Objective To analyze result of the external quality assessment for laboratories of toxicological pathology diagnosis in organizations in China. Methods A total of 86 organizations that participated in the 2020-2021 external quality assessment in laboratory of toxicological pathology diagnosis (hereinafter referred to as "reference units") were selected as research subjects using convenient sampling method, and the assessment results were analyzed. Results The median of total score was 92, and the 0-100 percentiles were 64-100 in these 86 reference units. Among these reference units, 76 were rated as excellent, 10 as qualified, with the excellent and the qualified rate of 88.4% and 11.6%, respectively. No reference unit was rated as unqualified. The rates of excellence of the reference units in public health institutions, pharmaceutical research institutions, drug safety evaluation centers and testing companies were 95.7%, 84.2%, 85.7% and 86.7%, and the qualified rates were 4.3%, 15.8%, 14.3% and 13.3%, respectively. The distribution of excellence and qualification among the four types of reference units showed no statistical difference (P>0.05). The distribution of sample scores according to the three grades of poor, good, and excellent were 4.9%, 20.7%, and 74.5% in public health institutions, 8.6%, 23.7%, and 67.8% in pharmaceutical research institutions, 12.5%, 25.0%, and 62.5% in drug safety evaluation centers, and 5.4%, 17.5%, and 77.1% in testing companies. The proportion of excellence unit in public health institutions was higher than that in pharmaceutical research institutions (P<0.05). Conclusion The overall toxicological pathology diagnostic capabilities in China are good, and various types of reference units demonstrate comparable technical capabilities. However, there is a need for standardization of diagnostic terminology.

OBJECTIVE: To explore the chronic toxicity and carcinogenicity of paclobutrazol in SD rats. METHODS: Specific pathogen free SD rats at the age of weaning were randomly divided into control group and low-,medium-,and high-dose groups according the body weight,with 120 rats in each group,half male and half female. The study of combined chronic toxicity and carcinogenicity test in rats was carried out in 2 years by feeding the rats with paclobutrazol. The doses in the 4 groups were 0. 0,11. 7,48. 5 and 193. 9 mg·kg~(-1)·d~(-1) for female rats and 0. 0,13. 5,54. 2 and 241. 9 mg·kg~(-1)·d~(-1) for male rats. The body weight of rats was weighted during the experiment. The blood routine,blood biochemistry,organ coefficient and histopathology examinations were performed at the end of paclobutrazol exposure. The mortality and tumor incidence in rats were calculated. RESULTS: The decrease of body weights in female and male rats in dose groups was observed at 1-2 weeks after the experiment,compared with the same sex control group at the same time point( P < 0. 05).At the end of the exposure,the body weights of female and male rats in all three dose groups were lower than that in the same sex rats of control group( P < 0. 05). The mortality rates of female and male rats in the four groups were not significantly different( P > 0. 05). The brain organ coefficients of female rats in the three dose groups were higher than those female rats in the control group( P < 0. 05). The organ coefficients of liver,kidney and ovary of female rats in highdose group were higher than that of female rats in control group( P < 0. 05). The level of total bilirubin in male rats in the three dose groups was lower than that in control group( P < 0. 05). The organ coefficients of brain and lung in male rats in the medium-and high-dose groups were higher than that in the control group( P < 0. 05). The liver organ coefficient in male rats in the high-dose group was higher than that in the control group( P < 0. 05). A total of 244 rats had 402 spontaneous tumors with a tumor incidence rate of 50. 8%(244/480). The incidence of tumor in control,low-,mediumand high-dose groups were 61. 7%( 74/120), 42. 5%( 51/120), 50. 0%( 60/120) and 49. 2%( 59/120)respectively. There was no statistical significance in the incidence of tumors in three dose groups compared with that of the control group. CONCLUSION: Under the dose conditions designed in this study,the lowest observed adverse effect level of paclobutrazol were 11. 7 and 13. 5 mg · kg~(-1)· d~(-1) in females and males respectively. Paclobutrazol was not found carcinogenic to SD rats.

OBJECTIVE: To observe the diagnostic capacity and its influencing factors in the toxicologic pathology diagnostic laboratories in China. METHODS: Inter-laboratory comparison of toxicologic pathology diagnosis was cosponsored by Chinese Society of Toxicology-Toxicologic Pathology Specialty Section and Guangdong Province Hospital for Occupational Disease Prevention and Treatment. Nine digital slices of digestive system lesions were screened as comparison samples,and the reference institution with toxicologic pathology diagnostic laboratories completed the diagnosis within the prescribed time. According to the three grades of “excellent”,“satisfaction”and “dissatisfaction”,the evaluation was carried out.RESULTS: A total of 74 reference institution participated in this comparison,which distributed in 20 provinces and 4 municipalities and 156 pathologists. The reference institutions were mainly distributed in North China,Southern China and East China. There was an average of 2 pathologists per laboratory,and in the quantity of academic title,the junior,intermediate,and senior was 15,70 and 46 persons respectively. Parasitic hepatocyte cysts( 97. 3%),adenocarcinoma of small intestine( 95. 9%) and polyarteritis nodosa of the pancreas( 89. 2%) had the highest rate of “excellent”grade,while the duodenal gland inflammation( 67. 6%),foam cell aggregation in colonic propria( 40. 5%) and hepatoma adenoma( 32. 4%) had the highest rate of dissatisfaction grade in the evaluation of single case. In the overall evaluation,reference laboratories reached the “excellent”grade and the “satisfaction”grade were 78. 4% and 21. 6% respectively.The number of pathologists provided by each reference laboratory had impacts on the overall evaluation level and the single case evaluation( neoplastic lesions) in the evaluation of single case( P < 0. 05). The types of the reference laboratory,the regional distribution and the grade of the academic title had no effect on the diagnostic ability( P > 0. 05). CONCLUSION: The reference laboratory is superior in diagnosing the digestive system lesions in the inter-laboratory comparison activity.The number of pathologists in the reference laboratory is one of the influencing factors of its diagnostic ability.

OBJECTIVE: To evaluate the diagnostic ability of toxicity pathology in patho-toxicological testing institutions in China. METHODS: The institutions participated in the 2018 Interlaboratory Comparison Activity of Toxicity Pathology Testing(hereinafter referred to as reference unit) were selected as the research subjects. The heart, spleen, skin, soft tissue, liver and mammary gland of SD rats of different groups in the 2-year carcinogenesis test were selected. The femur, knee joint and nose of Beagle dogs in the 4-week toxicity test and a total of 10 pathological tissues were selected as the comparison samples. The pathological diagnosis was carried out by the pathological diagnostic personnel of the reference unit, and the diagnostic results were reported. The expert appointed by the Toxicology and Pathology Committee of Chinese Toxicology Association compared the diagnostic results with the appointed value. RESULTS: A total of 167 pathological diagnostic personnel from 75 reference units in 24 provinces and municipalities participated in the comparison activity. The reference units were mainly distributed in East China, South China and North China, accounting for 77.3%(58/75). Totally 75 reference units fed back 750 effective diagnostic results. The qualified rates of diagnosis on heart, spleen, skin, soft tissue and breast samples were higher than 60.0%. The qualified rates of diagnosis on femur and knee joint, and nose samples were low(30.7% and 6.7%, respectively). There were 1(1.3%), 46(61.4%) and 28(37.3%) reference units rated as unqualified, qualified and excellent, respectively. CONCLUSION: Most of the testing institutions in China have a high level of patho-toxicological diagnostic ability, that can provide reliable diagnostic results for toxicology safety evaluation tests.

OBJECTIVE: To investigate the chronic toxicity and carcinogenicity of kresoxim-methyl in rats. METHODS: Specific pathogen free SD rats were randomly divided into control group and low-, medium-and high-dose groups according to the body weight of rats, 120 rats in each group with half male and half female rats. The chronic toxicity and carcinogenesis was induced in rats for 104 weeks by oral feeding. The dose of kresoxim-methyl in feed of male and female rats was 0, 75, 300 and 1 200 mg/kg. During the process of experiment, the body weight of rats was weighed. The blood biochemistry, organ coefficient and histopathology were examined at the end of the exposure, and the tumor incidence was calculated. RESULTS: There was no significant difference in mortality of the female or male rats in the four groups(P>0.05). At the 32 nd, 48 th and 56 th week after exposure, the body mass of female rats in the high dose group was lower than that in control group(P<0.05); at the 8 th, 16 th, 24 th and 32 nd week, the body mass of male rats in the high dose group was lower than that in the control group(P<0.05). The organ coefficients of heart and adrenal gland of female rats in the high dose group were higher than those in the control group and the low dose group(P<0.05). The organ coefficient of liver of male rats in the high dose group was lower than that in the control group(P<0.05). The alkaline phosphatase of male rats in the three dose groups was lower than that in the control group(P<0.05). The blood glucose of male rats in the high dose group was higher than that in the control group(P<0.05). The aspartate aminotransferase of male rats in the high dose group was lower than that in the control group(P<0.05). There was no significant difference among the three indexes in female rats(P>0.05). The tumor incidence of the control group and the low, medium and high dose groups were 68.3%, 75.0%, 75.0% and 78.8%, respectively, with no significant difference(P>0.05). The tumor incidence of the female rats was higher than that of the male rats(87.0% vs 61.5%,P<0.01).The tumor multiplicity of the above four groups were 38.3%, 35.8%, 35.0%, 39.8%, respectively, with no significant difference(P>0.05). The tumor multiplicity in female rats was higher than that in male rats(56.9% vs 17.6%,P<0.01). CONCLUSION: The no observed adverse effect level of kresoxim-methyl to female and male SD rats was 24.726 and 20.002 mg/(kg·d), respectively. No carcinogenicity of kresoxim-methyl to SD rats was observed.

OBJECTIVE: To observe the pathological changes of rat silicosis model at different time points. METHODS: The specific pathogen free SD rats were randomly divided into control group and 7, 15, 21, 30, 45, 60, 75 and 90 day model groups based on their body weight, with 5 rats in each group. Non-exposed endotracheal intubation was performed. Silicosis rat model was established by intratracheal instillation of 250 g/L silica suspension in each rat, and 0.9% sodium chloride solution was perfused into the trachea of rats in the control group. The rats in the control group were sacrificed on the 90 th day after exposure, and the model rats in the other 8 groups were sacrificed on the 7 th, 15 th, 21 st, 30 th, 45 th, 60 th, 75 th and 90 th days after the end of exposure. The gross appearance of the lung tissue of rats was observed. The rat lung tissues were stained with hematoxylin-eosin and Masson staining to observe the pathological changes, and Ashcroft score was evaluated. RESULTS: The gross observation showed that the lungs of rats in the model groups had varying degree of gray changes, hardened texture, and spots and nodules on the surface of the lobes. These changes were aggravated with the increase of time after dust exposure. The results of histopathological examination of the lungs showed that the rats developed acute alveolar inflammation, and a large number of macrophages and neutrophils were seen in the lung tissues in the 7 th and 15 th day model groups. Cellular nodules appeared in the lung tissue, and fibrosis appeared in the center of the nodule in the rats of 21 st, 30 th, and the 45 th day model groups; the silicosis nodules appeared in the lung tissues of rats in the 60 th, 75 th, and 90 th day model groups, and the small nodules gradually merged into larger ones. Simultaneously, with the increase of time after dust exposure, the lung tissue of rats gradually showed severe pulmonary fibrosis. The lung organ coefficient and Aschcroft score of rats increased with the increase of time after dust exposure(P<0.01). CONCLUSION: The rat lung changes after dust exposure. Acute alveolar inflammation occurs on the 7 th to 15 th day after dust exposure; cellular nodules develop on the 21 st to 45 th day after dust exposure; silicosis nodules develop on the 60 th to 90 th day after dust exposure. The severity of lung fibrosis after dust exposure showed a time-effect relationship in rats.

OBJECTIVE: To explore the non-neoplastic hepatic lesions in SD rats at different ages. METHODS: The specificpathogen free SD rats were collected from the blank control groups used in subacute toxicity tests,subchronic toxicity tests and chronic toxicity combined with carcinogenic tests for safety evaluation. At the end of each experiment,i. e. week 10,19,56 and 108(assigned into four groups: 10,19,56 and 108 weeks,each contained 100 rats with each sex),rats were executed. The liver organ coefficient was calculated,the pathological examination was performed,and the non-tumorous lesions in the liver were analyzed. RESULTS: The liver organ coefficients at the age of 19,56,108 weeks were lower than that of 10 weeks(P < 0. 05); those at the age of 56 and 108 weeks were lower than that of 19 weeks(P < 0. 05),and that of 108 weeks was greater than of 56 weeks(P < 0. 05). Among the 10-week-old,19-week-old,56-week-old and 108-week-old groups,the types of non-neoplastic hepatic lesions detected in the female rats were 6,6,13 and 15 respectively,meanwhile those in the male rats were 6,6,13 and 15 respectively. Both male and female rats,the incidences of hepatocyte fatty degeneration,edema and hepatic infiltration of inflammatory cells were significantly increased with the increase of age in each group(P < 0. 05). The incidences of intrahepatic bile duct proliferation and intrahepatic bile duct fibrosis in rats at the age of 56 and 108 weeks were higher than those at the age of 10 and 19 weeks(P < 0. 008).Moreover,the frequency of hepatic sinus expansion lesions in rats at the age of 108 weeks was higher than those of 19 weeks(P < 0. 008). CONCLUSION: Spontaneous non-neoplastic lesions in the liver of SD rats were common,primarily demonstrated as hepatocyte fatty degeneration,edema and infiltration of inflammatory cells. The incidences of lesions increased with the increase of age.

OBJECTIVE: To explore the spontaneous non-tumor lesion of kidney and its correlation with different age and sex in SD rats. METHODS: Eight hundred specific pathogen free SD rats were collected from the blank control groups used in subacute toxicity tests,subchronic toxicity tests and 1 or 2 years of chronic toxicity combined with carcinogenic tests. Rats were randomly divided into 4 groups with 10,19,56 or 108 weeks of experimental periods. Each group consisted of 100 female and 100 male rats. The renal tissues were collected at the end of each experiment,and the renal organ coefficients were calculated. The pathological non-tumor changes of the kidneys were analyzed. RESULTS: The renal organ coefficients in female rats at the age of 56 and 108 weeks were both lower than that of 10 and 19 weeks( P < 0. 008). The renal organ coefficient of male rats at the age of 56 weeks was lower than that of 10 and 19 weeks( P < 0. 008). The renal organ coefficient of male rats at the age of 108 weeks was higher than that of 56 weeks( P < 0. 008). The renal organ coefficient of male rats at the age of 108 weeks was higher than that of female rats of 108 weeks( P < 0. 008). The incidence of renal tubular calcium salt deposition,interstitial inflammatory cell infiltration and renal tubular dilatation in the female rats at the age of 108 weeks were higher than those in the male rats at the age of 108 weeks( P < 0. 05). The chronic progressive nephropathy incidence of female rats at the age of 108 weeks was lower than that of male rats aged 108 weeks( P < 0. 01).The renal tubular calcium salt deposition incidence of female rats aged 56 weeks was higher than that of male rats aged 56weeks( P < 0. 01). CONCLUSION: The spontaneous non-tumor lesions in the kidney of SD rats were common. The incidence of some lesions was different in the same age group with different sex.