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As an important measure to deepen the reform of the medical and pharmaceutical health system, the national essential public health services programs has been carried out for more than ten years. Therefore, it is of great significance to evaluate the effect and remaining problems of the programs over the decade of implementation period (2009-2019) and to further promote the country's basic public health services. With reference to Donabedian quality theory, this paper summarized and analyzed the key problems existing in China's basic public health services from the aspects of project objectives, project contents, operation mechanisms, implementation processes and effects, and make relevant suggestions from six aspects, mainly as follows: based on scientific reasoning, dynamically adjusting the programs; suggestion that the national basic public health services should be graded and managed by classification; timely revision of project specifications to improve service quality and efficiency; gradually promoting the effectiveness-oriented evaluation and assessment system; improving operational mechanisms and promoting sustainable development; fully playing the role of county medical community, and enhancing service coordination; establishing a scientific and long-term monitoring mechanism for national essential public health services programs. It provides reference for further improvement and optimization of national essential public health services progjects.

As the carcinogenic risk of herbs containing aristolochic acids (AAs) is a global health issue, quantitative evaluation of toxicity is needed for the regulatory decision-making and risk assessment of AAs. In this study, we selected AA I (AAI), the most abundant and representative compound in AAs, to treat transgenic gpt delta mice at six gradient doses ranging from 0.125 to 4 mg/kg/day for 28 days. AAI-DNA adduct frequencies and gpt gene mutation frequencies (MFs) in the kidney, as well as Pig-a gene MFs and micronucleated reticulocytes (MN-RETs) frequencies in peripheral blood, were monitored. The dose–response (DR) relationship data for these in vivo genotoxicity endpoints were quantitatively evaluated using an advanced benchmark dose (BMD) approach with different critical effect sizes (CESs; i.e. BMD5, BMD10, BMD50 and BMD100). The results showed that the AAI-DNA adduct frequencies, gpt MFs and the MN-RETs presented good DR relationship to the administrated doses, and the corresponding BMDL100 (the lower 90% confidence interval of the BMD100) values were 0.017, 0.509 and 3.9 mg/kg/day, respectively. No positive responses were observed in the Pig-a MFs due to bone marrow suppression caused by AAI. Overall, we quantitatively evaluated the genotoxicity of AAI at low doses for multiple endpoints for the first time. Comparisons of BMD100 values across different endpoints provide a basis for the risk assessment and regulatory decision-making of AAs and are also valuable for understanding the genotoxicity mechanism of AAs. [ABSTRACT FROM AUTHOR]

The rodent Pig‐a assay has been used extensively as a potential regulatory assay for evaluating the in vivo mutagenicity of test substances. Although the assay can be conducted in different mammalian species, there have been only a few reports describing its use in humans, and rarely in genotoxicant‐exposed human populations. In this study, PIG‐A mutation frequencies (MFs) were evaluated in 36 azathioprine (AZA; human carcinogen)‐treated inflammatory bowel disease (IBD) patients and 36 healthy volunteers. IBD patients exhibited a slight but statistically higher MF (6.10 ± 4.44 × 10−6) than healthy volunteers (4.97 ± 2.74 × 10−6) (P = 0.0489). The estimated relative risk for the exposed patients was 1.22 which indicated that AZA is a risk factor for inducing PIG‐A mutation. However, the PIG‐A MF showed no associations with AZA treatment duration or total AZA exposure. In addition, we performed the cytokinesis‐block micronucleus test on the same samples. The frequencies of micronuclei (MN) and nuclear buds (NBUD) in IBD patients (MN: 4.70 ± 2.86‰; NBUD: 1.89 ± 0.95‰) were significantly higher than in healthy volunteers (MN: 1.47 ± 0.77‰, P < 0.001; NBUD: 0.90 ± 0.58‰, P = 0.004). MN frequency also had significant correlations with AZA treatment duration (P = 0.011) and total AZA exposure (P = 0.018). Our findings indicate that AZA‐treated IBD patients have only a marginally significant increase in PIG‐A MF; in contrast, a much stronger AZA‐associated increase in genotoxicity was detected with the lymphocyte MN assay. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

A newly developed in vivo Pig‐a gene mutation assay displays great potential for integration into genotoxicity tests. To obtain more evidence for application of the Pig‐a assay, we integrated this assay, micronucleus test in peripheral blood (MN‐pb test) and bone marrow (MN‐bm test), as well as a Comet assay into a transgenic RasH2 mice carcinogenicity study. Fourteen male RasH2 mice and five wild‐type (WT) mice were treated with a strong mutagen aristolochic acid I at a dose of 5 mg/kg/day for 4 consecutive weeks. Mice recovered in 5 weeks. Peripheral bloods were collected for Pig‐a assay, MN‐pb test, and Comet assay at several time points, while bone marrow and target organs were harvested for the MN‐bm test and pathological diagnosis after mice were euthanized. Finally, 13 of the 14 RasH2 mice developed squamous cell carcinomas in the forestomach, while there were no carcinomas in the WT mice. Pig‐a mutant frequencies (MFs) consecutively increased throughout the study to a maximum value of approximately 63‐fold more than background. These frequencies were relative to the incidence, size, and malignant degree of tumors. Micronucleated reticulocytes increased from Day 1 to Day 49, before returning to background levels. No positive responses were observed in either the MN‐bm test or the Comet assay. Results suggested that, when compared with the other two tests, the Pig‐a assay persistently contributed to sustaining MFs, enhanced detection sensitivity due to the accumulation of Pig‐a mutations, and demonstrated better predictability for tumorigenicity. Environ. Mol. Mutagen. 61:266–275, 2020. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Metabolic activation is essential in standard in vitro genotoxicity test systems. At present, there is a lack of suitable cell models that can express the major characteristics of liver function for predicting substance toxicity in humans. Human-induced hepatocytes (hiHeps), which have been generated from fibroblasts by lentiviral expression of liver transcription factors, can express hepatic gene programs and can be expanded in vitro and display functional characteristics of mature hepatocytes, including cytochrome P450 enzyme activity and biliary drug clearance. Our purpose was to investigate whether hiHeps could be used as a more suitable model for genotoxicity evaluation of chemicals. Therefore, a direct mutagen, methylmethanesulfonate (MMS), and five promutagens [2-nitrofluorene (2-NF), benzo[a]pyrene (B[a]P), aflatoxin B1, cyclophosphamide and N-nitrosodiethylamine] were tested by the cytokinesis-block micronucleus test and the comet assay. Results from genotoxicity tests showed that the micronucleus frequencies were significantly increased by all of the six clastogens tested. Moreover, MMS, 2-NF and B[a]P induced significant increases in the % Tail DNA in the comet assay. In conclusion, our findings from the preliminary study demonstrated that hiHeps could detect the genotoxicity of indirect carcinogens, suggesting their potential to be applied as an effective tool for in vitro genotoxicity assessments. [ABSTRACT FROM AUTHOR]

Environmental pollutants, such as quinoline (QN) and 4-methylquinoline (4-MeQ), may be genotoxic and carcinogenic. Earlier studies, including in vitro genotoxicity tests, indicated that 4-MeQ is more mutagenic than QN. However, we hypothesized that the methyl group of 4-MeQ favors detoxication over bioactivation, and this factor may be overlooked in in vitro tests that do not incorporate supplementation with cofactors for enzymes that catalyze conjugation reactions. We used human induced hepatocyte cells (hiHeps), which express such enzymes, and compared the genotoxicity of 4-MeQ and QN. We also carried out an in vivo micronucleus (MN) test in rat liver, since 4-MeQ is not genotoxic in rodent bone marrow. In the Ames test and the Tk gene mutation assay, with rat S9 activation, 4-MeQ was more mutagenic than QN. However, QN induced significantly higher MN frequencies in hiHeps and rat liver than did 4-MeQ. Furthermore, QN upregulated genotoxicity marker genes much more than did 4-MeQ. We also investigated the roles of two important detoxication enzymes, UDP-glucuronosyltransferases (UGTs) and cytosolic sulfotransferases (SULTs). When hiHeps were preincubated with hesperetin (UGT inhibitor) and 2,6-dichloro-4-nitrophenol (SULT inhibitor), MN frequencies were elevated approximately 1.5-fold for 4-MeQ, whereas no significant effects were seen for QN. This study shows that QN is more genotoxic than 4-MeQ, when the roles of SULTs and UGTs in detoxication are considered and our results may improve understanding the structure-activity relationships of quinoline derivatives., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Metabolic activation is essential in standard in vitro genotoxicity test systems. At present, there is a lack of suitable cell models that can express the major characteristics of liver function for predicting substance toxicity in humans. Human-induced hepatocytes (hiHeps), which have been generated from fibroblasts by lentiviral expression of liver transcription factors, can express hepatic gene programs and can be expanded in vitro and display functional characteristics of mature hepatocytes, including cytochrome P450 enzyme activity and biliary drug clearance. Our purpose was to investigate whether hiHeps could be used as a more suitable model for genotoxicity evaluation of chemicals. Therefore, a direct mutagen, methylmethanesulfonate (MMS), and five promutagens [2-nitrofluorene (2-NF), benzo[a]pyrene (B[a]P), aflatoxin B1, cyclophosphamide and N-nitrosodiethylamine] were tested by the cytokinesis-block micronucleus test and the comet assay. Results from genotoxicity tests showed that the micronucleus frequencies were significantly increased by all of the six clastogens tested. Moreover, MMS, 2-NF and B[a]P induced significant increases in the % Tail DNA in the comet assay. In conclusion, our findings from the preliminary study demonstrated that hiHeps could detect the genotoxicity of indirect carcinogens, suggesting their potential to be applied as an effective tool for in vitro genotoxicity assessments., (© The Author(s) 2018. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)