Retrospective application of ICH M7 to anti-hypertensive drugs in Brazil: Risk assessment of potentially mutagenic impurities.

Potentially mutagenic impurities are likely to be formed in any drug substance, since their synthesis requires reactive intermediates which may also react with DNA. The ICH M7 guideline, which defines how to risk assess and control mutagenic impurities, was first published in 2014 and is not to be applied retrospectively; however, some impurities have been found above the permitted limits in drug products which were already on the market. This study assessed the implications of applying ICH M7 retrospectively to anti-hypertensive drugs marketed in Brazil by performing a risk assessment and establishing control strategies. The manufacturing processes of 15 drug substances were evaluated and 262 impurities were identified, from which 21% were classified as potentially mutagenic. Most of the impurities were identified below ICH M7 acceptable limits, except for impurities described in a pharmacopoeial monograph. Compendial specifications are defined based on scientific evidence and play an important role in setting quality and safety standards for pharmaceuticals, however there are opportunities for further alignment with ICH guidelines, aiming for a holistic assessment of the impurities profile to ensure the safety of medicines.

Multi-endpoint in vitro toxicological assessment of snus and tobacco-free nicotine pouch extracts.

'Modern' oral tobacco-free nicotine pouches (NPs) are a nicotine containing product similar in appearance and concept to Swedish snus. A three-step approach was taken to analyse the biological effects of NPs and snus extracts in vitro. ToxTracker was used to screen for biomarkers for oxidative stress, cell stress, protein damage and DNA damage. Cytotoxicity, mutagenicity, and genotoxicity were assessed in the following respective assays: Neutral Red Uptake (NRU), Ames and Mouse Lymphoma Assay (MLA). Targeted analysis of phosphorylation signalling and inflammatory markers under non-toxic conditions was used to investigate any potential signalling pathways or inflammatory response. A reference snus (CRP1.1) and four NPs with various flavours and nicotine strengths were assessed. Test article extracts was generated by incubating one pouch in 20 mL of media (specific to each assay) with the inclusion of the pouch material. NP extracts did not induce any cytotoxicity or mutagenic response, genotoxic response was minimal and limited signalling or inflammatory markers were induced. In contrast, CRP1.1 induced a positive response in four toxicological endpoints in the absence of S9: Srxn1 (oxidative stress), Btg2 (cell stress), Ddit3 (protein damage) and Rtkn (DNA damage), and three endpoints in presence of S9: Srxn1, Ddit3 and Rtkn. CRP1.1 was genotoxic when assessed in MLA and activated signalling pathways involved in proliferation and cellular stress and specifically induced phosphorylation of c-JUN, CREB1, p53, p38 MAPK and to a lesser extent AKT1S1, GSK3α/ß, ERK1/2 and RSK1 in a dose-dependent manner. CRP 1.1 extracts resulted in the release of several inflammatory mediators including cytokines IL-1α, IL5, IL6, IL8, IL-1RA, MIF and TNF-ß, receptor IL-2RA, and growth factors FGF-basic, VEGF and M-CSF. In conclusion these assays contribute to the weight of evidence assessment of the potential comparative health risks of NPs and snus.

Identification, trace level quantification, and in silico assessment of potential genotoxic impurity in Famotidine.

Potential genotoxic impurities in medications are an increasing concern in the pharmaceutical industry and regulatory bodies because of the risk of human carcinogenesis. To prevent the emergence of these impurities, it is crucial to carefully examine not only the final product but also the intermediates and key starting material (KSM) used in drug synthesis. During the related substances analysis of KSM of Famotidine, an unknown impurity in the range of 0.5-1.0% was found prompting the need for isolation and characterization due to the possibility of its to infiltrate into the final product. In this study, the impurity was isolated and characterized as 5-(2-chloroethyl)-3,3-dimethyl-3,4-dihydro-2H-1,2,4,6-thiatriazine 1,1-dioxide using multiple instrumental analysis, uncovering a structural alert that raises concern. Considering the potential impact of impurity on human health, an in silico genotoxicity assessment was established using Derek and Sarah tool in accordance with ICH M7 guideline. Furthermore, molecular docking and molecular dynamics simulation were performed to evaluate the specific interaction of the impurity with DNA. The findings reveal consistent interaction of the impurity with the dG-rich region of the DNA duplex and binding at the minor groove. Both in silico prediction and molecular dynamic study confirmed the genotoxic character of the impurity. The newly discovered impurity in famotidine has not been reported previously, and there is currently no analytical method available for its identification and control. A highly sensitive HPLC-UV method was developed and validated in accordance with ICH requirements, enabling quantification of the impurity at trace level in famotidine ensuring its safe release.

Strategy proposal using QSAR models to approach mutagenicity assessment of non intentionally added substances in recycled plastic resins.

CONTEXT: Transition to the use of recycled plastics raises an issue concerning safety assessment of Non Intentionally Added Substances (NIAS). To assess the mutagenic potential of the recycled polyethylene impurities and to evaluate the need to perform in vitro assays on recycled resins, this study lies in identifying existing NIAS associated with recycled Low/High Density Polyethylene and assessing the mutagenicity data-gaps by employing in silico tools. METHODS: Quantitative Structure-Activity Relationship (QSAR) models predicting Ames mutagenicity were selected from literature, then NIAS were run to 1/evaluate performances of each model, 2/apply a QSAR strategy on the NIAS molecular space and address data-gaps. RESULTS: Among the 165 NIAS identified, experimental Ames results were not found for 50 substances while the substances with experimental data were predominantly negatives. No individual model was able to predict all NIAS due to applicability domain limitations. Taking into account 1/calculated performances, 2/availability of applicability domain, 3/description of the Training Set, an Integrated Strategy was founded including Sarpy, Consensus and Protox to extend the applicability domain. CONCLUSION & PERSPECTIVES: Existing data and predictions generated by this strategy suggest a low mutagenic potential of NIAS. Further investigation is needed to explore other genotoxicity mechanisms.

Identification of non-volatile non-intentionally added substances from polyester food contact coatings and genotoxicity assessment of polyester coating's migrates.

Can's polyester coatings are intended to replace epoxy-phenolic ones due to rising safety concern regarding the potential release of bisphenol A under increased regulations and consumer pressure. In this study, hazard linked to the migration of non-intentionally added substances from a single polyester-coated tin plate (5 batches) to canned food has been studied. Migration tests were performed using acetonitrile (ACN) and ethanol (EtOH) 95 %. Non-targeted analyses by liquid chromatography-high-resolution mass spectrometry revealed the presence of four cyclic oligoesters classified as Cramer class III substances with an estimated exposure (calculated for French population only) below the threshold of toxicological concern value of 1.5 µg/kg b.w./day, suggesting a no safety concern. Moreover, migrates were tested using in vitro genotoxicity DNA damage response (DDR) test and mini mutagenicity test (MMT) with different strains of S. Typhimurium using direct incorporation (TA100, TA98, TA102, TA1537) and pre-incubation (TA100, TA98) methods. Samples were negative in both bioassays suggesting the absence of genotoxicity/mutagenicity of the mixtures. To verify any false negative response due to matrix effect, migrates were spiked with corresponding positive controls in parallel with the MMT and the DDR test. No matrix effect was observed in these experimental conditions.

Genotoxicity assessment: opportunities, challenges and perspectives for quantitative evaluations of dose-response data.

Genotoxicity data are mainly interpreted in a qualitative way, which typically results in a binary classification of chemical entities. For more than a decade, there has been a discussion about the need for a paradigm shift in this regard. Here, we review current opportunities, challenges and perspectives for a more quantitative approach to genotoxicity assessment. Currently discussed opportunities mainly include the determination of a reference point (e.g., a benchmark dose) from genetic toxicity dose-response data, followed by calculation of a margin of exposure (MOE) or derivation of a health-based guidance value (HBGV). In addition to new opportunities, major challenges emerge with the quantitative interpretation of genotoxicity data. These are mainly rooted in the limited capability of standard in vivo genotoxicity testing methods to detect different types of genetic damage in multiple target tissues and the unknown quantitative relationships between measurable genotoxic effects and the probability of experiencing an adverse health outcome. In addition, with respect to DNA-reactive mutagens, the question arises whether the widely accepted assumption of a non-threshold dose-response relationship is at all compatible with the derivation of a HBGV. Therefore, at present, any quantitative genotoxicity assessment approach remains to be evaluated case-by-case. The quantitative interpretation of in vivo genotoxicity data for prioritization purposes, e.g., in connection with the MOE approach, could be seen as a promising opportunity for routine application. However, additional research is needed to assess whether it is possible to define a genotoxicity-derived MOE that can be considered indicative of a low level of concern. To further advance quantitative genotoxicity assessment, priority should be given to the development of new experimental methods to provide a deeper mechanistic understanding and a more comprehensive basis for the analysis of dose-response relationships.

Mutagenicity of PM2.5 and Ethnic Susceptibility in Chengdu-Chongqing Economic Circle, China.

PM2.5 seriously endangers human health, and its mutagenicity is considered an important pathogenic mechanism. However, the mutagenicity of PM2.5 is mainly determined by traditional bioassays, which are limited in the large-scale identification of mutation sites. Single nucleoside polymorphisms (SNPs) can be used for the large-scale analysis of DNA mutation sites but have not yet been used on the mutagenicity of PM2.5. The Chengdu-Chongqing Economic Circle is one of China's four major economic circles and five major urban agglomerations, and the relationship between the mutagenicity of PM2.5 and ethnic susceptibility in this circle remains unclear. In this study, the representative samples are PM2.5 from Chengdu in summer (CDSUM), Chengdu in winter (CDWIN), Chongqing in summer (CQSUM) and Chongqing in winter (CQWIN) respectively. PM2.5 from CDWIN, CDSUM and CQSUM induce the highest levels of mutation in the regions of exon/5'Utr, upstream/splice site and downstream/3'Utr respectively. PM2.5 from CQWIN, CDWIN and CDSUM induce the highest ratio of missense, nonsense and synonymous mutation respectively. PM2.5 from CQWIN and CDWIN induce the highest transition and transversion mutations respectively. The ability of PM2.5 from the four groups to induce disruptive mutation effects is similar. For ethnic susceptibility, PM2.5 in this economic circle is more likely to induce DNA mutation in Chinese Dai from Xishuangbanna among Chinese ethnic groups. PM2.5 from CDSUM, CDWIN, CQSUM and CQWIN may particularly tend to induce Southern Han Chinese, Dai in Xishuangbanna, Dai in Xishuangbanna and Southern Han Chinese respectively. These findings may assist in the development of a new method for analyzing the mutagenicity of PM2.5. Moreover, this study not only promotes attention to ethnic susceptibility to PM2.5, but also introduces public protection policies for the susceptible population.

Assessment of Biological Activities and Genomic Changes on Microorganisms, Wheat, and Wilding Arise from Poly(pyrazole).

The rapidly growing human population has led to duplicate food production and also reduced product loss. Although the negative effects of synthetic chemicals were recorded, they are still used as agrochemical. The production of non-toxic synthetics makes their use particularly safe. The goal of our research is to evaluate antimicrobial activity of previously synthesized Poly(p-phenylene-1-(2,5-dimethylphenyl)-5-phenyl-1H-pyrazole-3,4-dicarboxy amide) (poly(PDPPD)) against selected Gram-negative, Gram-positive bacteria, and fungus. In addition, the possible genotoxic effects of the poly(PDPPD) were searched on Triticum vulgare and Amaranthus retroflexus seedlings using Random Amplified Polymorphic DNA (RAPD) marker. The binding affinity and binding energies of the synthesized chemical to B-DNA were simulated with AutoDock Vina. It was observed that the poly(PDPPD) affected most of the organisms in a dose-dependent manner. Pseudomonas aeruginosa was the most affected species in tested bacteria at 500 ppm with 21.5 mm diameters. Similarly, a prominent activity was observed for tested fungi. The poly(PDPPD) decreased root and stem length of the Triticum vulgare and Amaranthus retroflexus seedlings and also reduced the genomic template stability (GTS) value of Triticum vulgare more than Amaranthus retroflexus. The binding energy of poly(PDPPD) was found in range of -9.1 and -8.3 kcal/mol for nine residues of B-DNA.

Evaluating the applicability of the Ames test for cosmetic packaging assessment by comparing carcinogenic risk levels of migrants from plastics with biological detection limits.

Risk assessments for cosmetic packaging are required according to the EU Cosmetics Regulation (EC) No. 1223/2009, however, the assessment method is well-established for food packaging but limited for cosmetic packaging. In food packaging assessments, Cramer class III TTC (90 µg/day) is applied as the threshold for systemic toxicity when the Ames test including the process of sample concentration steps provides the negative results. However, the human health risks of mutagenic and carcinogenic migrants at exposure levels where the Ames test with the concentrated samples cannot detect are unclear. In the present study, to confirm the applicability of the Ames test for cosmetic packaging assessments, the toxicological data on 37 candidate migrants with Ames test-positive results was collected. For these migrants, the carcinogenic risk levels through cosmetics use were compared to the detection levels of the Ames test for concentrated samples. Regarding at least 32 migrants, the case study showed the negative result from the Ames test incorporating the sample concentration process would indicate negligible mutagenic and carcinogenic risks of packaging extracts. Therefore, application of the Ames test to cosmetic packaging assessments would be helpful to ensure the safety for mutagenicity and carcinogenicity as well as use Cramer-TTC for systemic toxicity.

Characterization of a new polymeric food contact coating with emphasis on the chemical analysis and safety assessment of non-intentionally added substances (NIAS).

Regulators have established safety requirements for food packaging raw materials and finished products, including by-products of polymer synthesis known as non-intentionally added substances (NIAS). However, there are no official guidance or regulations for best practices to evaluate the safety of NIAS. Here we described the process we followed to identify, characterize, and prioritize for safety assessment low molecular weight NIAS from an epoxy coating (V70) made with tetramethyl bisphenol F-based diglycidyl ether resin (TMBPF-DGE). We assembled a database of 15000 potential oligomers with masses up to 1000 Da and conducted extraction and migration testing of V70 coating. Acetonitrile extract contained higher number and concentration of substances compared to ethanolic-based food simulants. The extract contained 16 substances with matches in the database with estimated concentration of 18.27 µg/6 dm2; seven of these substances have potentially genotoxic oxirane functionality. TMBPF-DGE + hydroquinone (TMBPF-DGE + HQ) was most abundant (55% of total concentration) and was synthesized and prioritized for safety assessment. TMBPF-DGE + HQ exposure from can beverage was estimated at 5.2 µg/person/day, and it was not mutagenic or genotoxic in in vitro assays. The overall mixture of substances that migrated into ethanolic simulant was also negative in the mutagenicity bioassay. Our findings suggest that exposure to TMBPF-DGE + HQ from the V70 coating is exceedingly small and that the coating migrates are not genotoxic.

Unveiling Urinary Mutagenicity by the Ames Test for Occupational Risk Assessment: A Systematic Review.

Occupational exposure may involve a variety of toxic compounds. A mutagenicity analysis using the Ames test can provide valuable information regarding the toxicity of absorbed xenobiotics. Through a search of relevant databases, this systematic review gathers and critically discusses the published papers (excluding other types of publications) from 2001-2021 that have assessed urinary mutagenicity (Ames test with Salmonella typhimurium) in an occupational exposure context. Due to the heterogeneity of the study methods, a meta-analysis could not be conducted. The characterized occupations were firefighters, traffic policemen, bus drivers, mail carriers, coke oven and charcoal workers, chemical laboratory staff, farmers, pharmacy workers, and professionals from several other industrial sectors. The genetically modified bacterial strains (histidine dependent) TA98, TA100, YG1041, YG1021, YG1024 and YG1042 have been used for the health risk assessment of individual (e.g., polycyclic aromatic hydrocarbons) and mixtures of compounds (e.g., diesel engine exhaust, fire smoke, industrial fumes/dyes) in different contexts. Although comparison of the data between studies is challenging, urinary mutagenicity can be very informative of possible associations between work-related exposure and the respective mutagenic potential. Careful interpretation of results and their direct use for occupational health risk assessment are crucial and yet complex; the use of several strains is highly recommended since individual and/or synergistic effects of complex exposure to xenobiotics can be overlooked. Future studies should improve the methods used to reach a standardized protocol for specific occupational environments to strengthen the applicability of the urinary mutagenicity assay and reduce inter- and intra-individual variability and exposure source confounders.

Development and application of the Ames test using a direct-exposure module: The assessment of mutagenicity of incense and sidestream cigarette smoke.

We had previously developed an improved Ames module to directly determine the mutagenicity of gaseous formaldehyde (HCHO) and toluene without liquid extraction. This study further evaluated the suitability and sensitivity of this module on whole and real polluted air samples. For this, two common brands of stick incense (A and B) and cigarettes (A and B) were harvested, and various types of incense smoke (IS) and sidestream cigarette smoke (SCS) samples were generated by lighting 3, 6, 12, 24, 30, or 36 incense sticks, and by lighting 1, 2, or 3 cigarettes, respectively, in an acrylic box. CO2 , CO, total volatile organic compound (TVOC), PM1.0, and HCHO concentrations in the air samples were determined, and all air samples did not partially fit the requirements of the air quality standards. The smoke samples were then directly exposed to TA100 for 10, 20, 30, or 60 min in our exposure module. Exposure to IS (brand A) for 30 to 60 min and exposure to IS (brand B) for 60 min led to statistically (p < 0.05) weak (below the twofold rule) but dose-dependent mutagenic activities either with or without metabolic activation. Furthermore, a short-term exposure (10-60 min) to SCS (brands A and B) displayed statistically significant (p < 0.05) direct-acting, indirect-acting, time- and dose-dependent mutagenic activities. Furthermore, our data also support that the liver S9 enzyme could enhance the mutagenic activities in most IS and SCS samples. This study confirmed that the modified Ames module can be applied to directly detect the mutagenic activities of real polluted air samples.

Mutagenicity, health risk, and disease burden of exposure to organic micropollutants in water from a drinking water treatment plant in the Yangtze River Delta, China.

A wide variety of organic micropollutants in drinking water pose a serious threat to human health. This study was aimed to reveal the characteristics of organic micropollution profiles in water from a drinking water treatment plant (DWTP) in the Yangtze River Delta, China and investigate the mutagenicity, health risk and disease burden through mixed exposure to micropollutants in water. The presence of organic micropollutants in seven categories in organic extracts (OEs) of water from the DWTP was determined, and Ames test was conducted to test the mutagenic effect of OEs. Meanwhile, health risk of exposure to organic micropollutants in finished water through three exposure routes (ingestion, dermal absorption and inhalation) was assessed with the method proposed by U.S. EPA, and disability-adjusted life years (DALYs) were combined to estimate the disease burden of cancer based on the carcinogenic risk (CR) assessment. The results showed that 28 organic micropollutants were detected in the raw and finished water at total concentrations of 967.28 ng/L and 1073.45 ng/L, respectively, of which phthalate esters (PAEs) were the dominant category (95.79% in the raw water and 96.61% in the finished water). Although the results of the Ames test for OEs were negative and the non-carcinogenic hazard index of the organic micropollutants in the finished water was less than 1 in all age groups, the total CR was 2.17 × 10-5, higher than the negligible risk level (1.00 × 10-6). The total DALYs caused by the organic micropollutants in the finished water was 2945.59 person-years, and the average individual DALYs was 2.21 × 10-6 per person-year (ppy), which was 2.21 times the reference risk level (1.00 × 10-6 ppy) defined by the WHO. Exposure to nitrosamines (NAms) was the major contributor to the total CR (92.06%) and average individual DALYs (94.58%). This study demonstrated that despite the negative result of the mutagenicity test with TA98 and TA100 strains, the health risk of exposure to organic micropollutants in drinking water should not be neglected.

Ecological risk assessment and long-term environmental pollution caused by obsolete undisposed organochlorine pesticides.

Obsolete organochlorine pesticides (OSPs) are currently prohibited as persistent organic pollutants that contaminate the environment. If undisposed, they continue to pollute soil and water, to accumulate in the food chain and to harm plants, animals and the human body. The aim of the study was to assess water and soil pollution around the storehouses of undisposed, banned OSPs and their possible genotoxic effect. The storehouses in four villages near Almaty, Kazakhstan were investigated. Chemical analysis confirmed contamination of water and soil around storehouses with OSPs. The genotoxic effect of water and soil samples was evaluated using model objects: S.typhymurium, D.melanogaster, sheep lymphocytes cultures and human lymphocytes cultures. It was found that water and soil samples caused mutagenic effect in all model systems. They increased the frequency of revertants in Salmonella, the frequency of lethal mutations in Drosophila chromosomes, and the frequency of chromosome aberrations in cultures of human and sheep lymphocytes. Although a genotoxic effect was demonstrated for each of these models, various models showed different sensitivity to the effects of pesticides and they varied degree of response. The association between the total content of OCPs in soil and the level of mutations for different model systems was discovered.

Assessment of the mutagenicity of two common indoor air pollutants, formaldehyde and toluene.

Traditionally, direct-reading instruments have been used to directly determine the concentrations of indoor air pollutants that may exceed the regulation limits. However, these instruments cannot directly assess the potential health hazards of these pollutants to humans. In this study, we developed and improved a bacterial reverse mutation assay (Ames test) by using a direct gas exposure module to directly determine the mutagenicity of indoor air quality using five tester bacterial strains (TA98, TA100, TA102, TA1535, and TA1537). Thereafter, the module was used to evaluate the effects of exposure time, different concentrations of HCHO or toluene, and mutagenic activities. We found that TA100 was the most sensitive strain and was reverted by relatively lower concentrations of 0.035 ppm HCHO. Furthermore, 50 ppm of toluene exposures caused a significant increase in the number of revertant colonies of TA100 without S9 activation at the 1.5-8-h exposure time intervals. Our findings provide new evidence that gaseous HCHO exposure could display weak but direct, time-dependent, and dose-dependent mutagenic activities. The weak, direct-acting, indirect-acting, and time-dependent mutagen of 50 ppm toluene was also confirmed. Moreover, our improved Ames module and the exposure conditions provided in this study can be further applied to evaluate the mutagenicity of indoor air quality.

Targets and mechanisms of chemically induced aneuploidy. Part 1 of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases.

An aneuploidy workgroup was established as part of the 7th International Workshops on Genotoxicity Testing. The workgroup conducted a review of the scientific literature on the biological mechanisms of aneuploidy in mammalian cells and methods used to detect chemical aneugens. In addition, the current regulatory framework was discussed, with the objective to arrive at consensus statements on the ramifications of exposure to chemical aneugens for human health risk assessment. As part of these efforts, the workgroup explored the use of adverse outcome pathways (AOPs) to document mechanisms of chemically induced aneuploidy in mammalian somatic cells. The group worked on two molecular initiating events (MIEs), tubulin binding and binding to the catalytic domain of aurora kinase B, which result in several adverse outcomes, including aneuploidy. The workgroup agreed that the AOP framework provides a useful approach to link evidence for MIEs with aneuploidy on a cellular level. The evidence linking chemically induced aneuploidy with carcinogenicity and hereditary disease was also reviewed and is presented in two companion papers. In addition, the group came to the consensus that the current regulatory test batteries, while not ideal, are sufficient for the identification of aneugens and human risk assessment. While it is obvious that there are many different MIEs that could lead to the induction of aneuploidy, the most commonly observed mechanisms involving chemical aneugens are related to tubulin binding and, to a lesser extent, inhibition of mitotic kinases. The comprehensive review presented here should help with the identification and risk management of aneugenic agents.

Mutagenicity assessment of food contact material migrates with the Ames MPF assay.

A major challenge in the safety assessment of food contact materials (FCM) is the evaluation of unknown non-intentionally added substances (NIAS). Even though consumer exposure levels may be quantitatively low, these substances are considered to be of high toxicological concern if they act as DNA reactive mutagens. From a safety assessment perspective, it is therefore important to detect their presence in FCM migrates. The present study applied the Ames MPF assay to assess the mutagenicity of migrates obtained from 30 food contact material samples out of 3 categories: plastics, composite materials and coatings. As a food simulant, 95% ethanol (EtOH) had a superior performance to less volatile simulants when evaluating recovery rates of representative model substances in different volatility categories. To monitor possible interference of the FCM matrix with Ames MPF results, migrates were spiked with reference substances and recovery rates were established. Out of 30 samples tested, two caused significant inhibition of revertant formation in the presence of the spiking control. Overall detection limits of the applied test method were estimated by determination of the lowest effective concentrations (LEC) for 10 Ames-positive substances. Even though the current limits of detection are not sufficient to entirely fulfil regulatory and safety requirements, three out of 30 FCMs showed evidence of dose-dependent effects in the Ames MPF assay. Overall, the data obtained supported the relevance of testing FCM migrates for DNA reactive contaminants and showed the value of the Ames MPF assay for the safety assessment of FCMs.

Assessment of the autoxidation mechanism of p-toluenediamine by air and hydrogen peroxide and determination of mutagenic environmental contaminant in beauty salon effluent.

The present work investigated the autoxidation reaction of p-toluenediamine (PTD) - a precursor - widely used in permanent hair dyeing formulation, under experimental conditions close to the hair dyeing process (oxygen and/or peroxide in ammoniacal medium), by chromatographic and spectroscopic techniques. In additional, evaluated the mutagenicity of the PTD oxidation products and the presence of PTD and this products in wastewater from beauty salon, as well as in surface water and drinking water using HPLC coupled to a diode array detector and linear scan voltammetry. Through this study, it was possible the identification of semi-quinonediimine, quinonediimine, dimers (derived from toluenediamine), and trimer radical identified as Bandrowski's Base derivative (BBD) formed during autoxidation of PTD. Salmonella Typhimurium YG1041 assay with and without metabolic activation induced rat-liver (S9) indicated mutagenic activity for BBD. Levels of PTD were determined by the standard addition method in samples collected from the wastewater of a beauty salon, as well as from the water before and after treatment in a drinking water treatment plant (DWTP) reached concentrations of 2.08 ±â€¯0.21, 2.36 ±â€¯0.10 × 10-3, and 1.77 ±â€¯0.13 × 10-3 mg L-1, respectively. In addition, linear sweep voltammetry was used to monitor the BBD found at the concentration of 1.59 ±â€¯0.35 mg L-1 in wastewater collected from the beauty salon.

Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities.

The presence of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has triggered worldwide product recalls. The purpose of this article is to identify the potential gap area in current pharmaceutical industry practice that might have led to the NMDA and NDEA impurities escaping the drug manufacturer's and FDA's attention. The impact of process change was not adequately assessed by the manufacturer of contaminated APIs (active pharmaceutical ingredients), and potential for generation of mutagenic or other toxic impurities was not considered. The safety and risk associated with a chemical synthetic process was also not evaluated. This is primarily due to current industry practice which focuses on controlling the impurities above reporting threshold. ICH Q3A and FDA guidance on genotoxic and carcinogenic impurities in drug substances and products need to be integrated so that the ICH Q3A decision tree (attachment 3) begins by checking whether the synthetic process has been evaluated for the potential to generate toxic impurities. The compliance with ICH Q3A limits should be carried out only after the process has been determined to be safe without the risk of generating mutagenic and carcinogenic impurities.

Determination of polycyclic aromatic hydrocarbon content in heat-treated meat retailed in Egypt: Health risk assessment, benzo[a]pyrene induced mutagenicity and oxidative stress in human colon (CaCo-2) cells and protection using rosmarinic and ascorbic acids.

This study was undertaken to estimate the concentrations of the formed polycyclic aromatic hydrocarbons (PAHs) in heat-treated (boiled, pan-fried and grilled) meats collected from Egypt. Dietary intakes and cancer risks of PAHs among Egyptian adults were calculated. Benzo[a]pyrene (B[a]P)-induced mutagenicity and oxidative stress in human colon (CaCo-2) cell line and mechanisms behind such effects were also investigated. Finally, protection trials using rosmarinic (RMA) and ascorbic acids (ASA) were carried out. The results indicated formation of PAHs at high levels in the heat-treated meats. Calculated incremental life time cancer risk among Egyptian adults were 7.05179E-07, 7.00604 E-06 and 1.86069 E-05 due to ingestion of boiled, pan-fried and grilled meats, respectively. B[a]P-exposed CaCo-2 cells had high abilities for mutagenicity (490.05 ±â€¯21.37 His + revertants) and production of reactive oxygen species. RMA and ASA protected CaCo-2 cells via reduction of B[a]P-induced mutagenicity and oxidative stress and upregulation of phase II detoxification enzymes and xenobiotic transporters.