.[Result] Remarkable mutagenic effects occurred on the flight seeds,which were mainly presented by abnormal cotyledon,extended variation range of plant height and growth rate.Nineteen plants with increased plant height were preliminarily screened from the T0 progenies,but whether the mutated trait could inherit should be confirmed in further study.Three flight lines of alfalfa are different in the percentages of abnormal cotyledon(10%-18%),variation range of plant height(increased 30%-150% compared to control),selected plant number with increased plant height(5-7 plants),suggesting that differences exits between the three lines in mutation efficiency.[Conclusion] Valuable mutated materials could be obtained by space flight and applied in modern agriculture.

Study on Mutagenic Effect of Cobalt-60 Irradiation on Potato

[Objective] This study aimed to investigate the mutagenic effect of cobalt- 60 irradiation on potato. [Method] Potato tubers of Favorita and Zhongshu No.3 were irradiated with 5, 10, 20, 30, 50 and 70 Gy of cobalt-60 γ-ray respectively, to explore the mutagenic effect of different doses of γ-ray heavy ion irradiation on potato. [Result] The results showed that the emergence rate, seedling rate, plant growth, yield and commodity of potato varied after irradiated with different doses of cobalt-60 γ-ray; 10Gy of cobalt-60 irradiation played a positive effect on the growth and development of potato, while high doses played a negative effect on the growth and development of potato. After cobalt-60 irradiation, the botanical traits of M1 gen- eration varied greatly, resulting in a number of beneficial mutation traits; some traits of M2 and M3 generations became stably inherited. [Conclusion] Cobalt-60 irradiation breeding is conducive to the variety improvement and germplasm innovation as an effective means of genetic improvement for potato.

锰对雄性小鼠睾丸生殖功能的作用

锰对雄性小鼠睾丸生殖功能的作用罗圣庆，王子元，王秀玲，林磊光，马宝俊，王京花，熊惠娟（哈尔滨医科大学公共卫生学院，１５０００１）受试物为ＭｎＣｌ２·４Ｈ２Ｏ生理盐水溶液，剂量分别为１０、２０、５０ｍｇ／ｋｇ与９０ｍｇ／ｋｇ，生理盐水与１．７ｍｇ／ｋｇ...

大鼠腹腔注射氯化铍的毒性研究

大鼠腹腔注射氯化铍的毒性研究周安祥，慕玉梅，魏肖莹，王玉荣（甘肃省白银公司劳动卫生研究所，白银７３０９００）选用Ｗｉｓｔａｒ大鼠６０只，分染毒组和对照组，染毒组投与１．３ｍｇ／Ｌ的氯化铍水溶液，每４天腹腔注射１次，连续进行３个月。对照组注入等量生理盐...

Study on Mutagenic Effect of Space Flight in Two-line Sterile Rice

Seeds of two-line sterile rice cultivars Zhu 1S and Lu 18S were carried into space by ＂Shijian 8＂ breeding recoverable satellite, then planted in ground. Mutagenic effects from space induction were compared with those from y-irradiation and complex processing of space induction and y-irradiation. The results showed that agronomic effect was stimulated in Mo progenies of the two-line sterile rice varieties treated by space flight, and their radiosensitivities to the irradiation of space flight performed non-sensitive. The order of mutation frequency was determined to be SP ＋ γ 〉 γ 〉 SP in M2 generation. And a series of mutated elites（individuals） were screened. Physiological indices of mutants screened like the activity of protective enzymes were measured to explore the physiological and biochemical basis of biological effect in space environment to two-line sterile rice. The results of this study show that space mutation breeding is an effective novel mean for breeding.

“老来福”SOD口服液的致突变性、致畸性研究

“老来福”SOD 口服液是以天然植物为原料研制的一种新型抗衰老保健药,其主要成份为超氧化物歧化酶(SOD),刺梨多糖,维生素 C 及多种微量元素。本品主要适用于机体衰老引起的各种机能失调,具有增强人体免疫力,降低体内脂质过氧化物(LPO)的含量,阻断致癌物 N—亚硝基化合物体内合成等作用。急性毒性及长期毒性试验证明本品为无毒物质。

EMS与NaN_3对甘蓝型油菜和芥菜型油菜诱变的效果

采用化学诱变剂甲基磺酸乙酯(EMS)和叠氮化钠(NaN3)分别以不同浓度和处理时间组合,对3个甘蓝型油菜品种(湘油15号、中油821、中双9号)和3个芥菜型油菜品种(金油王2号、品系153和154)成熟种子进行诱变。以未处理组为对照,比较了诱变当代(M1)种子的发芽率和子代(M2)株高、叶色、花色、种皮颜色和花粉育性等生物学性状。结果发现,随着诱变剂浓度的增加和处理时间的延长各品种(系)M1代种子的发芽率逐渐降低,且相同处理条件下芥菜型油菜的平均发芽率要低于甘蓝型油菜;在M2代中初步筛选出28个甘蓝型油菜和38个芥菜型油菜的株高、叶色、花色等性状的突变体,为今后油菜遗传改良和功能基因组学研究提供了更丰富的研究材料。

镍对雌性大鼠生殖功能影响的实验研究

镍对雌性大鼠生殖功能影响的实验研究马明月，苏雅，李宏革，张玉敏（沈阳医学院毒理学教研室，１１００３１）选健康成年雌性Ｗｉｓｔａｒ大鼠３０只，分３组，每组１０只，设一个阴性对照组和两个染毒组，阴性对照组皮下注射生理盐水１ｍｌ／（ｋｇ·ｄ）；染毒Ⅰ组皮下...

铅染毒对大鼠神经行为功能及神经化学的影响

铅染毒对大鼠神经行为功能及神经化学的影响时胜利，陈自强，梁友信（上海医科大学公共卫生学院，２００３３５）铅对神经系统的毒作用过程较为复杂，铅可使脂质过氧化水平提高，降低脑组织中作为脑组织重要防护机制的巯基化合物（如还原型谷胱甘肽）的含量，继而导致组织...

气相色谱法测定空气中四氯乙烯

气相色谱法测定空气中四氯乙烯陈卫，苏汉惠（深圳市卫生防疫站，５１８０２０）四氯乙烯是常用的衣服干洗剂，空气中四氯乙烯的测定方法，国内还没有统一的标准。作者采用活性炭管吸收，二硫化碳解吸，气相色谱法测定，应用通用柱－聚乙二醇６０００柱分离，按车间空气中...

铅的肾细胞毒性及锌的保护作用

铅的肾细胞毒性及锌的保护作用陈卫平，刘世杰（北京医科大学公共卫生学院，１０００８３）本实验采用由猪肾脏起源建株并具有肾近曲小管功能的ＬＬＣ－ＰＫ１细胞系，从细胞水平上研究了铅对肾细胞的毒性及锌的保护作用。所选用的指标为细胞存活率和上清液中的乳酸脱氢酶...

Mutagenic Effect of ^(60)Co γ-rays Irradiation on Turf Characteristics of Buchloe dactyloides (Nutt.) Engelm.

[Objective] This study aimed to investigate the mutagenic effect of 60 Co γ-rays irradiation on turf characteristics of Buchloe dactyloides （Nutt.） Engelm. [Method] Buffalo grass were irradiated with 60 Co γ-rays at five different radiation intensities （1 200, 1 400, 1 600, 1 800, 2 000 Gy） to determine the related turf characteristics and analyze the mutagenic effect of 60 Co γ-rays at different radiation intensities on buffalo grass. [Result] Germination rates of buffalo grass irradiated by different radiation intensities of 60 Co γ-rays varied inconsistently, and the root length and bud length were shorter than the control; compared with the control, the height of irradiated seedlings was significantly reduced, and the number of tillers, plant height, leaf length and leaf blade width were smaller than the control; however, the stolon length, stolon diameter and number of stolon nods had no significant difference compared with the control. [Conclusion] This study laid foundation for determining the appropriate radiation intensity of 60 Co γ-rays and selecting useful mutants of buffalo grass.

A Comparative Study on Mutagenic Effects of Space Flight and Irradiation of γ-rays on Rice

The experiment was conducted to study the mutagenic effects of space environment on seedling growth in M1 generation and plant height and heading date in M2 generation in rice. Two types of lines of growth promotion （GP） and growth suppression （GS） were selected from the recombinant inbred lines （RILs） derived from a cross between a sensitive japonica Lemont and a nonsensitive indica Teqing to compare the mutation frequency and mutagenic efficiency for plant height and heading date in the M2 generation. Space environment resulted in 34.9% higher seedling height （SH） in the GP group than in the control, and 39.1% lower in the GS group than in the control, and there was no difference in seed fertility （SF） between the two groups. In M2, mutants of plant height and heading date can be induced by space treatment in both the two groups with lower mutation frequency and mutagenic efficiency in the GP group than in the GS group. There were no significant differences in the physiological damages in M1 between the two groups after γ-rays irradiation treatment. Mutation frequency and mutagenic efficiency of heading date in M2 were higher in the GS group than in the GP group, and the opposite was true for mutagenic efficiency of plant height although the mutation frequency varied between the two groups. The mutation frequencies of plant height and heading date induced by space environment were obviously lower than those by γ-rays irradiation, but the mutagenic efficiency was the opposite for most of the traits. For the GP and GS of seedlings induced by space environment, the GS had higher mutation frequency and mutagenic efficiency for plant height and heading date than the GP in M2.

克百威的毒性及致突变性研究

克百威的毒性及致突变性研究耿太保，李斌，王淑洁（中国预防医学科学院劳动卫生与职业病研究所，北京１０００５０）克百威是广谱内吸杀虫剂和杀线虫剂。作者对国产克百威进行的急性毒性、蓄积毒性和致突变试验研究结果：纯品克百威对雄雌大鼠和雄性小鼠经口ＬＤ５０分别...

Antimutagenicity of Propolis Against Some 0Mutagens in vivo and in vitro

Objective To evaluate the antimutagenicity of propolis in vivo and in vitro. Methods Salmonella typhimurium strains TA98 and TA100 were used as a test model in vitro against a direct mutagen DMC and an indirect mutagen 2AF with or without S9 mix, and MN formation of mice bone marrow cell and CAs induction of mice testicle cell were applied as a test model in vivo against two mutagens CP and MMC. Results The present study clearly demonstrated that propolis could inhibit mutagenicity of both DMC and 2AF directly in a dose-dependent manner, and significant antimutagenic effects (P<0.05) were obtained in TA98 strain at 2000 and 3000 mg/plate. It also could inhibit mutagenicity of both DMC and 2AF to TA98 strain in a dose-dependent manner, with significant antimutagenic effects (P<0.05) appeared at 1000, 2000, and 3000 mg/plate. The results of antimutagenicity test in vivo revealed that propolis could inhibit MN formation significantly (P<0.05) at the doses of 45.0 and 135.0 mg/kg b. w., and decrease the frequency of chromosome aberrants and chromosome aberrant cells significantly (P<0.05) only at the dose of 135.0 mg/kg b. w. Conclusion The propolis is a good inhibitor for mutagencity of DMC and 2AF in vitro, as well as for CP and MMC in vivo.

Study on the pathogenetic effect of salted pork from a high risk area of stomach cancer in China

AIM To study the pathogenetic effect of salted pork (SP) (special food in Zhuanghe City, a high risk area of stomach cancer in northern China) on stomach cancer, and provide scientific basis for primary prevention of stomach cancer in this high risk area. METHODS The study consisted of three parts. The first part was to study the mutagenicity of SP. The Ames test and micro nuclei assay of V 79 cell were employed in this part. The second part was to study the effect of SP on the gastric mucosa of residents in Zhuanghe area who had consumed SP for more than 10 years and the dose effect relations between SP and pathological changes of gastric mucosa. A total of 300 cases were analysed. The third part was to study the mucosal lesions of experimental dogs by gastroscopy and mucosal biopsy. Six healthy male dogs were chosen, three were fed with SP, and the others served as control. RESULTS In this study, the results showed that the extract of SP could lead to mutation of Salmonella typhimurium TA 98 and induce the increase of micro nuclei rate (MNR) and micro nuclei cell rate (MNCR) of V 79 at a dose range of 20～80μl/ml. There were dose effect relations between SP, MNR, MNCR. Pathological changes of gastric mucosa of local residents who had consumed SP showed significant difference from those of the control group. In people who had consumed SP for 10 years, mucosal lesions including necrosis and erosion were found; in those who consumed SP for 10～20 years, hyperplasia and dysplasia were also seen besides the above lesions and those for 20～30 years, severe dysplasia and even malignant changes could be observed. SP had damaging effect on the gastric mucosa of dogs fed with SP. The mucosal lesions became more severe with increasing feeding time. CONCLUSION SP is a strong mutagen and long term exposure to SP may result in repeated gastric mucosal damage and repair, and finally leading to severe dysplasia and malignancy.

Removal effect on Mesocyclops leukarti and mutagenicity with chlorine dioxide

Mesocyclops leukarti of zooplankton propagates excessively in eutrophic water body and it cannot be effectively inactivated by the conventional drinking water treatment process. In order to tackle this problem, a study of removal effect on Mesocylops leukarti with chlorine dioxide in a waterworks was performed. The results showed that Mesocyclops leukarti could be effectively removed from water by 1.0 mg/L chlorine dioxide prcoxidation combined with the conventional drinking water treatment process. Higher oxidizability and molecular state of chlorine dioxide in water is the key to the inactivation of Mesocyclops leukarti. The chlorite, disinfection by-products （DBPs） of chlorine dioxide, was stable at 0.45 mg/L, which is lower than that critical value of the USEPA. GC-MS examination showed that the quantity of organic substance in the water treated by chlorine dioxide obviously decreased. Ames test further revealed that the mutagenicity was reduced by chlorine dioxide with respect to prechlorine. The propagation ofMesocyclops leukorti can be inactivated effectively and safely by chlorine dioxide pre-oxidation.

MUTAGENICITY AND CARCINOGENICITY OF FISH SAUCE FROM A COUNTY WITH THE HIGH RISK FOR GASTRIC CANCER IN CHINA

The mutagenicity and carcinogenicity of fish sauce (FS) sample from Changle County, a high gastric cancer mortality (113.20/105) area, were investigated with the biologic short-term tests and laboratory animal experiment. The results showed that the extract of FS was markedly direct mutagenic toward S. typhimurium TA100, induced high sister chromatid exchanges (SCE) and micronucleus (MN) in V79 cells after nitrosation with sodium nitrite. But the non-nitrosated FS did not. The nitrosated fish sauce (NFS) also induced SOS in E. coli PQ37 and alkylation of calfthymus DNA. The potency of NFS to induce unscheduled DNA synthesis (UDS) in human normal gastric mucosal cells was increased about fivefold compared with FS. When the NFS extract was given to newborn rats by gavage, dys-plasia and adenocaroinoma were induced in the glandular stomach in the 4th and 16th experimental week, respectively. N-nitrosamides were also found in NFS, which may account for the mutagenicity and carcinogenicity of NFS. It is indicated that FS, a traditional daily eaten seasoning, may contribute to the causes of the high gastric cancer mortality for the local residents.