Hematological and clinical chemistry changes induced by subchronic dosing of a novel phosphorothionate (RPR-V) in Wistar male and female rats

A novel phosphorothionate [2-butenoic acid-3-(diethoxy phosphinothioyl)-ethyl ester; RPR-V] synthesized at Indian Institute of Chemical Technology (Hyderabad, India) was studied using subchronic doses of 0.033 (low), 0.066 (medium), and 0.099 (high) mg kg(- 1) in male and female rats daily for 90 days. Continuous treatment with RPR-V caused significant (p < 0.05) decreases in body-weight gain, feed intake, hemoglobin (Hb), hematocrit (Hct), and total erythrocyte count (TEC), whereas total leukocyte count (TLC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were increased. Similarly, RPR-V caused significant elevation in serum clinical chemistry parameters calcium, phosphorus, creatinine, and chloride contents, whereas protein and glucose levels were depressed in both male and female treated rats after 45 and 90 days of treatment. These alterations were significant when compared with two-way ANOVA showing that these changes were dose- and time-dependent. The effects of low dose were generally not statistically significant, whereas medium and high doses caused significant effects. The changes in male rats were not significant when compared with female rats showing no sexual dimorphism by this compound. Recovery was observed after 28 days post-treatment (withdrawal study), indicating that the compound entered into the system was eliminated from the body, and the blood parameters were improved. Hematological and clinical chemistry parameters can be detected rapidly and hence can be used for prediction and diagnosis of pesticide toxicity. Alterations in these parameters show toxic stress in the treated animals especially on blood and blood-forming organs.     

Alterations in hepatic detoxifying enzymes induced by new organophosphorus insecticides following subchronic exposure in rats.

The present study examined the structure-toxicity relationship of two novel phosphorothionates, a methyl ester (RPR-II) and an ethyl ester (RPR-V), with regard to their interaction with certain biochemical indices in rat. Male rats were treated orally with 10% (low), 20% (medium) and 30% (high) doses of the two compounds (14, 28 and 42 microg kg(-1) day (-1) of RPR-II and 33, 66 and 99 microg kg(-1) day(-1) of RPR-V) daily for 90 days. The activity of hepatic glutathione S-transferase (GST) and UDP-glucuronyl transferase (UDPGT) and the level of glutathione (GSH) were estimated at 0, 45 and 90 days of treatment as well as 28 days after cessation of treatment. RPR-II caused statistically significant depletion of GSH after 45 and 90 days of treatment at the high dose, whereas RPR-V depleted GSH only after 90 days at the high dose. RPR-II inhibited GST after 45 and 90 days at medium and high doses, whereas RPR-V caused inhibition of GST after 45 and 90 days only at the high dose. Significantly, UDPGT activity was increased only by the high dose of RPR-II after 90 days. However, a dose and time-dependent increase in UDPGT activity was observed at all three doses of RPR-V after 45 and 90 days. There was no modulation in any of the three indices at low doses of the two organophosphorus insecticides. The withdrawal study revealed that induced changes in hepatic parameters were reversible 28 days after cessation of treatment. The results indicated that the two insecticides had different potential to modulate hepatic GST, UDPGT and GSH due to subchronic exposure and that these metabolic alterations are quite reversible after withdrawal of treatment.     

Hematological parameters in tench Tinca tinca after short term exposure to lead

Alterations in the hematological parameters of Tinca tinca were studied after exposure to lead at different concentrations and durations of exposure. Dose of 75/24 (ppm/h) did not cause significant change in any blood parameter. The 300/48 dose caused a significant increase in hematocrit (Hct), mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) and a significant decrease in red blood cell (RBC) count and mean corpuscular hemoglobin concentration (MCHC). The 30/24 dose caused a significant increase in Hct and RBC count only. The 30/96 dose caused a significant increase in Hct and a significant decrease in MCHC only. The 30/504 dose caused a significant decrease in RBC count and a significant increase in MCV and MCH. The 75/96 dose caused a significant increase in Hct and a significant decrease in MCH and MCHC. The 75/504 dose caused a significant decrease in Hct, hemoglobin (Hb) and RBC count, and a significant increase in MCV and MCH. These alterations were attributed to direct or feedback responses of structural damage to RBC membranes resulting in hemolysis and impairment in hemoglobin synthesis, stress related release of RBCs from the spleen and hypoxia, induced by exposure to lead.     

Time-course changes of hematology and clinical chemistry values in pregnant rats

The aim of this study is to report how pregnancy alters hematology and clinical chemistry values in rats. Female and male Sprague-Dawley rats were mated; the day of copulation was designated as Day 0. Hematology and clinical chemistry measurements were conducted on Days 7, 14, 17 and 21 in pregnant rats. Measurements were also conducted in non-pregnant rats. Red blood cells (RBC), hemoglobin (Hb), hematocrit (Ht), total protein and albumin decreased on Days 7, 14, 17 and 21; sodium, chloride and glucose decreased on Days 14, 17 and 21; iron decreased on Days 17 and 21; hemoglobin content of reticulocytes (CHr), calcium, inorganic phosphorus and the albumin/globulin ratio decreased on Day 21; and total cholesterol, phospholipid and high-density lipoprotein cholesterol decreased on Day 14 in pregnant rats compared with non-pregnant rats. Reticulocyte increased on Days 7, 14 and 17; mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, neutrophil count and rate increased on Days 14, 17 and 21; platelets, fibrinogen, triglyceride and free fatty acid increased on Days 17 and 21; and activated partial thromboplastin time was prolonged on Days 17 and 21 in pregnant rats compared with non-pregnant rats. The decreased RBC, Hb, Ht, CHr and iron in pregnant rats indicated that they suffered from iron deficiency anemia. These data can be used as background information for effective evaluation in reproductive toxicology studies.     

Subchronic toxicity of chlorpropham (CIPC) in ICR mice.

Male and female ICR mice were given 0, 1875, 7500 or 30,000 ppm of chlorpropham (CIPC) in the diet for 13 weeks. Methemoglobin levels of male and female mice in the 7500 and 30,000 ppm groups were significantly elevated. Hemoglobin concentration, packed cell volume, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and white blood cell count of male and female mice in the 30,000 ppm group were significantly increased. Dose-dependent splenomegaly was observed in male and female mice in the 7500 and 30,000 ppm group. Congestion, increased hemosiderin deposition and increased extramedullary hematopoiesis in the spleen, hematopoietic cell hyperplasia and hemosiderin deposition in bone marrow was observed dose dependently in male and female mice in the 7500 or 30,000 ppm group. Eosinophilic granular cytoplasm of hepatocytes, sinusoidal dilatation, hemosiderin deposition, extramedullary hematopoiesis and necrosis of hepatocytes were observed in the liver of male and female mice in the 30,000 ppm group. Hemosiderin deposition was increased in the kidney of male and female mice in the 30,000 ppm group. Administration of CIPC in diet for 13 weeks caused methemoglobinemia and splenomegaly in ICR mice.     

Haematolohical profile of subacute oral toxicity of molybdenum and ameliorative efficacy of copper salt in goats

Molybdenum toxicity produces a state of secondary hypocuprosis, resulting into alterations in normal hematological profile. In the present study, ammonium molybdate alone and with copper sulfate (II) pentahydrate (ameliorative agent) was administered orally for 30 consecutive days in healthy goats of group 1 and 2, respectively, to access the effect on the hematological profile on different predetermined days of dosing. Administration of ammonium molybdate alone produced significant decline in the mean values of hemoglobin (Hb), packed cell volume (PCV), total leukocyte count (TLC), total erythrocyte count (TEC), and mean corpuscular hemoglobin concentration (MCHC), with a significant increase in neutrophil level and mean corpuscular volume (MCV). However, values of erythrocyte sedimentation rate, mean corpuscular hemoglobin, and differential leukocyte count were not significantly altered. On comparing observations of ameliorative group with the group 1 goats, it is concluded that the ameliorative copper salt has beneficial effects in alleviating the alterations in the values of Hb, PCV, TLC, TEC, MCV, MCHC, and neutrophils.     

Imidacloprid-based commercial pesticide causes behavioral,biochemical, and hematological impairments in Wistar rats

Imidacloprid (IMI) is a neonicotinoid insecticide employed worldwide for crop protection. IMI’s mode of action occurs through the agonism of postsynaptic nicotinic acetylcholine receptors (nAChRs), with high specificity for insect nAChRs although there are reports of mammals’ toxicity. Studies on IMI’s neurotoxicity are not conclusive; therefore, the aim of this study was to evaluate the subchronic toxic effects of an IMI based commercial pesticide on rats. Adult male Wistar rats received an IMI suspension via the oral route at doses of 1.5, 5, and 15 mg/kg for 45 consecutive days. IMI caused an increase in rearing and time spent at the periphery in the locomotor activity test and a decrease in time spent to finish the OX maze task (p < 0.05; ANOVA/Bonferroni). In blood, there was a decrease in mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration (p < 0.05; ANOVA/Bonferroni) and an increase in serum butyrylcholinesterase activity (p < 0.001; ANOVA/Bonferroni). Therefore, subchronic administration of an IMI-based-pesticide caused behavioral and systemic impairments in rats.     

Safety of high doses of Propionibacterium freudenreichii ET-3 culture in healthy adult subjects

Propionibacterium freudenreichii ET-3 (7025) culture, a cell-free product of whey fermentation by P. freudenreichii ET-3, has been shown to promote the growth of Bifidobacteria through the action of 1,4-dihydroxy-2-naphthoic acid (DHNA). Here we report the results of two clinical studies designed to evaluate the safety of high doses of P. freudenreichii ET-3 culture medium. Study 1 had a randomized, double-blind, crossover design. Ten healthy male and four healthy female subjects received 45 tablets of either P. freudenreichii ET-3 culture medium (total daily intake of 3g solid content and 283.5μg of DHNA; active group) or placebo (unfermented product) during two 1-week supplementation periods separated by a 4-week washout period. In Study 2, 11 healthy men took four tablets of P. freudenreichii ET-3 culture medium per day (total daily intake of 0.267g solid content and 22.5μg of DHNA) for a period of 13weeks. In both studies, hematological, clinical chemistry, and urinary parameters were measured before and after each supplementation period and gastrointestinal symptoms were assessed by questionnaire. In Study 1, there were no statistically significant differences between placebo and active supplementation periods in any measured parameter and the incidence of gastrointestinal symptoms were similar between groups. In Study 2, total protein, white blood cell count, hemoglobin, and mean corpuscular hemoglobin concentration decreased significantly from baseline and mean corpuscular volume and urine pH increased from baseline. The changes in hematological parameters were deemed not to be due to P. freudenreichii ET-3 culture medium supplementation given that all parameters remained within normal ranges and were not consistent with any clinically meaningful effect.     

Acute and subchronic oral toxicities of benzo[a]pyrene in F-344 rats.

We have studied the acute and subchronic oral toxicities of benzo[a]pyrene (BaP) in male and female F-344 rats. Single acute BaP doses of 0, 100, 600, and 1000 mg /kg dissolved in peanut oil were administered by oral gavage. Subchronic doses of 0, 5, 50, and 100 mg/kg/day were administered for 90 days in the animal diet. The major toxicological endpoints examined included animal body weight, selected tissue weights, and histopathological examinations (liver, kidney, stomach, prostate, testes, and ovaries). In addition, we examined blood elements: red blood cells (RBC), white blood cells (WBC), hemoglobin (Hgb), hematocrit (Hct), mean cell volume (MCV), mean cell hematocrit (MCH), and mean cell hemoglobin concentration (MCHC), blood chemistry (ALT, AST, and BUN), and urine chemistry (glucose, bilirubin, specific gravity, pH, protein, urobilinogen, nitrite, occult blood, and leucocytes). In the acute study, WBC were significantly decreased and mean cell-hemoglobin concentration was significantly increased, both in males only. The liver:body weight ratio was significantly increased in males and females (up to 30%). None of the blood chemistry or urine parameters were significantly affected. In the subchronic study, mean body weight was significantly decreased in males only (13%), and the liver:body weight ratio in males was significantly increased. Several of the blood elements were significantly decreased in males and females after 90 days; RBCs (up to 10%), Hct (up to 12%), and Hgb (up to 12%). For blood chemistry parameters (AST, ALT, BUN), only BUN in males was significantly increased in the high dose group (100 mg/kg) at the 90 day time point. The histopathological examination of selected tissues showed significant abnormalities (tubular casts) only in the male kidney, at the 2 highest doses, after 90 days. These studies indicate that the acute and subchronic toxicities of BaP are relatively low, BaP affects specific blood elements and organs, and BaP has a greater effect on males than females. The induction of non-carcinogenic kidney abnormalities in males only may be indicative of renal dysfunction and further substantiates an apparent sex difference in tolerance to BAP:     

Micronuclei induction by 13 week-inhalation of 1,1-dichloro-1-fluoroethane in Sprague-Dawley rats

To investigate the genotoxic effect of l,1-dichloro-1-fluoroethane (HCFC-141b), which was currently widely used as a cleaning solvent in the electronic parts industry and suggested as a potential reproductive effector, in vivo micronucleus tests were performed. Groups of 10 male and 10 female Sprague-Dawley rats were exposed, by inhalation (6h/day, 5 days/week) to the vapors of HCFC-141b for 13 weeks using whole body exposure chambers at the concentrations of 0 (control), 1500, 3000, and 6000 ppm. The micronuclei frequencies among the polychromatic erythrocytes (PCEs) and the percentage of polychromatic erythrocytes among the total number of erythrocytes were counted in the bone marrow of rats, and body weights, organ weights, histopathology, clinical chemistry and hematologic changes were also observed. Statistically significant and dose-dependant increases were found in the micronuclei frequencies in the male rats (P<0.01), yet not in the females. The decreases in the percentage of polychromatic erythrocytes among the total number of erythrocytes were also statistically significant (P<0.05) in both sexes of the high concentration groups. However, no exposure-related effects of toxicological significance were noted with respect to organ weights, clinical chemistry and histopathology. Apart from it, only slightly decreased mean corpuscular hemoglobin concentration (MCHC) was noted in the females of 6000 ppm group (P<0.05). These results suggest that HCFC 141b can induce the genetic effects, micronuclei in the rat bone marrows, especially in males, at earlier stages before the other general clinical and histopathologic changes occur if with more prolonged exposure.     

Effects of phenylhydrazine or phlebotomy on peripheral blood, bone marrow and erythropoietin in Wistar rats

This study was conducted to characterize better the response of rats to blood loss and hemolysis and to incorporate automated methods into the routine evaluations of those responses. Serial phlebotomies of 1.5-2.0 ml of blood per day for 5 days, or intraperitoneal injection of 50 mg kg(-1) phenylhydrazine (PHZ) for 3 days, were used to cause anemia associated with blood loss or hemolysis, respectively. Maximum decreases in red blood counts were observed on Day 3 in PHZ-treated animals (68%) and Day 4 in blood-loss animals (35%). In the routine complete blood count (CBC), hemoglobin, hematocrit/hemoglobin ratio and erythrocyte indices could be used to discriminate between the two treatments. Free plasma hemoglobin in PHZ-treated animals resulted in marked elevations of mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) with a 2:1 hematocrit/hemoglobin ratio rather than the anticipated 3:1 ratio. Although both groups of animals had elevated white blood cell counts, PHZ-treated animals also had monocytosis and basophilia. Reticulocyte counts were more sensitive than erythropoietin (EPO) concentrations in predicting erythroid changes. Maximum mean reticulocyte values were ca. 24% in serially phlebotomized animals and >99% in PHZ-treated rats. Plasma EPO levels were 4-10-fold higher than EPO levels in urine, kidney or liver. Flow cytometric differentials of rat bone marrow using 2, 7-dichlorofluorescin successfully predicted erythroid hyperplasia in both experimental groups. Erythrocyte indices returned to normal within 14 days and the remaining CBC parameters were normal within 28 days for both treatment groups. Reticulocyte counts remained slightly elevated on Day 28, but were normal when assessed at Day 56 in blood-loss and PHZ-treated animals.     

Assessment of biochemical,hematological and behavioral biomarkers of Cyprinus carpio on exposure to a type-II pyrethroid insecticide Alpha-cypermethrin

This study assessed some important physiological biomarkers of freshwater edible fish Cyprinus carpio following exposure to 10 % (T1) and 20 % (T2) sublethal concentrations of Alpha-cypermethrin (A-cyp) over a total period of 45 days. Behavioral responses were noticed and Kaplan-Meier survival curves were prepared during acute toxicity study. Total serum protein concentration, total erythrocyte count, hemoglobin, packed cell volume, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and total leukocytes count were decreased significantly (p < 0.05), while the blood glucose, total serum lipid concentration, and clotting time were increased significantly (p < 0.05) over control. The most affected fish group and most significantly altered biomarker under toxic stress of A-cyp were identified using integrated biomarker response (IBR). The biomarker response index (BRI) values measured the overall health status of the treated fish and indicated that moderate adverse effects were exerted on the fish group exposed to T2 for 45 days.     

Haematological and hepatotoxic effects of silken styles of corn in albino rats.

The alterations of haematological parameters in albino rats were studied after oral administration of an aqueous extract of silken styles of corn (Zea maize Linn.) at 50, 100 and 150 mg kg-1 daily for 21 days. The following haematological values were significantly reduced on the 7th and 21st day following extract administration: haemoglobin (Hb), red blood corpuscles (RBC), clotting time (CT), mean corpuscular volume (MCV), haematocrit (Ht), serum glucose, blood urea nitrogen (BUN), cholesterol, aspartate transaminase (AST), alanine transaminase (ALT), calcium, total protein, total albumin and total acid phosphatase; and white blood corpuscles (WBC), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), alkaline phosphatase and creatinine increased. The remaining parameters were not significantly affected, except body weight parameters at the two highest doses. The results emphasize that the biochemical changes caused through aqueous extract of silken styles of corn (Zea maize Linn.) are not significantly toxic at low and medium doses (50 and 100 mg kg-1).     

Acid and alkaline phosphatase activities in a novel phosphorothionate (RPR-11) treated male and female rats. Evidence of dose and time-dependent response

The effect of a novel phosphorothionate, the methyl ester of 2-butenoic acid-3-diethoxy phosphinothioyl (RPR-II) was studied on membrane bound target enzymes Acid (AcP) and Alkaline (AkP) Phosphatases in different tissues of male and female albino Wistar rats. Three sub-chronic doses 0.014 (low), 0.028 (medium) and 0.042 (high)mg/kg-1 were administered to the rats daily for a period of 90 days. The long term and repeated administration of RPR-II caused significant increase of AcP and AkP in serum and kidney (AcP), whereas these enzymes simultaneously decreased significantly in liver, kidney (female rat AkP) and lung tissues in both male and female rats after 45 and 90 days of treatment. However, the kidney AcP increased significantly in both the sexes which is suggestive of an increase in synthesis of this enzyme which may be an adaptive mechanism to the toxicant stress. The changes in serum, liver, kidney and lung of both male and female rats by this compound were statistically significant when compared with two way Anova showing that they are dose and time dependent. The alterations in male rats were statistically insignificant when compared with female rats showing no sexual dimorphism by this compound. Recovery was observed after 28 days of post treatment (withdrawal study) indicating reversal of the toxic symptoms once the toxicant is removed. High degree negative correlation was observed for serum versus liver and lung and in other cases substantial correlation was observed. The changes observed in these enzymes showed that liver was most susceptible followed by lung and kidney. There are marker enzymes and their increase in different tissues might be due to the increased permeability of plasma membrane or cellular necrosis, showing the stress condition of the treated rats. This investigation elucidates the effect of these biomarker enzymes which increased in blood, might be due to the necrosis of liver, kidney and lung tissues by this compound.     

Toxicological assessments of aqueous extract of Eugenia jambolana stem bark

Eugenia jambolana Lam. (Myrtaceae) is widely used in folk medicine as an antidiabetic, but there is a lack of information about its toxicity, especially for the stem bark. The present study evaluated acute oral and repeated-dose toxicity of the stem bark aqueous extract of Eugenia jambolana (EJ) in albino mice and Wistar rats. In the acute toxicity tests, mice received oral doses of EJ extract as 300, 2000, and 5000?mg/kg body weight. Mortality, signs of toxicity, body weight, food consumption, and gross findings were observed for 14 days post-treatment. In repeated toxicity, rats were orally treated with 300, 1000, and 2000?mg/kg body weight, and animals were observed till the 28th day of treatment. At the end of the study period, surviving animals were fasted overnight and anesthetized for blood collection and removal of some vital organs for histopathology. No significant differences were noted in body and organ weights between the control and treated groups from either of the studies. In addition, hematological parameters, e.g., red blood cell count (RBC), hemoglobin concentration (Hb), mean corpuscular hemoglobin concentration (MCHC), platelets (PLT), and white blood cell differential count, biochemical parameters, e.g., blood glucose, creatinine, blood urea nitrogen (BUN), alkaline phosphatase (ALP), bilirubin, total protein, and albumin, and ions, e.g., potassium, sodium, chloride, calcium, and phosphorus, were studied in the repeated-dose toxicity study. In conclusion, these investigations indicate the safety of acute and repeated oral administration of the aqueous extract of EJ stem bark, suggesting therefore that it may be continuously used safely.     

血常规检验诊断缺铁性贫血的临床价值分析

目的探究对缺铁性贫血患者采取血常规检验进行诊断的临床价值。方法 80例贫血患者,按贫血类型不同分为对照组(缺铁性贫血)与研究组(地中海贫血),每组40例。两组均接受血常规检验。比较两组患者红细胞计数(RBC)、血红蛋白(Hb)、红细胞分布宽度(RDW)、平均红细胞体积(MCV)、平均红细胞血红蛋白含量(MCH)以及平均红细胞血红蛋白浓度(MCHC)。结果研究组红细胞计数(3.13±0.92)×10¹²/L、平均红细胞体积(64.99±1.78)fl、红细胞分布宽度(12.35±0.82)%低于对照组的(5.21±1.51)×10¹²/L、(77.54±3.58)fl、(20.05±1.32)%,血红蛋白(108.54±12.76)g/L、平均红细胞血红蛋白含量(24.25±2.33)pg、平均红细胞血红蛋白浓度(321.58±5.22)g/L高于对照组的(82.11±10.78)g/L、(22.51±1.56)pg、(278.33±4.21)g/L,差异具有统计学意义(P<0.05)。结论针对缺铁性贫血患者采取血常规检验能有效区分缺铁性贫血与地中海贫血,利于为病情的进一步治疗做好准备,临床检验价值显著,值得推广应用。     

Clinical Pathology Changes Related to Cutaneous Irritation in the Fischer 344 Rat and New Zealand White Rabbit

Abstract

An evaluation of 27 repeated dose cutaneous application studies (9 applications of 6 h over an 11-day period) indicated that several hematologic and clinical chemistry parameters may be altered by chemically induced skin irritation. Irrespective of species, values that were generally decreased included hemoglobin concentration, hematocrit, erythrocyte count, and serum concentrations of calcium, potassium, inorganic phosphorus, and creatinine. Values that were increased included the neutrophil and total leukocyte counts. Some species differences were seen; for example, while the platelet count and serum globulin concentration were increased in rabbits only, the serum glucose, sodium, and chloride concentrations were increased in rats only. The mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and serum albumin and total protein concentrations were variably affected. Changes were generally well associated with the degree of cutaneous irritation, but did not appear to be related to the chemical class of the test substances, decreased food consumption, loss of body weight, or systemic toxicity of the chemical. However, the relationship of the changes in the clinical pathology measurements to cutaneous irritation or secondary effects was not always clear. Some measurements were considered to be secondary to the cutaneous inflammation while others may be related to vascular and fluid balance alterations. Regardless of the cause of these changes, their frequent occurrence and consistent direction of change suggest a relationship to cutaneous irritation rather than systemic toxicity of the test substances. It is considered important that the interpreter of toxicologic studies be aware of these irritation-induced changes when evaluating the findings of repeated cutaneous application studies.     

Hematotoxic and hepatotoxic effects of dichlorvos at sublethal dosages in rats

The present study was designed to understand the effects of sublethal concentrations of dichlorvos (DIC) on hematological constituent [red blood corpuscles, white blood corpuscles (WBC), mean cell volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet counts, hemoglobin and hematocrite levels] and serum damage marker enzymes (aspartate aminotransferase, alanin aminotransferase, alkaline phosphatase, and lactate dehydrogenase) in rats at subacute period under laboratory conditions. DIC at dosages of 5 and 10 ppm was administered orally to six male rats ad libitum during the tests for 4 weeks consecutively. According to the results, DIC treatments increased significantly the levels of serum marker enzyme activities, whereas they did not change hematologic constituent except for WBC number treated with both dosages of DIC. The observations presented led us to conclude that the administrations of subacute DIC induced the levels of damage marker enzymes and leukocytosis.     

ACID AND ALKALINE PHOSPHATASE ACTIVITIES IN A NOVEL PHOSPHOROTHIONATE (RPR-11) TREATED MALE AND FEMALE RATS. EVIDENCE OF DOSE AND TIME-DEPENDENT RESPONSE

The effect of a novel phosphorothionate, the methyl ester of 2-butenoic acid-3-diethoxy phosphinothioyl (RPR-II) was studied on membrane bound target enzymes Acid (AcP) and Alkaline (AkP) Phosphatases in different tissues of male and female albino Wistar rats. Three sub-chronic doses 0.014 (low), 0.028 (medium) and 0.042 (high) mg/kg-1 were administered to the rats daily for a period of 90 days. The long term and repeated administration of RPR-II caused significant increase of AcP and AkP in serum and kidney (AcP), whereas these enzymes simultaneously decreased significantly in liver, kidney (female rat AkP) and lung tissues in both male and female rats after 45 and 90 days of treatment. However, the kidney AcP increased significantly in both the sexes which is suggestive of an increase in synthesis of this enzyme which may be an adaptive mechanism to the toxicant stress. The changes in serum, liver, kidney and lung of both male and female rats by this compound were statistically significant when compared with two way Anova showing that they are dose and time dependent. The alterations in male rats were statistically insignificant when compared with female rats showing no sexual dimorphism by this compound. Recovery was observed after 28 days of post treatment (withdrawal study) indicating reversal of the toxic symptoms once the toxicant is removed. High degree negative correlation was observed for serum versus liver and lung and in other cases substantial correlation was observed. The changes observed in these enzymes showed that liver was most susceptible followed by lung and kidney. There are marker enzymes and their increase in different tissues might be due to the increased permeability of plasma membrane or cellular necrosis, showing the stress condition of the treated rats. This investigation elucidates the effect of these biomarker enzymes which increased in blood, might be due to the necrosis of liver, kidney and lung tissues by this compound.     

Oral (gavage), in utero and post-natal exposure of Sprague-Dawley rats to low doses of tributyltin chloride. Part II: effects on the immune system.

The immunotoxic effects of tributyltin chloride (TBTC) were examined in the offspring of Sprague-Dawley rats exposed in utero from day 8 of gestation, through lactation and post-weaning until pups reached the age of 30 days (male and female), 60 days (female) and 90 days (male). Daily oral (gavage) doses of 0.025, 0.25 and 2.5 mg/kg body weight/day were administered in olive oil 7 days/week. Immunologic endpoints were investigated at the termination of each study. Statistically significant results (P<0.05) included the following: At 30 days, the mean percent and absolute natural killer (NK) cell numbers were increased in male and female rats treated with the high TBTC dose. At 60 days, female rats had increased mean serum IgM levels at the low and high TBTC doses, increased mean percentage CD4(+)8(+) (immature) T lymphocytes at the middle and high doses, a non-linear dose-response increase in NK cell activity at the 50:1 and 100:1 effector:target cell ratios (pairwise comparisons significant at the low dose compared with control), and increased mean numbers of L. monocytogenes colony-forming bacteria on Day 2 post-infection (significant for trend) and Day 3 post infection (pairwise comparisons significant only in the middle dose). The 90-day male rats had decreased mean serum IgA levels at the middle dose group; increased IgM levels at the high dose group, increased IgG levels at the middle and high doses; decreased IgG2(a) in the high dose compared to the control; a dose-related increase in the mean percentage NK cell numbers (pairwise comparisons significant at the high dose compared with the control) and increased mean NK cell activity (pairwise comparisons significant at all dose groups compared with the control). The delayed-type hypersensitivity response to oxazolone was increased in the low and middle doses and decreased in the high dose. Thymus atrophy was observed in the high TBTC dose across all ages. Thus, in utero and post-natal treatment of F1 rats with low levels of TBTC affected some aspects of humoral and cell mediated immunity as well as the number and function of cells which are involved in the host's immunosurveillance mechanisms against tumours and viral infections.