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All rats survived to the end of the study, and no treatment-related adverse clinical appearances were found during the 90-day study. Compared with the controls, the body weights of both male and female rats in the 144.0 mg/kg BW treatment group showed a downward trend from the first week and decreased significantly from week 6 to the end of the administration and recovery periods (P < 0.05) (Figure 1A). The food intake of both male and female rats in the 144.0 mg/kg BW treatment group significantly decreased from the fourth week to the end of the administration and recovery periods. There were significant decreases in total food consumption of male and female rats in the 144.0 mg/kg BW treatment group compared with controls (Figure 1C). No significant differences in food utilization ratio were observed between the treatment groups and the control group of either sex (Figure 1D).
Figure 1. Weekly body weight (A) and total food intake (B), weekly food consumption (C) and food utilization (D) of rats gavaged by different dose of La for 90 days (13 weeks) or 119 days (4 weeks recovery period) (n = 10 in each test group and n = 5 in recovery group; mean ± SD). *P < 0.05, compared with control group.
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Most of the hematological parameters were not significantly different between treatment groups and the control; however, significant differences were observed in some parameters, including an increase in PT in the 1.5 mg/kg BW dose group and a decrease in WBC and RET at the highest dose in male rats (Table 1). During the recovery period, a decrease in basophils (BAS)% in males and eosinophils (EOS)% in females, a decrease in RET at the 144.0 mg/kg BW dose both in male and female rats, and an increase in monocytes (MON)% and neutrophils (NEUT)% in males were observed.
Table 1. Hematological Findings in Rats Gavaged with Different Concentrations of Lanthanum Nitrate for 90 Days (n = 10/group; mean ± SD)
Parameters Sex End of Treatment Period Dosage (mg/kg BW) End of Recovery Period Dosage (mg/kg BW) 0 1.5 6.0 24.0 144.0 0 144.0 WBC (109/L) F 2.3 ± 0.7 2.4 ± 0.7 2.2 ± 0.6 2.7 ± 0.6 3.0 ± 0.8 2.1 ± 0.2 2.7 ± 0.4 M 5.1 ± 0.9 5.0 ± 0.7 4.5 ± 0.6 5.0 ± 1.2 4.1 ± 0.5* 2.2 ± 0.4 3.3 ± 0.2 RBC (1012/L) F 6.8 ± 0.2 6.7 ± 0.3 6.8 ± 0.4 6.7 ± 0.3 6.7 ± 0.4 7.1 ± 0.2 7.7 ± 0.3 M 7.8 ± 0.4 8.5 ± 0.4* 8.1 ± 0.52 8.0 ± 0.5 8.0 ± 0.5 8.2 ± 0.4 8.3 ± 0.2 HGB (g/L) F 139.3 ± 5.6 140.4 ± 6.9 142.3 ± 8.6 136.7 ± 6.7 140.6 ± 6.8 138 ± 4.1 145.25 ± 4.9 M 157.3 ± 8.1 162.4 ± 8.9 158.2 ± 4.4 151.3 ±7.1 157.2 ± 7.6 149.1 ± 4.0 150.7 ± 4.6 HCT (%) F 39.4 ± 1.4 39.3 ± 2.0 39.6 ± 2.5 38.8 ± 1.6 39.1 ± 2.2 39.8 ± 1.5 42.1 ± 1.51 M 42.3 ± 2.6 44.7 ± 2.6 43.2 ± 1.7 42.2 ± 1.7 43.1 ± 2.4 42.9 ± 1.3 44.3 ± 1.08 MCH (pg) F 20.5 ± 0.9 21.0 ± 0.8 20.8 ± 0.9 20.5 ± 0.5 20.9 ± 0.8 19.1 ± 0.6 18.8 ± 0.4 M 20.1 ± 0.7 19.0 ± 0.5 19.6 ± 0.9 19.0 ± 0.9 19.8 ± 1.3 18.0 ± 1.2 18.0 ± 1.1 MCHC (g/L) F 353.8 ± 10.3 357.0 ± 8.9 359.0 ± 9.1 352.7 ± 7.7 359.6 ± 9.1 346.6 ± 5.8 344.5 ± 2.1 M 372.6 ± 10.0 363.7 ± 6.1 366.8 ± 9.5 358.3 ± 11.3 365.1 ± 11.4 347.8 ± 11.8 339.7 ± 3.5 PLT (109/L) F 801.8 ± 105.0 770.9 ± 89.9 747.6 ± 101.4 740.6 ± 102.1 743.8 ± 90.8 702.8 ± 62.2 726 ± 82.9 M 871.0 ± 118.6 964.2 ± 104.0 861.0 ± 122.8 837.7 ± 62.8 785.1 ± 79.2 867.6 ± 57.8 795.5 ± 127.0 RET (‰) F 9.3 ± 2.5 9.3 ± 4.5 9.0 ± 4.7 9.9 ± 5.0 11.9 ± 4.9 11.6 ± 3.6 7.0 ± 1.7* M 10.7 ± 5.3 10.4 ± 5.1 10.1 ± 3.2 6.6 ± 3.2* 7.7 ± 3.5* 15.6 ± 3.9 9.5 ± 3.6* PT (s) F 13.6 ± 0.6 13.4 ± 0.4 12.8 ± 1.4 13.3 ± 1.1 13.8 ± 0.7 14.7 ± 0.9 14.1 ± 0.3 M 14.0 ± 0.8 17.9 ± 6.1 13.8 ± 0.8 14.0 ± 0.6 14.6 ± 1.3 15.4 ± 0.5 15.4 ± 0.4 APTT (s) F 15.2 ± 1.5 18.0 ± 7.9 16.0 ± 2.2 15.6 ± 2.2 17.0 ± 4.3 14.4 ± 1.2 15.2 ± 1.5 M 22.1 ± 4.2 32.8 ± 18.2* 20.2 ± 3.0 19.8 ± 1.7 22.7 ± 8.9 14.7 ± 1.2 17.6 ± 1.5 LYM (%) F 90.6 ± 2.5 90.4 ± 2.3 90.5 ± 2.1 89.7 ± 3.7 88.5 ± 2.7 86.4 ± 1.8 87.4 ± 1.7 M 93.5 ± 1.9 93.7 ± 2.2 92.8 ± 2.2 91.1 ± 2.3 92.4 ± 2.2 89.2 ± 1.1 87.5 ± 1.3 MON (%) F 1.5 ± 1.0 1.3 ± 1.0 1.5 ± 0.9 1.1 ± 1.1 1.7 ± 1.3 0.6 ± 0.4 0.6 ± 0.3 M 1.3 ± 1.2 1.0 ± 0.7 1.1 ± 0.7 1.1 ± 0.6 1.0 ± 0.8 0.3 ± 0.16 0.5 ± 0.2* NEUT (%) F 6.9 ± 2.3 7.5 ± 2.2 7.4 ± 1.8 7.9 ± 3.3 8.6 ± 3.3 11.2 ± 1.6 11.0 ± 1.4 M 4.7 ± 1.8 4.6 ± 2.4 5.6 ± 2.2 6.8 ± 2.2 6.0 ± 2.6 9.6 ± 1.3 11.3 ± 1.3* BAS (%) F M 0.2 ± 0.3 0.3 ± 0.4 0.2 ± 0.3 0.3 ± 0.5 0.4 ± 0.6 1.4 ± 0.6 0.7 ± 0.3* 0.2 ± 0.1 0.3 ± 0.3 0.1 ± 0.2 0.3 ± 0.3 0.2 ± 0.1 0.6 ± 0.3 0.5 ± 0.2 EOS (%) F 0.8 ± 1.0 0.5 ± 0.3 0.5 ± 0.5 0.9 ± 0.9 0.8 ± 0.8 0.3 ± 0.4 0.2 ± 0.4 M 0.4 ± 0.3 0.4 ± 0.3 0.4 ± 0.2 0.6 ± 0.6 0.4 ± 0.2 0.1 ± 0.1 0.1 ± 0.0* Note. WBC, white blood cell; RBC, red blood cell; HGB, hemoglobin; HCT, red blood cell specific volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; PLT, platelet count; RET, reticulocyte count; PT, prothrombin time; APTT, activated partial thromboplastin time; LYM, lymphocytes; MON, monocytes; NEUT, neutrophils; EOS, eosinophils; BAS, basophils; F, female; M, male. *P < 0.05, significantly different from controls. -
Compared with controls, there were some significant differences in blood biochemistry, including a decrease in TG at doses of 24.0 and 144.0 mg/kg, an increase in P at the 144.0 mg/kg dose in male rats, and an increase in ALT, AST, GLU, urea, CREA, and Ca in the female group given the highest dose. There were no significant differences in any other parameters (Table 2).
Table 2. Blood Biochemistry of Rats Gavaged with Different Doses of Lanthanum Nitrate for 90 Days (n = 10/group; mean ± SD)
Parameters Sex End of Treatment Period Dosage (mg/kg BW) End of Recovery Period Dosage (mg/kg BW) 0 1.5 6.0 24.0 144.0 0 144.0 ALT (U/L) F 21.0 ± 5.2 21.5 ± 5.7 24.0 ± 6.5 24.2 ± 6.6 32.6 ± 9.9* 30 ± 4.65 34 ± 6.9 M 29.1 ± 3.0 30.9 ± 5.0 34.2 ± 2.6 30.9 ± 6.7 28.4 ± 6.4 29.6 ± 6.8 33.75 ± 7.2 AST (U/L) F 65.8 ± 22.1 64.0 ± 20.9 76.2 ± 13.8 72.2 ± 18.2 91.1 ± 17.8* 82.4 ± 4.1 98.2 ± 3.8 M 105.4 ± 20.2 103.1 ± 19.2 108.5 ± 24.5 104.9 ± 29.1 89.3 ± 22.2 99.8 ± 11.7 103.2 ± 19.0 TP (g/L) F 38.5 ± 17.5 48.0 ± 8.3 49.3 ± 14.2 48.5 ± 14.7 55.5 ± 8.6 58.1 ± 3.3 58.45 ± 1.9 M 50.7 ± 8.8 51.8 ± 5.4 52.8 ± 6.4 50.2 ± 9.9 47.4 ± 8.1 52.1 ± 1.9 52.95 ± 3.5 ALP (U/L) F 59.2 ± 30.3 41.7 ± 15.3 40.0 ± 4.5 42.8 ± 9.4 49.4 ± 14.3 34.4 ± 9.4 49.3 ± 9.3 M 79.3 ± 13.3 78.4 ± 12.7 82.5 ± 15.5 72.2 ± 17.7 74.6 ± 22.9 58.4 ± 14.0 68.25 ± 9.8 ALB (g/L) F 18.8 ± 6.6 21.9 ± 3.8 23.1 ± 5.9 22.5 ± 5.7 25.5 ± 4.1 28.6 ± 1.7 27.2 ± 0.2 M 21.3 ± 4.1 22.2 ± 2.5 22.8 ± 2.3 21.1 ± 3.1 20.5 ± 4.1 23.6 ± 0.6 23.2 ± 0.6 TBIL (μmol/L) F 0.8 ± 0.4 0.8 ± 0.3 0.8 ± 0.2 0.8 ± 0.2 0.8 ± 0.3 1.2 ± 0.3 1.3 ± 0.2 M 1.2 ± 0.4 1.1 ± 0.3 1.1 ± 0.3 1.1 ± 0.3 1.0 ± 0.4 1.0 ± 0.4 1.2 ± 0.3 GLU (mmol/L) F 5.7 ± 1.4 6.3 ± 0.6 6.2 ± 1.0 6.3 ± 1.3 7.0 ± 0.8* 6.3 ± 1.3 6.9 ± 1.2 M 6.7 ± 1.3 6.6 ± 1.2 7.1 ± 1.0 6.6 ± 1.3 6.9 ± 1.0 7.9 ± 1.2 6.7 ± 0.9 Urea (mmol/L) F 5.0 ± 0.7 5.1 ± 0.6 5.4 ± 0.6 5.8 ± 1.3 6.4 ± 1.1* 6.4 ± 1.0 5.7 ± 0.8 M 4.9 ± 0.5 5.3 ± 0.5 5.4 ± 0.3 5.3 ± 0.8 5.6 ± 1.1 5.2 ± 0.4 5.9 ± 0.3 Crea (μmol/L) F 28.8 ± 10.4 36.7 ± 11.2 37.1 ± 8.9 35.0 ± 12.2 41.6 ± 9.2* 26.4 ± 5.6 24.3 ± 2.4 M 35.5 ± 7.7 36.0 ± 4.2 37.6 ± 6.3 34.8 ± 8.4 35.0 ± 11.1 24.6 ± 3.6 21.5 ± 2.2 CHOL (mmol/L) F 1.3 ± 0.5 1.4 ± 0.4 1.5 ± 0.4 1.5 ± 0.5 1.6 ± 0.3 1.8 ± 0.1 1.8 ± 0.4 M 1.3 ± 0.5 1.5 ± 0.4 1.4 ± 0.3 1.5 ± 0.4 1.3 ± 0.3 1.5 ± 0.2 1.5 ± 0.5 TG (mmol/L) F 0.3 ± 0.2 0.3 ± 0.2 0.3 ± 0.2 0.3 ± 0.1 0.4 ± 0.1 0.3 ± 0.1 0.3 ± 0.1 M 0.7 ± 0.3 0.5 ± 0.2 0.5 ± 0.2 0.4 ± 0.2* 0.3 ± 0.3* 0.3 ± 0.07 0.3 ± 0.1 K (mmol/L) F 4.4 ± 0.7 4.3 ± 0.3 4.3 ± 0.2 4.3 ± 0.2 4.3 ± 0.2 4.6 ± 0.2 4.5 ± 0.1 M 4.5 ± 0.4 4.7 ± 0.3 4.4 ± 0.2 4.5 ± 0.3 4.3 ± 0.2 4.9 ± 0.2 4.6 ± 0.3 CL (mmol/L) F 106.8 ± 4.6 107.5 ± 3.2 112.9 ± 5.3 106.7 ± 3.4 105.7 ± 1.2 107.6 ± 0.9 108.2 ± 0.7 M 105.2 ± 6.3 107.0 ± 3.5 106.5 ± 1.3 109.1 ± 4.5 106.0 ± 2.9 107.8 ± 1.4 109.1 ± 0.7 P (mmol/L) F 2.2 ± 0.4 2.0 ± 0.3 2.1 ± 0.3 2.4 ± 0.5 2.5 ± 0.4 2.1 ± 0.2 2.4 ± 0.4 M 2.0 ± 0.3 2.1 ± 0.3 2.2 ± 0.3 2.1 ± 0.3 2.6 ± 0.7* 2.0 ± 0.3 2.3 ± 0.4 Ca (mmol/L) F 1.7 ± 0.4 1.7 ± 0.3 1.9 ± 0.4 1.9 ± 0.3 2.1 ± 0.3* 2.4 ± 0.02 2.3 ± 0.03 M 1.9 ± 0.3 1.9 ± 0.2 2.0 ± 0.2 1.9 ± 0.3 1.8 ± 0.3 2.2 ± 0.07 2.2 ± 0.06 Note. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; ALB, albumin; TP, total protein; TBIL, total bilirubin; GLU, glucose; Crea, creatinine; CHOL, cholesterol; TG, triglyceride; K, potassium; Cl, chloride; Ca, calcium, P, phosphorous; F, female; M, male. *P < 0.05, significantly different from controls. -
In both male and female rats, there were no signi- ficant differences in any of the 9 urinary parameters between treatment groups and controls (data not shown).
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The body weights before dissection of both male and female rats were significantly higher in controls versus the highest treatment group (Table 3). In male rats, the organ weights of the liver, spleen, kidney, heart, and thymus in the highest treatment group were significantly lower than those in the controls, and relative brain weight and epididymis weight in male rats increased significantly in the highest treatment group compared with the controls (Table 4). Except for body weight, there were no statistically significant gross pathological alterations in female animals.
Table 3. Absolute Organ Weights of Rats Gavaged with Different Dose of Lanthanum Nitrate for 90 Days (n = 10/group; mean ± SD)
Parameters Sex Dosage (mg/kg BW) 0 1.5 6.0 24.0 144.0 Liver (g) M 11.525 ± 0.96 11.208 ± 1.12 10.765 ± 0.95 10.576 ± 2.87 8.494 ± 1.35* F 7.314 ± 1.06 6.549 ± 0.76 6.500 ± 0.77 6.489 ± 1.42 6.338 ± 1.13 Spleen (g) M 0.810 ± 0.05 0.815 ± 0.10 0.790 ± 0.15 0.739 ± 0.79 0.637 ± 0.17* F 0.585 ± 0.06 0.577 ± 0.10 0.598 ± 0.14 0.591 ± 0.04 0.534 ± 0.07 Kidney (g) M 2.870 ± 0.20 2.876 ± 0.23 2.861 ± 0.29 2.718 ± 0.27 2.250 ± 0.30* F 1.608 ± 0.21 1.666 ± 0.15 1.732 ± 0.16 1.587 ± 0.19 1.598 ± 0.14 Heart (g) M 1.466 ± 0.11 1.495 ± 0.11 1.508 ± 0.18 1.386 ± 0.11 1.210 ± 0.07* F 0.977 ± 0.15 0.967 ± 0.09 0.938 ± 0.12 0.936 ± 0.11 0.915 ± 0.06 Brain (g) M 2.111 ± 0.16 2.115 ± 0.14 2.135 ± 0.15 2.122 ± 0.11 2.012 ± 0.07 F 1.997 ± 0.09 1.937 ± 0.07 2.024 ± 0.11 1.927 ± 0.13 1.969 ± 0.10 Thymus (g) M 0.370 ± 0.10 0.330 ± 0.07 0.358 ± 0.10 0.303 ± 0.07 0.269 ± 0.07* F 0.310 ± 0.16 0.304 ± 0.06 0.263 ± 0.07 0.312 ± 0.12 0.266 ± 0.09 Adrenals (g) M 0.053 ± 0.07 0.046 ± 0.07 0.052 ± 0.06 0.058 ± 0.07 0.044 ± 0.06 F 0.070 ± 0.01 0.062 ± 0.01 0.063 ± 0.01 0.065 ± 0.01 0.062 ± 0.00 Testes (g) M 3.266 ± 0.30 3.382 ± 0.36 3.297 ± 0.78 3.390 ± 0.39 3.034 ± 0.37 Epididymides (g) M 1.170 ± 1.37 1.286 ± 1.47 1.237 ± 1.51 1.226 ± 1.48 1.193 ± 1.39 Note. *P < 0.05, significantly different from control. F, female; M, male. Table 4. Effects of Repeated Oral Exposure to Lanthanum Nitrate for 90 Days on Relative Organ Weights (%) of Rats (n = 10/group; mean ± SD)
Parameters Sex Dosage (mg/kg BW) 0 1.5 6.0 24.0 144.0 Liver/body weight (%) M 2.30 ± 0.08 2.24 ± 0.17 2.23 ± 0.12 2.11 ± 0.23 2.44 ± 0.62 F 2.49 ± 0.35 2.30 ± 0.14 2.22 ± 0.11 2.47 ± 0.56 2.49 ± 0.35 Spleen /body weight (%) M 0.16 ± 0.02 0.16 ± 0.01 0.16 ± 0.03 0.16 ± 0.02 0.16 ± 0.03 F 0.20 ± 0.02 0.20 ± 0.03 0.21 ± 0.05 0.22 ± 0.01 0.20 ± 0.02 Kidney/body weight (%) M 0.57 ± 0.04 0.58 ± 0.05 0.59 ± 0.06 0.57 ± 0.06 0.57 ± 0.04 F 0.58 ± 0.05 0.59 ± 0.05 0.60 ± 0.03 0.60 ± 0.08 0.58 ± 0.05 Heart/body weight (%) M 0.29 ± 0.01 0.30 ± 0.02 0.31 ± 0.03 0.30 ± 0.03 0.29 ± 0.01 F 0.33 ± 0.04 0.34 ± 0.03 0.32 ± 0.03 0.35 ± 0.05 0.33 ± 0.04 Brain/body weight (%) M 0.42 ± 0.02 0.44 ± 0.03 0.44 ± 0.04 0.45 ± 0.05 0.54 ± 0.02* F 0.70 ± 0.04 0.68 ± 0.05 0.73 ± 0.11 0.73 ± 0.06 0.70 ± 0.04 Thymus/body weight (%) M 0.07 ± 0.02 0.07 ± 0.01 0.07 ± 0.02 0.06 ± 0.03 0.07 ± 0.02 F 0.11 ± 0.02 0.11 ± 0.02 0.10 ± 0.03 0.12 ± 0.05 0.11 ± 0.02 Adrenals/body weight (%) M 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 F 0.02 ± 0.00 0.02 ± 0.00 0.02 ± 0.00 0.03 ± 0.00 0.02 ± 0.00 Testes/body weight (%) M 0.65 ± 0.06 0.68 ± 0.05 0.67 ± 0.16 0.72 ± 0.11 0.65 ± 0.06 Epididymides/body weight (%) M 0.25 ± 0.03 0.28 ± 0.02 0.28 ± 0.04 0.29 ± 0.05 0.25 ± 0.03* Note. *P < 0.05, significantly different from control. F, female; M, male. Most of the histopathological findings in all treatment groups were comparable with those in the controls (Table 5). Observations included hepatocyte spotty necrosis, renal interstitial inflammation, testicular atrophy, and the absence of mature sperm in the epididymal duct in individual male specimens, vaginitis in individual female specimens, myocardial cell necrosis, Rathke's cyst, prostatitis, and dacryoadenitis. Based on the historical occurrence rates of chronic inflammation in the heart, liver, kidneys, and lungs of control SD rats from our previous repeated oral exposure toxicological studies, we consider the chronic inflammation observed in the present study to be frequent, spontaneous background changes in SD rats, rather than treatment-related pathological changes. As shown in Figure 2, pulmonary macrophage accumulation and chronic interstitial inflammation were observed in the control animals and in the 1.5 and 6.0 mg/kg BW group, while macrophage accumulation and proliferation and foreign body granuloma was observed in alveolar tissues in the 24.0 and 144.0 mg/(kg·day) treatment groups (Figure 2, Table 5). No abnormalities were detected in other organs and tissues.
Table 5. Histopathology Examination of Rats after Lanthanum Nitrate Administration
Microscopic Lesions Dosage (mg/kg BW) Male Female 0 1.5 6.0 24.0 144.0 0 1.5 6.0 24.0 144.0 Heart Myocardial cell necrosis 2(+) 1(+) -(+) -(+) -(+) -(+) 1(+) -(+) -(+) -(+) Kidney Renal interstitial inflammation -(+) -(+) 1(+) -(+) -(+) -(+) 1(+) -(+) -(+) -(+) Liver Spotty necrosis 4(+) 1(+) 1(+) -(+) 4(+) 3(+) 2(+) 1(+) 2(+) -(+) Testis Testicular atrophy -(+) 1(+) 1(+) -(+) -(+) - - - - - Epididymis No mature sperm -(+) 1(+) -(+) -(+) -(+) - - - - - Vagina Epithelial necrosis - - - - - 1(+) -(+) 1(+) -(+) 1(+) Prostate Prostatitis 2(+) 2(+) 1(+) 3(+) 2(+) - - - - - Harderian Gland Lymphocytic infiltration, dacryoadenitis 2(+) 1(+) 1(+) 1(+) 2(+) 2(+) 1(+) 2(+) 2(+) 0(+) Lung Macrophage accumulation 2(+) 4(+) 3(+) 4(+) 3(+) 3(+) 5(+) 7(+) 3(+) 4(+) -(++) -(+) -(+) 2(++) 2(++) -(+) 1(+) 2(++) 2(++) 0(+) Foreign body granuloma -(+) -(+) -(+) -(+) 1(+) -(+) -(+) -(+) -(+) 1(+) -(++) -(++) -(++) -(++) 1(++) -(++) -(++) -(++) (++) 2(++) -(+++) -(+++) -(+++) 1(+++) 1(+++) -(+++) -(+++) -(+++) 1(+++) 1(+++) -(++++) -(++++) -(++++) -(++++) 0(++++) -(++++) -(++++) -(++++) (++++) 1(++++) Note. Tissues from 10 animals were examined in each group. Numbers of + in the brackets indicate the degree of histopathologic changes: +-minimal; ++-mild; +++-moderate; ++++-severe. Numbers before the brackets indicate the incidence of histopathologic changes. '-' means no observed changes. Figure 2. Pulmonary macrophage accumulation and foreign body granuloma in lung of rats gavaged at different concentrations of lanthanum nitrate for 90 days. Magnification: ×100. A: males; B: females. Arrows refer to macrophage accumulation in 1.5 and 6.0 mg/kg BW, and foreign body granuloma in 24.0 and 144.0 mg/kg BW groups.
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Body weight was evaluated for BMD determination since the body weight appeared to be the most sensitive target for the effects of lanthanum toxicity. The calculations of BMD and BMDL values are summarized in Table 6. Since they were not divergent, the lowest AIC was used for model comparison, and the Hill model was chosen for BMDL calculations as recommended by the US EPA[32, 22]. Based on tests for goodness-of-fit, the Hill model was acceptable to describe the data for both male and female rats. The BMDLs were determined as 9.4 mg/kg BW (Figure 3A) and 19.3 mg/kg BW (Figure 3B) for female and male animals, respectively. To protect the health of the entire population, BMDL = 9.4 mg/kg could be use conservatively as the point of departure to estimate the health-based guidance values such as a Reference Dose (RfD) or ADI.
Table 6. BMDs and BMDLs of Lanthanum Nitrate Based on Body Weight from 90-day Repeated Dose Study
Test Models Male Female P for Fit* BMD BMDL P for Fit* BMD BMDL Exponential 2 0.6499 -41.5631 Bad_Completion 0.5933 -78.1534 Bad_Completion Exponential 3 0.6499 -41.5631 Bad_Completion 0.5933 -78.1534 Bad_Completion Exponential 4 < 0.0001 Not_Computed 0 0.0001449 Not_Computed 0 Exponential 5 < 0.0001 Not_Computed 0 < 0.0001 Not_Computed 0 Hill 0.4087 25.0033 19.321 0.7899 32.2593 9.43561 Linear 0.6319 -9999 0.5717 90.8346 64.0651 Polynomial 0.6777 150.437 146.535 0.7729 32.2032 6.17507 Power 0.6319 50.4918 39.7307 0.5717 90.8346 64.0651 Note. *P > 0.1 implies that the model seems to adequately describe the data according to the US EPA BMDS Software. Figure 3. Benchmark dose modeling of lanthanum nitrate for the body weight of rats in the subchronic oral toxicity study. The fit and curve of Hill model with experimental data (A: females; B: males). For each graph, the experimental data are shown in gray (mean ± SD) with the model fit as the red line. The black lines represent the BMD and BMDL calculated based on BMR.
doi: 10.3967/bes2018.047
Subchronic Oral Toxicity Evaluation of Lanthanum: A 90-day, Repeated Dose Study in Rats
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Abstract:
Objective The present study was undertaken to evaluate the subchronic toxicity of lanthanum and to determine the no observed adverse effect level (NOAEL), which is a critical factor in the establishment of an acceptable dietary intake (ADI). Methods In accordance with the Organization for Economic Co-operation and Development (OECD) testing guidelines, lanthanum nitrate was administered once daily by gavage to Sprague-Dawley (SD) rats at dose levels of 0, 1.5, 6.0, 24.0, and 144.0 mg/kg body weight (BW) per day for 90 days, followed by a recovery period of 4 weeks in the 144.0 mg/kg BW per day and normal control groups. Outcome parameters were mortality, clinical symptoms, body and organ weights, serum chemistry, and food consumption, as well as ophthalmic, urinary, hematologic, and histopathologic indicators. The benchmark dose (BMD) approach was applied to estimate a point of departure for the hazard risk assessment of lanthanum. Results Significant decreases were found in the 144.0 mg/kg BW group in the growth index, including body weight, organ weights, and food consumption. This study suggests that the NOAEL of lanthanum nitrate is 24.0 mg/kg BW per day. Importantly, the 95% lower confidence value of the benchmark dose (BMDL) was estimated as 9.4 mg/kg BW per day in females and 19.3 mg/kg BW per day in males. Conclusion The present subchronic oral exposure toxicity study may provide scientific data for the risk assessment of lanthanum and other rare earth elements (REEs). -
Figure 1. Weekly body weight (A) and total food intake (B), weekly food consumption (C) and food utilization (D) of rats gavaged by different dose of La for 90 days (13 weeks) or 119 days (4 weeks recovery period) (n = 10 in each test group and n = 5 in recovery group; mean ± SD). *P < 0.05, compared with control group.
Figure 2. Pulmonary macrophage accumulation and foreign body granuloma in lung of rats gavaged at different concentrations of lanthanum nitrate for 90 days. Magnification: ×100. A: males; B: females. Arrows refer to macrophage accumulation in 1.5 and 6.0 mg/kg BW, and foreign body granuloma in 24.0 and 144.0 mg/kg BW groups.
Figure 3. Benchmark dose modeling of lanthanum nitrate for the body weight of rats in the subchronic oral toxicity study. The fit and curve of Hill model with experimental data (A: females; B: males). For each graph, the experimental data are shown in gray (mean ± SD) with the model fit as the red line. The black lines represent the BMD and BMDL calculated based on BMR.
Table 1. Hematological Findings in Rats Gavaged with Different Concentrations of Lanthanum Nitrate for 90 Days (n = 10/group; mean ± SD)
Parameters Sex End of Treatment Period Dosage (mg/kg BW) End of Recovery Period Dosage (mg/kg BW) 0 1.5 6.0 24.0 144.0 0 144.0 WBC (109/L) F 2.3 ± 0.7 2.4 ± 0.7 2.2 ± 0.6 2.7 ± 0.6 3.0 ± 0.8 2.1 ± 0.2 2.7 ± 0.4 M 5.1 ± 0.9 5.0 ± 0.7 4.5 ± 0.6 5.0 ± 1.2 4.1 ± 0.5* 2.2 ± 0.4 3.3 ± 0.2 RBC (1012/L) F 6.8 ± 0.2 6.7 ± 0.3 6.8 ± 0.4 6.7 ± 0.3 6.7 ± 0.4 7.1 ± 0.2 7.7 ± 0.3 M 7.8 ± 0.4 8.5 ± 0.4* 8.1 ± 0.52 8.0 ± 0.5 8.0 ± 0.5 8.2 ± 0.4 8.3 ± 0.2 HGB (g/L) F 139.3 ± 5.6 140.4 ± 6.9 142.3 ± 8.6 136.7 ± 6.7 140.6 ± 6.8 138 ± 4.1 145.25 ± 4.9 M 157.3 ± 8.1 162.4 ± 8.9 158.2 ± 4.4 151.3 ±7.1 157.2 ± 7.6 149.1 ± 4.0 150.7 ± 4.6 HCT (%) F 39.4 ± 1.4 39.3 ± 2.0 39.6 ± 2.5 38.8 ± 1.6 39.1 ± 2.2 39.8 ± 1.5 42.1 ± 1.51 M 42.3 ± 2.6 44.7 ± 2.6 43.2 ± 1.7 42.2 ± 1.7 43.1 ± 2.4 42.9 ± 1.3 44.3 ± 1.08 MCH (pg) F 20.5 ± 0.9 21.0 ± 0.8 20.8 ± 0.9 20.5 ± 0.5 20.9 ± 0.8 19.1 ± 0.6 18.8 ± 0.4 M 20.1 ± 0.7 19.0 ± 0.5 19.6 ± 0.9 19.0 ± 0.9 19.8 ± 1.3 18.0 ± 1.2 18.0 ± 1.1 MCHC (g/L) F 353.8 ± 10.3 357.0 ± 8.9 359.0 ± 9.1 352.7 ± 7.7 359.6 ± 9.1 346.6 ± 5.8 344.5 ± 2.1 M 372.6 ± 10.0 363.7 ± 6.1 366.8 ± 9.5 358.3 ± 11.3 365.1 ± 11.4 347.8 ± 11.8 339.7 ± 3.5 PLT (109/L) F 801.8 ± 105.0 770.9 ± 89.9 747.6 ± 101.4 740.6 ± 102.1 743.8 ± 90.8 702.8 ± 62.2 726 ± 82.9 M 871.0 ± 118.6 964.2 ± 104.0 861.0 ± 122.8 837.7 ± 62.8 785.1 ± 79.2 867.6 ± 57.8 795.5 ± 127.0 RET (‰) F 9.3 ± 2.5 9.3 ± 4.5 9.0 ± 4.7 9.9 ± 5.0 11.9 ± 4.9 11.6 ± 3.6 7.0 ± 1.7* M 10.7 ± 5.3 10.4 ± 5.1 10.1 ± 3.2 6.6 ± 3.2* 7.7 ± 3.5* 15.6 ± 3.9 9.5 ± 3.6* PT (s) F 13.6 ± 0.6 13.4 ± 0.4 12.8 ± 1.4 13.3 ± 1.1 13.8 ± 0.7 14.7 ± 0.9 14.1 ± 0.3 M 14.0 ± 0.8 17.9 ± 6.1 13.8 ± 0.8 14.0 ± 0.6 14.6 ± 1.3 15.4 ± 0.5 15.4 ± 0.4 APTT (s) F 15.2 ± 1.5 18.0 ± 7.9 16.0 ± 2.2 15.6 ± 2.2 17.0 ± 4.3 14.4 ± 1.2 15.2 ± 1.5 M 22.1 ± 4.2 32.8 ± 18.2* 20.2 ± 3.0 19.8 ± 1.7 22.7 ± 8.9 14.7 ± 1.2 17.6 ± 1.5 LYM (%) F 90.6 ± 2.5 90.4 ± 2.3 90.5 ± 2.1 89.7 ± 3.7 88.5 ± 2.7 86.4 ± 1.8 87.4 ± 1.7 M 93.5 ± 1.9 93.7 ± 2.2 92.8 ± 2.2 91.1 ± 2.3 92.4 ± 2.2 89.2 ± 1.1 87.5 ± 1.3 MON (%) F 1.5 ± 1.0 1.3 ± 1.0 1.5 ± 0.9 1.1 ± 1.1 1.7 ± 1.3 0.6 ± 0.4 0.6 ± 0.3 M 1.3 ± 1.2 1.0 ± 0.7 1.1 ± 0.7 1.1 ± 0.6 1.0 ± 0.8 0.3 ± 0.16 0.5 ± 0.2* NEUT (%) F 6.9 ± 2.3 7.5 ± 2.2 7.4 ± 1.8 7.9 ± 3.3 8.6 ± 3.3 11.2 ± 1.6 11.0 ± 1.4 M 4.7 ± 1.8 4.6 ± 2.4 5.6 ± 2.2 6.8 ± 2.2 6.0 ± 2.6 9.6 ± 1.3 11.3 ± 1.3* BAS (%) F M 0.2 ± 0.3 0.3 ± 0.4 0.2 ± 0.3 0.3 ± 0.5 0.4 ± 0.6 1.4 ± 0.6 0.7 ± 0.3* 0.2 ± 0.1 0.3 ± 0.3 0.1 ± 0.2 0.3 ± 0.3 0.2 ± 0.1 0.6 ± 0.3 0.5 ± 0.2 EOS (%) F 0.8 ± 1.0 0.5 ± 0.3 0.5 ± 0.5 0.9 ± 0.9 0.8 ± 0.8 0.3 ± 0.4 0.2 ± 0.4 M 0.4 ± 0.3 0.4 ± 0.3 0.4 ± 0.2 0.6 ± 0.6 0.4 ± 0.2 0.1 ± 0.1 0.1 ± 0.0* Note. WBC, white blood cell; RBC, red blood cell; HGB, hemoglobin; HCT, red blood cell specific volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; PLT, platelet count; RET, reticulocyte count; PT, prothrombin time; APTT, activated partial thromboplastin time; LYM, lymphocytes; MON, monocytes; NEUT, neutrophils; EOS, eosinophils; BAS, basophils; F, female; M, male. *P < 0.05, significantly different from controls. Table 2. Blood Biochemistry of Rats Gavaged with Different Doses of Lanthanum Nitrate for 90 Days (n = 10/group; mean ± SD)
Parameters Sex End of Treatment Period Dosage (mg/kg BW) End of Recovery Period Dosage (mg/kg BW) 0 1.5 6.0 24.0 144.0 0 144.0 ALT (U/L) F 21.0 ± 5.2 21.5 ± 5.7 24.0 ± 6.5 24.2 ± 6.6 32.6 ± 9.9* 30 ± 4.65 34 ± 6.9 M 29.1 ± 3.0 30.9 ± 5.0 34.2 ± 2.6 30.9 ± 6.7 28.4 ± 6.4 29.6 ± 6.8 33.75 ± 7.2 AST (U/L) F 65.8 ± 22.1 64.0 ± 20.9 76.2 ± 13.8 72.2 ± 18.2 91.1 ± 17.8* 82.4 ± 4.1 98.2 ± 3.8 M 105.4 ± 20.2 103.1 ± 19.2 108.5 ± 24.5 104.9 ± 29.1 89.3 ± 22.2 99.8 ± 11.7 103.2 ± 19.0 TP (g/L) F 38.5 ± 17.5 48.0 ± 8.3 49.3 ± 14.2 48.5 ± 14.7 55.5 ± 8.6 58.1 ± 3.3 58.45 ± 1.9 M 50.7 ± 8.8 51.8 ± 5.4 52.8 ± 6.4 50.2 ± 9.9 47.4 ± 8.1 52.1 ± 1.9 52.95 ± 3.5 ALP (U/L) F 59.2 ± 30.3 41.7 ± 15.3 40.0 ± 4.5 42.8 ± 9.4 49.4 ± 14.3 34.4 ± 9.4 49.3 ± 9.3 M 79.3 ± 13.3 78.4 ± 12.7 82.5 ± 15.5 72.2 ± 17.7 74.6 ± 22.9 58.4 ± 14.0 68.25 ± 9.8 ALB (g/L) F 18.8 ± 6.6 21.9 ± 3.8 23.1 ± 5.9 22.5 ± 5.7 25.5 ± 4.1 28.6 ± 1.7 27.2 ± 0.2 M 21.3 ± 4.1 22.2 ± 2.5 22.8 ± 2.3 21.1 ± 3.1 20.5 ± 4.1 23.6 ± 0.6 23.2 ± 0.6 TBIL (μmol/L) F 0.8 ± 0.4 0.8 ± 0.3 0.8 ± 0.2 0.8 ± 0.2 0.8 ± 0.3 1.2 ± 0.3 1.3 ± 0.2 M 1.2 ± 0.4 1.1 ± 0.3 1.1 ± 0.3 1.1 ± 0.3 1.0 ± 0.4 1.0 ± 0.4 1.2 ± 0.3 GLU (mmol/L) F 5.7 ± 1.4 6.3 ± 0.6 6.2 ± 1.0 6.3 ± 1.3 7.0 ± 0.8* 6.3 ± 1.3 6.9 ± 1.2 M 6.7 ± 1.3 6.6 ± 1.2 7.1 ± 1.0 6.6 ± 1.3 6.9 ± 1.0 7.9 ± 1.2 6.7 ± 0.9 Urea (mmol/L) F 5.0 ± 0.7 5.1 ± 0.6 5.4 ± 0.6 5.8 ± 1.3 6.4 ± 1.1* 6.4 ± 1.0 5.7 ± 0.8 M 4.9 ± 0.5 5.3 ± 0.5 5.4 ± 0.3 5.3 ± 0.8 5.6 ± 1.1 5.2 ± 0.4 5.9 ± 0.3 Crea (μmol/L) F 28.8 ± 10.4 36.7 ± 11.2 37.1 ± 8.9 35.0 ± 12.2 41.6 ± 9.2* 26.4 ± 5.6 24.3 ± 2.4 M 35.5 ± 7.7 36.0 ± 4.2 37.6 ± 6.3 34.8 ± 8.4 35.0 ± 11.1 24.6 ± 3.6 21.5 ± 2.2 CHOL (mmol/L) F 1.3 ± 0.5 1.4 ± 0.4 1.5 ± 0.4 1.5 ± 0.5 1.6 ± 0.3 1.8 ± 0.1 1.8 ± 0.4 M 1.3 ± 0.5 1.5 ± 0.4 1.4 ± 0.3 1.5 ± 0.4 1.3 ± 0.3 1.5 ± 0.2 1.5 ± 0.5 TG (mmol/L) F 0.3 ± 0.2 0.3 ± 0.2 0.3 ± 0.2 0.3 ± 0.1 0.4 ± 0.1 0.3 ± 0.1 0.3 ± 0.1 M 0.7 ± 0.3 0.5 ± 0.2 0.5 ± 0.2 0.4 ± 0.2* 0.3 ± 0.3* 0.3 ± 0.07 0.3 ± 0.1 K (mmol/L) F 4.4 ± 0.7 4.3 ± 0.3 4.3 ± 0.2 4.3 ± 0.2 4.3 ± 0.2 4.6 ± 0.2 4.5 ± 0.1 M 4.5 ± 0.4 4.7 ± 0.3 4.4 ± 0.2 4.5 ± 0.3 4.3 ± 0.2 4.9 ± 0.2 4.6 ± 0.3 CL (mmol/L) F 106.8 ± 4.6 107.5 ± 3.2 112.9 ± 5.3 106.7 ± 3.4 105.7 ± 1.2 107.6 ± 0.9 108.2 ± 0.7 M 105.2 ± 6.3 107.0 ± 3.5 106.5 ± 1.3 109.1 ± 4.5 106.0 ± 2.9 107.8 ± 1.4 109.1 ± 0.7 P (mmol/L) F 2.2 ± 0.4 2.0 ± 0.3 2.1 ± 0.3 2.4 ± 0.5 2.5 ± 0.4 2.1 ± 0.2 2.4 ± 0.4 M 2.0 ± 0.3 2.1 ± 0.3 2.2 ± 0.3 2.1 ± 0.3 2.6 ± 0.7* 2.0 ± 0.3 2.3 ± 0.4 Ca (mmol/L) F 1.7 ± 0.4 1.7 ± 0.3 1.9 ± 0.4 1.9 ± 0.3 2.1 ± 0.3* 2.4 ± 0.02 2.3 ± 0.03 M 1.9 ± 0.3 1.9 ± 0.2 2.0 ± 0.2 1.9 ± 0.3 1.8 ± 0.3 2.2 ± 0.07 2.2 ± 0.06 Note. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; ALB, albumin; TP, total protein; TBIL, total bilirubin; GLU, glucose; Crea, creatinine; CHOL, cholesterol; TG, triglyceride; K, potassium; Cl, chloride; Ca, calcium, P, phosphorous; F, female; M, male. *P < 0.05, significantly different from controls. Table 3. Absolute Organ Weights of Rats Gavaged with Different Dose of Lanthanum Nitrate for 90 Days (n = 10/group; mean ± SD)
Parameters Sex Dosage (mg/kg BW) 0 1.5 6.0 24.0 144.0 Liver (g) M 11.525 ± 0.96 11.208 ± 1.12 10.765 ± 0.95 10.576 ± 2.87 8.494 ± 1.35* F 7.314 ± 1.06 6.549 ± 0.76 6.500 ± 0.77 6.489 ± 1.42 6.338 ± 1.13 Spleen (g) M 0.810 ± 0.05 0.815 ± 0.10 0.790 ± 0.15 0.739 ± 0.79 0.637 ± 0.17* F 0.585 ± 0.06 0.577 ± 0.10 0.598 ± 0.14 0.591 ± 0.04 0.534 ± 0.07 Kidney (g) M 2.870 ± 0.20 2.876 ± 0.23 2.861 ± 0.29 2.718 ± 0.27 2.250 ± 0.30* F 1.608 ± 0.21 1.666 ± 0.15 1.732 ± 0.16 1.587 ± 0.19 1.598 ± 0.14 Heart (g) M 1.466 ± 0.11 1.495 ± 0.11 1.508 ± 0.18 1.386 ± 0.11 1.210 ± 0.07* F 0.977 ± 0.15 0.967 ± 0.09 0.938 ± 0.12 0.936 ± 0.11 0.915 ± 0.06 Brain (g) M 2.111 ± 0.16 2.115 ± 0.14 2.135 ± 0.15 2.122 ± 0.11 2.012 ± 0.07 F 1.997 ± 0.09 1.937 ± 0.07 2.024 ± 0.11 1.927 ± 0.13 1.969 ± 0.10 Thymus (g) M 0.370 ± 0.10 0.330 ± 0.07 0.358 ± 0.10 0.303 ± 0.07 0.269 ± 0.07* F 0.310 ± 0.16 0.304 ± 0.06 0.263 ± 0.07 0.312 ± 0.12 0.266 ± 0.09 Adrenals (g) M 0.053 ± 0.07 0.046 ± 0.07 0.052 ± 0.06 0.058 ± 0.07 0.044 ± 0.06 F 0.070 ± 0.01 0.062 ± 0.01 0.063 ± 0.01 0.065 ± 0.01 0.062 ± 0.00 Testes (g) M 3.266 ± 0.30 3.382 ± 0.36 3.297 ± 0.78 3.390 ± 0.39 3.034 ± 0.37 Epididymides (g) M 1.170 ± 1.37 1.286 ± 1.47 1.237 ± 1.51 1.226 ± 1.48 1.193 ± 1.39 Note. *P < 0.05, significantly different from control. F, female; M, male. Table 4. Effects of Repeated Oral Exposure to Lanthanum Nitrate for 90 Days on Relative Organ Weights (%) of Rats (n = 10/group; mean ± SD)
Parameters Sex Dosage (mg/kg BW) 0 1.5 6.0 24.0 144.0 Liver/body weight (%) M 2.30 ± 0.08 2.24 ± 0.17 2.23 ± 0.12 2.11 ± 0.23 2.44 ± 0.62 F 2.49 ± 0.35 2.30 ± 0.14 2.22 ± 0.11 2.47 ± 0.56 2.49 ± 0.35 Spleen /body weight (%) M 0.16 ± 0.02 0.16 ± 0.01 0.16 ± 0.03 0.16 ± 0.02 0.16 ± 0.03 F 0.20 ± 0.02 0.20 ± 0.03 0.21 ± 0.05 0.22 ± 0.01 0.20 ± 0.02 Kidney/body weight (%) M 0.57 ± 0.04 0.58 ± 0.05 0.59 ± 0.06 0.57 ± 0.06 0.57 ± 0.04 F 0.58 ± 0.05 0.59 ± 0.05 0.60 ± 0.03 0.60 ± 0.08 0.58 ± 0.05 Heart/body weight (%) M 0.29 ± 0.01 0.30 ± 0.02 0.31 ± 0.03 0.30 ± 0.03 0.29 ± 0.01 F 0.33 ± 0.04 0.34 ± 0.03 0.32 ± 0.03 0.35 ± 0.05 0.33 ± 0.04 Brain/body weight (%) M 0.42 ± 0.02 0.44 ± 0.03 0.44 ± 0.04 0.45 ± 0.05 0.54 ± 0.02* F 0.70 ± 0.04 0.68 ± 0.05 0.73 ± 0.11 0.73 ± 0.06 0.70 ± 0.04 Thymus/body weight (%) M 0.07 ± 0.02 0.07 ± 0.01 0.07 ± 0.02 0.06 ± 0.03 0.07 ± 0.02 F 0.11 ± 0.02 0.11 ± 0.02 0.10 ± 0.03 0.12 ± 0.05 0.11 ± 0.02 Adrenals/body weight (%) M 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 F 0.02 ± 0.00 0.02 ± 0.00 0.02 ± 0.00 0.03 ± 0.00 0.02 ± 0.00 Testes/body weight (%) M 0.65 ± 0.06 0.68 ± 0.05 0.67 ± 0.16 0.72 ± 0.11 0.65 ± 0.06 Epididymides/body weight (%) M 0.25 ± 0.03 0.28 ± 0.02 0.28 ± 0.04 0.29 ± 0.05 0.25 ± 0.03* Note. *P < 0.05, significantly different from control. F, female; M, male. Table 5. Histopathology Examination of Rats after Lanthanum Nitrate Administration
Microscopic Lesions Dosage (mg/kg BW) Male Female 0 1.5 6.0 24.0 144.0 0 1.5 6.0 24.0 144.0 Heart Myocardial cell necrosis 2(+) 1(+) -(+) -(+) -(+) -(+) 1(+) -(+) -(+) -(+) Kidney Renal interstitial inflammation -(+) -(+) 1(+) -(+) -(+) -(+) 1(+) -(+) -(+) -(+) Liver Spotty necrosis 4(+) 1(+) 1(+) -(+) 4(+) 3(+) 2(+) 1(+) 2(+) -(+) Testis Testicular atrophy -(+) 1(+) 1(+) -(+) -(+) - - - - - Epididymis No mature sperm -(+) 1(+) -(+) -(+) -(+) - - - - - Vagina Epithelial necrosis - - - - - 1(+) -(+) 1(+) -(+) 1(+) Prostate Prostatitis 2(+) 2(+) 1(+) 3(+) 2(+) - - - - - Harderian Gland Lymphocytic infiltration, dacryoadenitis 2(+) 1(+) 1(+) 1(+) 2(+) 2(+) 1(+) 2(+) 2(+) 0(+) Lung Macrophage accumulation 2(+) 4(+) 3(+) 4(+) 3(+) 3(+) 5(+) 7(+) 3(+) 4(+) -(++) -(+) -(+) 2(++) 2(++) -(+) 1(+) 2(++) 2(++) 0(+) Foreign body granuloma -(+) -(+) -(+) -(+) 1(+) -(+) -(+) -(+) -(+) 1(+) -(++) -(++) -(++) -(++) 1(++) -(++) -(++) -(++) (++) 2(++) -(+++) -(+++) -(+++) 1(+++) 1(+++) -(+++) -(+++) -(+++) 1(+++) 1(+++) -(++++) -(++++) -(++++) -(++++) 0(++++) -(++++) -(++++) -(++++) (++++) 1(++++) Note. Tissues from 10 animals were examined in each group. Numbers of + in the brackets indicate the degree of histopathologic changes: +-minimal; ++-mild; +++-moderate; ++++-severe. Numbers before the brackets indicate the incidence of histopathologic changes. '-' means no observed changes. Table 6. BMDs and BMDLs of Lanthanum Nitrate Based on Body Weight from 90-day Repeated Dose Study
Test Models Male Female P for Fit* BMD BMDL P for Fit* BMD BMDL Exponential 2 0.6499 -41.5631 Bad_Completion 0.5933 -78.1534 Bad_Completion Exponential 3 0.6499 -41.5631 Bad_Completion 0.5933 -78.1534 Bad_Completion Exponential 4 < 0.0001 Not_Computed 0 0.0001449 Not_Computed 0 Exponential 5 < 0.0001 Not_Computed 0 < 0.0001 Not_Computed 0 Hill 0.4087 25.0033 19.321 0.7899 32.2593 9.43561 Linear 0.6319 -9999 0.5717 90.8346 64.0651 Polynomial 0.6777 150.437 146.535 0.7729 32.2032 6.17507 Power 0.6319 50.4918 39.7307 0.5717 90.8346 64.0651 Note. *P > 0.1 implies that the model seems to adequately describe the data according to the US EPA BMDS Software. -
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