Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care

BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients.Cumulative immunosuppression has been shown to contribute to post-transplant malignancy(PTM)risk.There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs,independent of the net effect of immunosuppression.Calcineurin inhibitors such as tacrolimus may promote tumourigenesis,whereas mycophenolic acid(MPA),the active metabolite of mycophenolate mofetil,may limit tumour progression.Liver transplantation(LT)is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable,which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort.However,there is limited clinical data on this subject in both LT and other solid organ transplant recipients.AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation.METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms“solid organ transplantation”,“tacrolimus”,“mycophenolic acid”,and“carcinogenicity”,in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022.Related terms,synonyms and explosion of MeSH terms,Boolean operators and truncations were also utilised in the search.Reference lists of retrieved articles were also reviewed to identify any additional articles.Excluding duplicates,abstracts from 1230 records were screened by a single reviewer,whereby 31 records were reviewed in detail.Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria.RESULTS A total of 6 studies were included in this review.All studies were large population registries or cohort studies,which varied in transplant era,type of organ transplanted and immunosuppression protocol used.Overall,there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation.Furthermore,no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients.CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies,and its application in solid organ transplantation,is yet to be confirmed in clinical studies.Thus,the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

The transcriptome analysis of cleft lip/palate-related PTCH1 variants in GMSM-K cells show carcinogenic potential

Cancer progression involves the sonic hedgehog(SHH)pathway,in which the receptor PTCH1 actives the downstream pathways.Dysfunction of PTCH1 can lead to nevoid basal cell carcinoma Syndrome(NBCCs)including neoplastic disease and congenital disorder.To evaluate the relationship between PTCH1 and cancer,we applied the CRISPR/Cas9 system to knock out PTCH1 in oral nontumorous epithelial cells(GMSM-K).Then we screened six PTCH1 variants associated with cleft lip/palate(CL/P),one of the congenital disorders in NBCCs,and generated PTCH1 variant and wild-type recombinant PTCH1^(−/−)GMSM-K cell lines.Transcriptome sequencing was conducted in these cell lines.The results revealed that differentially expressed genes(DEGs)in PTCH1^(−/−)GMSM-K were enriched in extracellular compartments,contributing epithelial diseases by pathway enrichment analysis.RT-PCR confirmed that KRT34,KRT81,KRT86,PDGFB,and WNT10B genes,associated with extracellular compartments were highly expressed in PTCH1^(−/−).The Kyoto Encyclopedia of Genes and Genomes analysis also suggested that DEGs are closely related to focal adhesion,transcriptional misregulation,and proteoglycans in breast and gastric cancers.Comparative analysis of samples revealed that the CL/P-associated PTCH1 variants A443G and V908G are potentially carcinogenic.These findings provide new insights into the carcinogenic potential of PTCH1 dysfunction.

Dietary Intake, Carcinogenic and Non-Carcinogenic Risk Potentials of Lead, Cadmium, Mercury and Arsenic Exposure via Consumption of Dried Crayfish in Calabar, Nigeria

Intense pressure from both onshore and offshore oil exploration and exploitation activities, together with the accompanying urbanization and industrialization has resulted in massive contamination of land and water resources in Niger Delta, Nigeria. Whereas crayfish is very sensitive to contaminant in the aquatic environment and constitute an important part of human diet, its quality and safety from environmental pollutant is of serious health concern. Evaluation of dietary intake, potential carcinogenic and non-carcinogenic risk of lead, cadmium, mercury and arsenic exposure via consumption of dried crayfish purchased from major markets in Calabar, Nigeria was carried out between June and August 2021. Thirty-six composite samples of dried crayfish purchased from 180 vendors were used for the study. Heavy metals concentrations were determined using Atomic Absorption Spectrophotometer (Model AA-6800, Japan) after wet digestion. Metals concentrations (Mg/kg) were of the ranges 0.02 - 0.24, 0.14 - 0.86, 0.32 - 0.72, 0.04 - 0.19 for Pb, Cd, Hg and As respectively. The mean content of cadmium and mercury exceeded FAO/ WHO and Commission of European Communities maximum levels for crustaceans. Average Estimated Daily Intake for each of the metals was found to be above the recommended daily intake level except for arsenic. The average estimated daily intake values for Cd and Hg were also above the tolerable upper intake level. Average Target Hazard Quotient of all the metals and Hazard Index of all the markets were below 1.00. The Incremental Lifetime Cancer Risk of the metals was greater than the standard tolerable regulatory risk (10-4) for carcinogens. Consumption of crayfish purchased from major markets in Calabar could pose a range of carcinogenic and non-carcinogenic human health risks.

Opisthorchis viverrini:The carcinogenic human liver fluke

Opisthorchiasis caused by Opisthorchis viverrini remains a major public health problem in many parts of Southeast Asia, including Thailand, Lao PDR, Vietnam and Cambodia. The infection is associated with a number of hepatobiliary diseases, including cholangitis, obstructive jaundice, hepatomegaly, cholecystitis and cholelithiasis. Multi-factorial etiology of cholangiocarcinoma, mechanical damage, parasite secretions, and immunopathology may enhance cholangiocarcinogenesis. Moreover, both experimental and epidemiological evidences strongly implicate liver fluke infection as the major risk factor in cholangiocarcinoma, cancer of the bile ducts. The liver fluke infection is induced by eating raw or uncooked fish products that is the tradition and popular in the northeastern and northern region, particularly in rural areas, of Thailand. The health education programs to prevent and control opisthorchiasis are still required in the high-risk areas.

Maternal and Fetal Exposure to Four Carcinogenic Environmental Metals

Objective To examine maternal and fetal exposure levels to four carcinogenic metals, arsenic （As）, cadmium （Cd）, nickel （Ni）, and beryllium （Be）, and to investigate their environmental influences. Methods Metal concentrations in maternal and umbilical cord blood were measured by inductively coupled plasma-mass spectrometry （ICP-MS）. Environmental factors that might play a role in exposure were analyzed using Mann Whitney nonparametric U-tests and multiple linear regression. Results The concentrations of As, Cd, and Ni in umbilical cord blood （5.41, 0.87, and 139.54 gg/L） were significantly lower than those in maternal blood （6.91, 1.93, and 165.93 p.g/L）. There were significant positive correlations between the maternal and cord concentrations of each carcinogen. Our results showed that： （i） exposures to potentially harmful occupational factors during pregnancy were associated with high levels of maternal As, Cd, and Ni; （ii） living close to major transportation routes （〈500 m） or exposure to second-hand smoke during pregnancy increased the maternal Cd levels and （iii） living close to industrial chimneys induced high maternal Ni levels. Multiple linear regression analysis showed that these environmental factors remained significant in models of the influences of these four carcinogens. Conclusion Both mothers and fetuses had been exposed to As, Cd, Ni, and Be. The increased levels of these carcinogens in pregnant women were associated with some detrimental environmental factors, such as occupational exposure, contact with second-hand smoke and living close to major transportation routes or industrial chimneys.

Toxicity and Carcinogenicity of Ozone in Combination with 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone and Dibutyl Phthalate in B6C3F1 Mice for 16 and 32 Weeks

Objective To evaluate the toxic and carcinogenic potential of ozone alone or in combination with 4-（N-methyl-N-nitrosamino）-1-（3-pyridyl）-1-butanone （NNK） and/or dibutyl phthalate （DBP）. Methods Male and female B6C3F1 mice were exposed, through inhalation, intravenous administration and diet, to 0.5 ppm of ozone, 1.0 mg/kg of NNK and 5000 ppm of DBP, individually and in combination for 16 and 32 weeks. Results No treatment-related death was seen, but significant differences in body and organ weights between control and treated mice were observed during the study. No incidence of lung tumor incidence was recorded in mice exposed to either ozone alone or combined treatment. Oviductal carcinomas were observed in female mice exposed to ozone or DBP alone for 16 weeks and ozone in combination with NNK and DBP for 32 weeks. Conclusion Although ozone alone and in conjunction with NNK and/or DBP does not induce lung cancer under our experimental conditions, they induce oviductal carcinomas in B6C3F1 mice.

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.

Relationship between Structures and Carcinogenicities of Heterocyclic Amines

Semi-empirical molecular orbital calculations were performed on heterocyclic aromatic amines(HCAs). The relationship between the structures and the carcinogenicities can be rationally elucidated by the models based on the metabolism of HCAs and the Di-region theory. The degree of easiness for the formation of Di-region electrophilic centers determines the carcinogenic activity. There is a good linear relationship between the observed carcinogenicities and the PM3 calculated parameters, with r=0.973 and F=29.8>F ** 0.01 .

Studies on the Mutagenicity and Teratogenicity of Kuianchun and Its Potential Carcinogenicity Prediction

Kuianchun is a newly synthesized antibacterial and growth-promoting drug. This paper selected a battery of three short-term tests, including Ames test, micronucleus test and sperm abnormality test, to detect the mutagenicity of Kuianchun. The carcinogenicity prediction and battery selection method (CPBS method) was used to determine the probability of carcinogenicity of Kuianchun based upon the results of short-term tests mentioned above. In addition, traditional teratogenic test was selected to study teratogenicity of Kuianchun. In Ames test, Kuianchun showed mutagenic for Salmonella typhimurium strains TA98 and TA100 in the absence and presence of microsomal metabolic activation system (S9-mix). However, the mutagenicity was reduced by the addition of S9-mix. In micronucleus test, Kuianchun was administered intra-peritoneally to male mouse 30 hours and 6 hours before they were killed respectively. The result indicated that there was no significant difference on the number of micronucleated polychromatic erythrocytes (PCEs) in the mouse bone marrow induced by Kuianchun compared with the negative contrast (50% DMSO) (P>0.05). In sperm abnormality test, Kuianchun was administered through a gastric incubation to male mouse as a suspension in 2% Tween-80. The dosage levels were 450, 750, 1000 and 1500mg/kg per day for 5 days. The result indicated that the percentage of abnormal sperms induced by Kuianchun was not significant compared with the negative contrast (P > 0.05). In traditional teratogenic test, Kuianchun was given orally to pregnant mouse at 1730, 1/20 and 1/15 LD50 during 6 - 15days of pregnancy period (the LD50 = 9000mg/kg). No toxicity was found either on mother and embryo in mouse, and teratogenic effects were also not observed at all tested dosages.The probability of carcinogenicity of Kuianchun is 23.8%(6 = 0.238). The result demonstrated that Kuianchun is a non-carcinogen.

Hexavalent Chrome: Threshold Concept for Carcinogenicity

Certain hexavalent chromium (Cr^(6+)) compounds when administered via inhalation at high doses have the potential to induce lung tumors in humans and experimental animals. Trivalent chromium (Cr^(3+)) is an essential human and animal nutrient at levels of 50 to 200 μg/day. Recent data have shown that the human body is able to reduce Cr^(6+) to Cr^(3+). This reduction occurs in bodily fluids such as gastric juice, epithelial lining fluid of.the respiratory tract, blood, and other fluids. Secondary reduction occurs at the cellular level by the cytosol, mitochondria, and microsomes. Thus, at low levels of exposure hexavalent chromium ions are reduced befor the 6+ ions can interact with DNA unless the dose is sufficient to overwhelm the body's reduction capacity. This paper summarizes the available data concerning the reducing ability of the body and formulates the steps in the mechanism of cancer induction. These steps include: (1) only certain Cr^(6+) compounds have the capacity to interact with cellular components; (2) Cr^(6+) is reduced by body fluids and excess Cr^(6+) enters the cell (Cr^(3+) is poorly absorbed across membranes); (3) cellular organelles and the cytoplasm reduce Cr^(6+) to Cr^(3+); (4) excess Cr^(6+) can enter the nucleus; (5) Cr^(6+) reduction through 5+ and 4+ to 3+ has a potential to interact with the DNA molecule; and (6) if unrepaired, this DNA damage can lead to cancer induction. On the basis of current evidence Cr^(6+) has a threshold for carcinogenic potential in humans that is greater than the current TLV. 1990 Academic Press. Inc.

Activation of Carcinogenic Non-aminoazo Compounds iu Horseradish Peroxidase/H_2O_2 System

Eriochrome black T and Nitrosulfophenol S were advocated as the chemical models of carcinogenic non-aminoazo compounds. The main products of their oxidative cleavage in horseradish peroxidase/H2O2 system was identified as the benezenediazonium ion, the ultimate carcinogens, which could bind to DNA. The reaction conditions were investigated preliminarily. Some inhibitors and inducers of the reaction were discovered.

Pairwise comparisons in the analysis of carcinogenicity data

Analysis of carcinogenicity data generally involves a trend test across all dose groups and a pairwise comparison of the high dose group with the control. The most commonly used test for a positive trend is the Cochran-Armitage test. This test is asymptotically normal. For the pairwise comparison of the high dose group with the control group, we propose two modifications: the first modification is to apply the test on the data from high dose and control groups after dropping the data from the low and the medium dose groups;the second modification is to adjust the test conditional on data from all dose groups. We compare the power performance of these two modifications for the pairwise comparisons.

Levels of Genotoxic and Carcinogenic Ingredients in Plant Food Supplements and Associated Risk Assessment

The present study describes the selection, analysis and risk assessment of genotoxic and carcinogenic ingredients of botanicals and botanical preparations which can be found in food and plant food supplements (PFS). First an inventory was made of botanical ingredients that are of possible concern for human health because of their genotoxic and/or carcinogenic properties. In total, 30 botanical ingredients were selected and subsequently judged for their actual genotoxic and/or carcinogenic potential. Among the 30 compounds considered, 18 compounds were judged to be both genotoxic and carcinogenic. Interestingly, the majority of these compounds belong to the group of alkenylbenzenes or unsaturated pyrrolizidine alkaloids. Subsequently, based on available carcinogenicity data and estimated daily human exposure that was determined focusing on the intake from PFS, the Margin of Exposure (MOE) was calculated for the alkenylbenzenes estragole, methyleugenol, safrole and β-asarone. Calculating the MOEs for intake estimates of these alkenylbenzenes from PFS resulted in MOE values that were generally lower than 10,000 and often lower than 100. In some cases the MOE was even below 10 meaning that the estimated daily intake is in the range of dose levels causing malignant tumors in experimental animals. This result indicates that the use of PFS containing the genotoxic carcinogens estragole, methyleugenol, safrole or β-asarone might raise a potential concern for human health and would be of high priority for risk management.

CARCINOGENICITY OF FUSARIN C ISOLATED FROM FUSARIUM MONILIFORME

Fusarium monilljorme, a fungus of established carcinogenic potential, is one of the most common fungal contaminants of maize, millet and other grains in Linxian County, China. Fusarin C, a major product of F. monilljorme grown on corn in the laboratory, is mutagenic in Salmonella tester strains and in V79 cells. Fusarin C showed several characteristics of malignant transformation including the implantation of the rat esophageal epithelial cell line (RE ?525) in nude mice. The present work demonstrated that fusarin C can induce esophageal and forestomach carcinomas in DBA mice and Wistar rats, and thus the experimental results substantiated further the carcinogenicity of fusarin C.

The Uniform Carcinogenic Action of Alkylnitrosoureas in Syrian Hamsters

The carcinogenic effects of a number of alkylnitrosoureas in Syrian golden hamsters have been compared by administering them by gavage as solutions in corn oil/ethyl acetate.The compounds were methyl-,ethyl-,2-hydroxyethyl-,2-oxopropyl-,and 2-phenylethylnitrosourea and the dialkylnitrosoureas dimethyl- and diethylnitrosourea,ethylnitrosohydroxyethylurea, ethylnitroso-2-oxopropylurea,2-oxopropylnitrosochloroethylurea,and hydroxyethylnitroso- ethylurea.All were given at approximately equimolar doses and,in most cases,to male and female hamsters.Most of the hamsters died with tumors associated with the treatments.Methyl- nitrosourea,ethylnitrosourea,and hydroxyethylnitrosourea,but not oxopropylnitrosourea, gave rise to a high incidence of tumors of the forestomach,while the dialkylnitrosoureas pro- duced smaller numbers of forestomach tumors.All of the alkylnitrosoureas induced hemangio- sarcomas of the spleen,which was the most common tumor produced by these carcinogens. Tumors of other types were uncommon,except that ethylnitrosourea and ethylnitrosohydroxy- ethylurea induced tumors of the cervix in about half of the animals and ethylnitrosooxopropyl- urea induced some nervous system tumors.The small number of common target organs of alkylnitrosoureas in hamsters contrasted sharply with the broad spectrum of tumors they in- duced in rats,depending on the nature of the alkyl groups,and with a quite different order of potency in the latter species,1989 Academic Press.Inc.

Hemoglobin Adducts as Biomarkers of Exposure to and metabolic Activation of Carcinogenic Tobacco-Specific Nitrosamines

The carcinogenic tobacco-specific nitrosamines N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) form hemoglobin adducts in laboratory animals and humans. These adducts release 4-hydroxy-l-(3-pyridyl)-l-butanone (HPB) upon mild base hydrolysis. HPB released from human hemoglobin can be quantified by gas chromatography-mass spectrometry. It is the only available biochemical marker for determination of exposure to, and metabolic activation of, carcinogens present only in tobacco. Levels of HPB were highest in snuff-dippers, followed by smokers and nonsmokers. Large interindividual variations in adduct levels were observed. The relationship between HPB levels in globin and DNA of rats treated with NNK has been investigated in order to aid in interpretation of the data from humans. These studies have provided the initial database for understanding the metabolic activation of tobacco-specific nitrosamines in humans.

The Anatomic Pathology Evaluation of Liver with Diethylinitrosamine Treated via Intraperitoneal Injection Singly and Peros for 90 Days Carcinogenicity Study in F344 Rats

Objective：To establish the integrity experiment method of short（ medium）- term carcinogenicity test pursuant to GLP, make into relative SOP and improve the safeguard in the center. Methods：Diethylinitrosamine（DEN） is known as carcinogenic agent, whose target organ is liver. Using the two-stage carcinogenesis test method, DEN was treated to F344 rats via intraperitoneal injection singly（200 mg/kg） , and peros administrated for 90 days（10 ppm）. The liver in any group rat will be examined by light microscopy. Results：In pathologic examination, no liver cell tumor was shown in the livers of the rats that were singly treated with a carcinogenic chemical-DEN. Foci of cellular alteration were observed in the livers of these rats. The proliferation lesions of liver from slight to seveity （foci of cellular aherationepatocelluar adenoma-hepatocellular carcinoma） were observed in the livers of the rats which exposed peros to a low dose of DEN for 90 days after initiation by a single intraperitoneal injection. The incidence of hepatocelluar tumor was 35% in male animal ,which was not shown in the liver of female rat. Conclusion：For current results, it may be possible that low-dose DEN acts as a promotor of hepatocelluar tumor if it was exposed in a population for a long time. It is considered that male hormone has a synergistic effect on hepatocelluar tumor development of DEN. This two-stage carcinogenesis test might be a new model for the study of drug induced and promoted carcinogenesis, which could be used to evaluate the carcinogenesis of chemical compound fast.

Carcinogenic potential of duodenal reflux juice from patients with long-standing postgastrectomy

AIM: To determine whether study on the carcinogenic potential of reflux juice from patients with remote gastrectomy could clarify the inherent relationship between duodenal reflux and gastric stump cancer. METHODS: A total of 37 reflux juice samples (13 Billroth I, 24 Billroth II) were employed in the present study. A two-stage transformation assay using BALB/c 3T3 cells was carried out to test the initiating or promoting activity of these samples. RESULTS: Two of 18 (11.1%) reflux samples exerted initiating activities, whereas 9/19 (47.4%) samples enhanced the MNNG-initiating cell transformation, suggesting the duodenal reflux juice might more frequently possess the tumor-promoter activity (P = 0.029). In addition, there was no difference in initiating activities of the samples irrespective of surgical procedures (P = 0.488), while Billroth II samples exhibited stronger tumor-promoter activity than Billroth I samples (P = 0.027). Furthermore, the promoter activities were well correlated with the histological changes of the stomas (r(s) = 0.625, P = 0.004), but neither their cytotoxicities nor initiating activities had this correlation (Probabilities were 0.523 and 0.085, respectively). CONCLUSION: The duodenal reflux juice from patients with remote postgastrectomy did have carcinogenic potential, and suggested that tumor-promoting activity should principally account for the high incidence of gastric cancer in gastrectomy patients. In contrast, it is difficult to explain the high stump-cancer incidence with the N-nitroso compounds theory-a popular theory for the intact stomach carcinogenesis, and it seemed to be justified to focus chemo-prevention of this cancer on the tumor-promoting potential of reflux juice.

Contamination assessment,source apportionment and associated health risks of PTEs in agricultural soil under five land-use patterns in Sanya,China

To understand the levels of potentially toxic elements(PTEs)contamination in soils and their effects on human health from different agricultural land use in Sanya,China.128 soil samples(64 topsoil samples and corresponding subsoil samples)were collected from the five representative land-use patterns.Inductively coupled plasma mass spectrometry(ICP-MS),Atomic fluorescence spectrometry(AFS),and Inductively coupled plasma optical emission spectrometry(ICP-OES)were used to determine the content of PTEs(As,Cd,Hg,Cu,Cr,Ni,Pb,Zn,Co,Mo,Sb,and V).Correlation analysis and factor analysis were used to determine the source of PTEs.Geo-accumulation index(I_(geo)),hazard quotient(HQ),and total carcinogenic risk index(TR)were used to measure the PTEs contamination and its relative health impacts.Results showed that the average values of 12 PTEs in topsoil were higher than the Hainan soil geochemical baseline,showing different degrees of PTEs accumulation effect.The concentration of PTEs in the topsoil was lower than those in the subsoil except for Cd and Hg.The I_(geo)revealed that the major accumulated element in soils was As followed by Mo.Source apportionment suggested that parent materials and agricultural practices were the dominant factors for PTEs accumulation in the topsoil.Noncarcinogenic risks of soil samples from five land-use patterns presented a trend of paddy field>dry field>woodland>orchard>garden plot.However,the HQ values of 12 PTEs were less than the recommended limit of HQ=1,representing that there are no non-carcinogenic risks of PTEs for children and adults in the study area.The TR values are within 6.95×10^(-6)-1.38×10^(-5),which corresponds to the low level.Therefore the PTEs in the agricultural soil of the study area show little influence on the health status of the local population.

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.