A nude mutant rat derived from Sprague Dawley-National Institute of Nutrition rat colony with normal thymus: A potential model for noncommunicable diseases.

BACKGROUND: A spontaneous mutant rat with a hairless phenotype and an intact thymus was discovered in a long-standing Sprague Dawley-National Institute of Nutrition (SD/NIN) rat colony at a national animal resource facility. OBJECTIVE: We conducted extensive phenotypic and biochemical analyses on this mutant strain to determine its suitability as a preclinical model for immunocompetent testing in noncommunicable disease research. MATERIALS AND METHODS: We subjected the mutant rats to strict and frequent phenotypic and genetic surveillance to accomplish this objective. The animals were assessed for food intake, body weight, blood cell profile, clinical chemistry, adipose tissue deposition, and bone mineral density (BMD) using total electrical body conductance (TOBEC) and dual-energy X-ray absorptiometry (DXA) analysis. RESULTS: Initially, only two hairless mutant rats, a male and a female, were born from a single dam in the SD/NIN rat strain. However, the results indicate that the mutant colony propagated from these unique pups displayed distinct phenotypic features and exhibited differences in feeding behavior, weight gain, and clinical biochemistry. The food conversion rate was significantly higher in nude females (2.8-fold) while 26% lower in nude males. Both sexes of nude rats had significantly higher triglycerides and lower glucose levels in females. However, glucose levels did not change in male nude rats. Furthermore, nude female and male rats had significantly lower fat (TOBEC) and bone mineral content (DXA). Nonetheless, BMD was only slightly lower (7%-8%) compared to the heterozygous groups. CONCLUSIONS: These findings indicate that the spontaneous mutant rat has the potential to serve as an immunopotent and modulatory testing system in pharmacokinetics/pharmacodynamics and toxicology, which can be further explored for therapeutic drug discovery.

Effect of ethyl gallate and propyl gallate on dextran sulfate sodium (DSS)-induced ulcerative colitis in C57BL/6 J mice: preventive and protective.

OBJECTIVE AND DESIGN: Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition of the digestive system marked by oxidative stress, leukocyte infiltration, and elevation of inflammatory mediators. In this study, we demonstrate the protective effect of ethyl gallate (EG), a phytochemical, and propyl gallate (PG), an anti-oxidant, given through normal drinking water (DW) and copper water (CW) in various combinations, which had a positive effect on the amelioration of DSS-induced ulcerative colitis in C57BL/6 J mice. MATERIALS AND METHODS: We successfully determined the levels of proinflammatory cytokines and anti-oxidant enzymes by ELISA, tracked oxidative/nitrosative stress (RO/NS) by in vivo imaging (IVIS) using L-012 chemiluminescent probe, disease activity index (DAI), and histopathological and morphometric analysis of colon in DSS-induced colitis in a model. RESULTS: The results revealed that oral administration of ethyl gallate and propyl gallate at a dose of 50 mg/kg considerably reduced the severity of colitis and improved both macroscopic and microscopic clinical symptoms. The level of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, and IFN-γ) in colonic tissue was considerably reduced in the DSS + EG-treated and DSS + PG-treated groups, compared to the DSS alone-treated group. IVIS imaging of animals from the DSS + EG and DSS + PG-treated groups showed a highly significant decrease in RO/NS species relative to the DSS control group, with the exception of the DSS + PG/CW and DSS + EG + PG/CW-treated groups. We also observed lower levels of myeloperoxidase (MPO), nitric oxide (NO), and lipid peroxidation (LPO), and restored levels of GST and superoxide dismutase (SOD) in DSS + EG-DW/CW, DSS + PG/DW, and DSS + EG + PG/DW groups compared to DSS alone-treated group. In addition, we showed that the EG, PG, and EG + PG treatment significantly reduced the DAI score, and counteracted the body weight loss and colon shortening in mice compared to DSS alone-treated group. In this 21-day study, mice were treated daily with test substances and were challenged to DSS from day-8 to 14. CONCLUSION: Our study highlights the protective effect of ethyl gallate and propyl gallate in various combinations which, in pre-clinical animals, serve as an anti-inflammatory drug against the severe form of colitis, indicating its potential for the treatment of IBD in humans. In addition, propyl gallate was investigated for the first time in this study for its anti-colitogenic effect with normal drinking water and reduced effect with copper water.

An innovative method of nonclinical efficacy and toxicological evaluation of recombinant Salmonella typhi Ty21a expressing HPV16 and 18 L1 proteins.

Advancement in technology led to development of live attenuated Salmonella typhi Ty21a as enteric vector for expression of foreign proteins. Such vector platform is inevitable for development of vaccine candidate against human papilloma virus (HPV), the etiological agent of cervical cancer with high prevalence in developing nations. The high risk HPVs like type 16 and 18 contributes to 70% of cervical cancer, hence Indian Immunologicals Limited (IIL), Hyderabad, India developed a recombinant HPV vaccine by introducing HPV 16 and 18 L1 protein coding genes into attenuated S. typhi Ty21a vector. Being a genetically engineered enteric vector vaccine, it would be less expensive, with an ease of oral administration, instead of injectable that needs trained personale, is an added advantage for low socioeconomic setup compared to existing HPV vaccines. Establishing the nonclinical efficacy and safety/toxicity as per the national/international regulatory guidelines has become major constrain for such recombinant S. typhi HPV (rSt.HPV) vaccine. Since, the intended clinical mode of rSt.HPV is through oral route, whereas the live attenuated S. typhi Ty21a doesn't colonize in gut of laboratory animals to be used for nonclinical experiments. Hence, an alternate and unconventional method of 'intranasal drug testing', was followed for nonclinical efficacy and toxicity evaluations. An array of parameters specified by regulatory agencies were investigated in mice, rat and rabbits administered with rSt.HPV through, intra-peritoneal, intranasal and oral routes, the intended clinical route.•Current unconventional and innovative nonclinical testing procedures helps in exploring the alternate methods by pharmacologist/toxicologist.•Ultimately, such new drugs developed through technology must serve the humankind justifying the guidelines of regulatory agencies.

Toxicological data of rats and rabbits: Sub-chronic testing of recombinant HPV vaccine through oral and intranasal routes.

Current article illustrates the data of body weight, biochemical, haematological profile, and organ weights of rats and rabbits administered with recombinant human papilloma virus (HPV) vaccine, along with genotoxicity effect. The data was collected from nonclinical safety/toxicity and immune response evaluations of recombinant Salmonella typhi expressing the HPV 16 and 18 L1 proteins as vaccine. The intended clinical route of vaccine administration is through oral route, whereas it is established fact that attenuated S. typhi could not colonize in laboratory animals. In view of this it is challenging to undertake the nonclinical safety/toxicity evaluations following the regulatory guidelines. Hence sub chronic safety/toxicity testing was carried out in rat and rabbits by administration of HPV vaccine through oral (intended clinical route) and innovative intranasal routes. The prophylactic dose derived from adult human clinical dose (2 × 109CFU/70 kg) was administered to SD rats (PD: 0.18 × 109CFU/kg) and New Zealand White (NZW) rabbits (PD: 0.09 × 109CFU/kg) through oral and intranasal routes. Similarly, average dose (AD:5xPD) was administered to rats (AD:0.9 × 109CFU/kg) and rabbits (AD: 0.45 × 109CFU/kg) through intranasal route only. The repeated doses were administered on 3rd and 5th days of post-exposure of 1st dose through specified routes and test compound effects in relation with time of exposure was assessed by euthanizing animals and data collection at different time points i.e. 15th (25% of animals), 29th (25% of animals) and 93rd days (50% of animals) of post-exposure of 1st dose. The retro-orbital plexus blood was collected before euthanizing animals to unveil the biochemical and haematological profile. The data on genotoxicity effect of test compound, if any, was obtained by assessing the bone-marrow micronucleus assay. The immune response and allergenicity in terms of specific IgG and IgE levels against HPV 16 and 18 L1 proteins were determined in mice. The raw data of various parameters collected at different time points were compiled and computed according to the groups. The haematological profile and organ weights data can be used as reference data for SD rats and NZW rabbits for future studies.

Nonclinical safety evaluation of oral recombinant anti-human papilloma virus vaccine (RHPV 16 & 18): Regulatory toxicology studies in mice, rats and rabbits - An innovative approach.

AIM: The human papilloma virus (HPV) type 16 and 18 causes nearly 70% of uterine cervical cancers. Oral administration of live Salmonella typhi Ty21a, expressing major capsid proteins (L1) of HPV 16 and 18 is a potential choice for immunization in adolescent girls under low resource settings. Present study aimed to assess the nonclinical safety of recombinant S. typhi expressing HPV 16 and 18 (rStHPV) proteins. METHODOLOGY: The acute toxicity of rStHPV was tested by intranasal single dose administration, of 10 and 50 folds higher than clinical prophylactic dose, in mice and rat followed by monitoring their survival for 14 days. Sub-chronic toxicity was evaluated in rats and rabbits with prophylactic and 5 times (average) to clinical prophylactic dosages on scheduled days (1st, 3rd & 5th day) through oral and intranasal routes. The immune/allergic response of rStHPV was assessed in mice through intranasal and intra-peritoneal routes. Experimental animals were daily monitored for live phase, and clinical chemistry, haematology, immunotoxicology, immunogenic response and histopathological examination of vital organs on 15th, 29th and 93rd days. RESULTS: No abnormal changes were noticed in live phase activity, clinical chemistry and haematology profile. The gross necropsy, organ weights and histopathology were found to be normal. No immunotoxicity was recorded as evaluated by tier I tests. Allergic immune response, as evaluated with IgE levels was also negative irrespective of test routes. On the other hand, a significant (P < 0.01) increase of anti-HPV IgG levels was noted in mice exposed through intranasal route. Though the pre-terminal mortality was noted in mice (6-15%), rats (10%) and rabbits (15%), the autopsy revealed no signs of toxicity related to rStHPV, as the changes neither significant nor dose dependent; and even noted in vehicle control also. CONCLUSION: The study results suggested 'no observable adverse effects' of rStHPV even at higher dosages (5, 10 & 50 folds) than intended clinical dose. A significant increase of anti-HPV specific IgG suggests the immunogenicity of vaccine. The innovative approach of current study is nonclinical toxicology evaluation of vaccine through intra-nasal route, an alternate route apart from stipulated regulatory guidelines.

Disease surveillance during a large religious mass gathering in India: The Prayagraj Kumbh 2019 experience.

BACKGROUND: Mass gathering (MG) events are associated with public health risks. During the period January 14 to March 4, 2019, Kumbh Mela in Prayagraj, India was attended by an estimated 120 million visitors. An onsite disease surveillance was established to identify and respond to disease outbreaks. METHODS: A health coordination committee was established for planning. Disease surveillance was prioritized and risk assessment was done to identify diseases/conditions based on epidemic potential, severity of illness, and reporting requirement under the International Health Regulations (IHR) of 2005. A daily indicator and event-based disease surveillance was planned. The indicator-based surveillance (IBS) manually and electronically recorded data from patient hospital visits and collected MG area water testing data to assess trends. The event-based surveillance (EBS) helped identify outbreak signals based on pre-identified event triggers from the media, private health facilities, and the food safety department. Epidemic intelligence was used to analyse the data and events to detect signals, verify alerts, and initiate the response. RESULTS: At Kumbh Mela, disease surveillance was established for 22 acute diseases/syndromes. Sixty-five health facilities reported 156 154 illnesses (21% of a total 738 526 hospital encounters). Among the reported illnesses, 95% (n = 148 834) were communicable diseases such as acute respiratory illness (n = 52 504, 5%), acute fever (n = 41 957, 28%), and skin infections (n = 27 094, 18%). The remaining 5% (n = 7300) were non-communicable diseases (injuries n = 6601, 90%; hypothermia n = 224, 3%; burns n = 210, 3%). Water samples tested inadequate for residual chlorine in 20% of samples (102/521). The incident command centre generated 12 early warning signals from IBS and EBS: acute diarrheal disease (n = 8, 66%), vector-borne disease (n = 2, 16%), vaccine-preventable disease (n = 1, 8%), and thermal event (n = 1, 8%). There were two outbreaks (acute gastroenteritis and chickenpox) that were investigated and controlled. CONCLUSIONS: This onsite disease surveillance imparted a public health legacy by successfully implementing an epidemic intelligence enabled system for early disease detection and response to monitor public health risks. Acute respiratory illnesses emerged as a leading cause of morbidity among visitors. Future MG events should include disease surveillance as part of planning and augment capacity for acute respiratory illness diagnosis and management.

Podophyllotoxin and Rutin Modulate M1 (iNOS+) Macrophages and Mitigate Lethal Radiation (LR) Induced Inflammatory Responses in Mice.

Accidental exposure to lethal doses of Gamma radiation leads to the systemic inflammatory syndrome which causes mortality. In view of this, management of hemopoietic syndrome by modulating pro-inflammatory response in clinically manageable time period seems to be the most appropriate strategy for encountering radiation induced damage and recovery. As both tissue and peripheral macrophages are critical for the management of radiation induced injuries, we have unraveled the immunomodulatory potential of radioprotective formulation (G-003M) on peripheral macrophages populations in this study. G-003M inhibited lethal radiation induced NO and Th1 effector cytokines in the exposed macrophages indicating its M1 dim polarizing capacity. In similar lines, conditioning of mice with G-003M before lethal irradiation (LR) inhibited LR induced titre of Th1 effector cytokines in both serums as well as in lung, small intestine, and spleen tissue confirming its immunomodulatory potential. G-003M potentially down modulated inflammatory response in LPS induced inflammatory model and enhanced M2 polarization of iNOS+ M1 effector macrophages providing a molecular hint on G-003M mechanism of action on macrophages. These observations revealed that G-003M potentially modulate pro-inflammatory programming of macrophages and mitigate radiation-induced inflammatory stress which is believed to contribute significantly to radioprotective attribute of G-003M. In this study, we demonstrate that Rutin and Podophyllotoxin drive M1dim/M2 polarization of LR primed macrophages apart from protecting DNA from radiation. These drugs have the capacity to programme innate immune cells like macrophages which may be involved in homeostasis during recovery.

Sphingosine-1-Phosphate (S-1P) Promotes Differentiation of Naive Macrophages and Enhances Protective Immunity Against Mycobacterium tuberculosis.

Sphingosine-1-phosphate (S-1P) is a key sphingolipid involved in the pathobiology of various respiratory diseases. We have previously demonstrated the significance of S-1P in controlling non-pathogenic mycobacterial infection in macrophages, and here we demonstrate the therapeutic potential of S-1P against pathogenic Mycobacterium tuberculosis (H37Rv) in the mouse model of infection. Our study revealed that S-1P is involved in the expression of iNOS proteins in macrophages, their polarization toward M1 phenotype, and secretion of interferon (IFN)-γ during the course of infection. S-1P is also capable of enhancing infiltration of pulmonary CD11b+ macrophages and expression of S-1P receptor-3 (S-1PR3) in the lungs during the course of infection. We further revealed the influence of S-1P on major signaling components of inflammatory signaling pathways during M. tuberculosis infection, thus highlighting antimycobacterial potential of S-1P in animals. Our data suggest that enhancing S-1P levels by sphingolipid mimetic compounds/drugs can be used as an immunoadjuvant for boosting immunity against pathogenic mycobacteria.

Exploring antiurolithic effects of gokshuradi polyherbal ayurvedic formulation in ethylene-glycol-induced urolithic rats.

Gokshuradi Yog (GY) is a polyherbal ayurvedic formulation used traditionally for several decades in India for the treatment of urolithiasis. The aim of the present study was to determine the underlying mechanism of GY action in the management of calcium oxalate urolithiasis. The effect of Gokshuradi polyherbal aqueous extracts (GPAEs) was studied on various biochemical parameters involved in calcium oxalate formation by employing in vitro and in vivo methods. GPAE exhibited significant antioxidant activity against 1, 1-diphenyl-2-picrylhydrazyl free radical and inhibited lipid peroxidation in the in vitro experiments. The rat model of urolithiasis induced by 0.75% ethylene glycol (EG) and 1% ammonium chloride (AC) in water caused polyuria, weight loss, impairment of renal function, and oxidative stress and decreased antioxidant enzyme activities in untreated control groups. However, GPAE- (25, 50, and 100 mg/kg) treated groups caused diuresis accompanied by a saluretic effect and revealed significant increase in antioxidant enzyme activities along with decreased oxalate synthesizing biochemical parameters at higher doses. This study revealed the antiurolithic effect of GPAE mediated possibly through inhibiting biochemical parameters involved in calcium oxalate formation, along with its diuretic and antioxidant effects, hence supporting its use in the treatment of calcium oxalate urolithiasis.

Incorporation of Cestrum diurnum leaf improves intestinal Ca transport in broilers.

The economy of Ca utilization is under the control of vitamin D(3), particularly its active metabolite 1,25-dihydroxy cholecalciferol [1,25(OH)(2)D(3)]. In sufficient Ca absorption leads to tibial dyschondroplasia resulting in not attaining optimum body weight. Our earlier studies [T.P. Prema, N. Raghuramulu, Phytochemistry 37 (1994) 167] have shown that the Cestrum diurnum (CD) leaves contain vitamin D(3) metabolites. It was felt whether incorporation of CD as a source of 1,25(OH)(2)D(3) could improve the Ca absorption in broilers. Four groups of 60 birds each were fed with either normal diet or normal diet+0.25% CD or normal diet without vitamin D(3) or normal diet without vitamin D(3)+0.25% CD leaf powder for 45 days. In subsample of six birds it was observed that incorporation of CD leaves in the feed had the maximal effect on all the parameters studied. The results indicate that the intestinal Ca transport as represented by Serosa/Mucosa (S/M) ratio was found to be significantly (p<0.01) higher in broilers fed diet with CD leaf powder and the 1alpha hydroxylase activity in kidney is significantly (p<0.001) higher in negative controls. On the other hand the supplementation of CD leaves enhanced the serum Ca, body weight, tibia weight, density and strength resulting in the disappearance of tibial dyschondroplasia. No lesions of toxicity were observed in any of the soft tissue examined. The results suggest that the incorporation of CD leaf powder in poultry feed could be beneficial to the poultry.

Cestrum diurnum leaf as a source of 1,25(OH)2 Vitamin D3 improves egg shell thickness.

A continuing concern of the poultry industry is the high incidence (12%) of egg losses in the laying house due to poor egg shell quality. Calcium (Ca) homeostasis is a key factor in egg shell formation. The economy of Ca utilisation is under the control of Vitamin D(3), particularly its active metabolite 1,25-dihydroxy cholecalciferol [1,25(OH)(2)D(3)]. Supplementation of 1,25(OH)(2)D(3) has been shown to increase specific gravity, shell thickness and shell weight of the egg. However, commercially available synthetic 1,25(OH)(2)D(3) is very expensive. Earlier studies from our Institute [Phytochemistry 37 (1994) 677] have identified a cheap, natural and rich source of 1,25(OH)(2)D(3) in the leaves of Cestrum diurnum (CD), a member of the Solanaceae family. In this study, CD leaves were explored as a source of 1,25(OH)(2)D(3) in the feed of layer birds to improve the egg shell thickness. Fifteen-week-old white leghorn layers were divided into four treatments of 60 birds each and as follows: (I) normal diet with Vitamin D(3), (II) normal diet with Vitamin D(3) + CD, (III) normal diet without Vitamin D(3) and, (IV) normal diet without Vitamin D(3) + CD powder. CD leaf powder was incorporated in to the feed at 0.3% level. The experimental feeding was continued up to 72 weeks of age of the birds. Weekly food intake and daily egg production were noted throughout the experimental period and the specific gravity of the eggs, feed consumed to lay one egg and egg shell thickness were determined. Incorporation of CD leaves in the feed had the maximal effect on all the parameters studied. The feed consumed to lay one egg was 20 g less than the control group. The specific gravity of the egg was higher by 0.005, than the control egg, indicating a 5% decrease in the breakage of eggs in CD fed chicks. Also there was a significant increase (P < 0.001) in egg shell thickness. The data suggest that incorporation of CD leaf powder in the feed of poultry layers increased the egg shell thickness, which in turn could decrease the economic loss due to breakage of eggs.

Changes in biochemical indicators of iron status during iron repletion and depletion in monkeys.

Different modes of iron depletion and repletion were studied in monkeys to understand the sequential changes in and the relative importance of different biochemical indicators of iron status. Six control monkeys were divided into two groups, one was fed an iron-deficient diet (group 1) and the other underwent phlebotomy in addition to receiving an iron-deficient diet (group 2). Previously iron-depleted monkeys were subdivided into 4 groups of 3 animals each. While one group was continued on the iron-deficient diet (group 3), the second group received parenteral iron (group 4), the third group (group 5) received a sufficient-iron-containing diet, and the fourth group was fed 50% of the iron requirement. All indicators of iron status like hemoglobin (Hb), erythrocyte protoporphyrin (EPP), serum transferrin saturation and serum ferritin were monitored periodically, in addition to liver and bone marrow iron. all the indicators except serum ferritin and liver iron showed a decrease in group 2. On the other hand, animals receiving parenteral iron (group 4) showed an increase in all the parameters except serum ferritin. The dietary supplementation produced an increase in Hb and a decrease in EPP only (groups 5 and 6). There was a significant positive correlation between changes in bone marrow iron and Hb concentration depending on the severity of depletion and repletion. Both serum ferritin and liver iron did not respond to changes in dietary iron. Another parameter which responded to repletion was EPP. Serum ferritin and liver iron did not respond to changes in dietary iron or was not sensitive to subclinical iron deficiency. The results indicate that change in Hb is more sensitive to detect the deficiency of iron. It was also observed that different parameters respond variably under different modes of depletion and repletion.

Induction of dietary iron deficiency in rhesus monkeys: sequential changes in serum ferritin and other biochemical indicators of iron status.

The usefulness of serum ferritin as a measure of subclinical stages of iron deficiency has been tested in monkeys by inducing a mild iron deficiency dietarily over a period of 12 months. Various biochemical indicators of iron status were measured periodically along with analysis of liver iron and iron staining of bone marrow samples obtained by biopsy, at the end of the experiment. A mild form of iron deficiency was confirmed by bone marrow staining for iron. Of all the biochemical indicators tested, significant decreases were seen in hemoglobin and hematocrit at the 11th and 10th months, respectively. These changes were consistent with the changes later found in bone marrow grading for iron. Serum ferritin concentration and liver iron concentration did not show any significant difference between the controls and iron-deficient monkeys. Thus, these results do not support the existence of a latent stage of iron deficiency. In the mild form of iron deficiency, the functional compartment, represented by bone marrow iron and hemoglobin, is sensitive to depletion even when there were no changes in storage compartment represented by liver iron and serum ferritin.

Acute toxicity and anti acetylcholinesterase potential of some biphenyl derivatives to non target species.

Five newly synthesised biphenyl derivatives were evaluated for their acute contact toxicity (LC50) against rice weevil and honey bee and anti acetylcholinesterase potential (I50) against honey bee, fish, pigeon and rat. Amongst, O,O-dimethyl-O, p-Nitro-biphenyl phosphate was most potent against rice weevil, whereas p-(4-Nitrophenyl) phenyl-N-methyl carbamate against honey bee. Based on I50 values the biphenyl derivatives of phosphoric acid esters were more potent anti acetylcholinesterase (AChE) agents against rat and fish brain AChE while derivative of carbamic esters towards pigeon brain AChE. The anti AChE potency of both groups appear to be of the same order towards bee head AChE.

Haemotoxicity to chicken (Gallus gallus domesticus) by technical and formulation grades of some phosphoric and synthetic pyrethroid esters.

Acute toxicity was studied by administering an encapsulated single dose to chickens (G.g. domesticus) and observing them for 21 days. Azodrin-71 (Tech.) was found to be extremely toxic, whereas Cypermethrin-92 (Tech.), Cypermethrin-25 EC and Permasect-25 EC (Form.) were practically non-toxic based on LD50 value determinations. Sub-acute oral haemotoxicity of technical and formulation grades of these insecticides was also studied by administering encapsulated low, medium and high daily doses for 21 days to chickens and recording clinical symptoms, mortality and haematological parameters pre and post-dosing. Clinically high doses of Azodrin-71 (Tech.) caused tremors and ataxia among chicks on the 10th day after dosing. Synthetic pyrethroids caused slight tremours in the whole body accompanied by salivation. In general, hyperactivity to external stimuli and loss of appetite and body weight were also observed. With sub-acute oral doses, Permasect-25 EC (Form.) more potently affected haemoglobin (Hb), red cell (RBC) counts and chloride level. Cypermethrin-92 (Tech.) was most potent towards thrombocytes and clotting time. Azodrin-71 (Tech.) was more potent to white cell (WBC) counts and serum protein level. The present Haematological studies have disclosed the possible reaction of blood and blood forming organs to these insecticides.

Some metabolic changes induced by endosulfan in hepatic and extra hepatic tissues of rat.

Effects of three different doses of endosulfan respectively designated as low, medium and high on cytochrome P450(Cyt.P450), glutathione S-transferase(GST) activity and glutathione content (GSH) of hepatic and extra hepatic tissues of rat were determined after 24 hours of treatment. Endosulfan caused induction of cyt. P450 in liver, lung and brain at all the three doses tested while in kidney, spleen and heart either induction or reduction took place and was unrelated with dosages of endosulfan. Similarly, GST activity significantly changed in extra hepatic tissues while liver GST activity did not record any significant alteration under the experimental conditions. The GSH content also showed changes (increase/decrease) unrelated to endosulfan dosages in different organs. Thus, the effects varied with organ and dosages. As these metabolic parameters are involved in biotransformation of many endogenous molecules as well, the study may throw some light on physiological disturbances due to changes in metabolizing system on one side and organ specificity in toxic action of endosulfan on the other.

Effect of dermal application of phosphamidon-92 (technical) on different tissues and hematobiochemical parameters in albino rat.

The histological disturbances occurring from the dermal application of low, medium, and high doses of phosphamidon-92 (technical) to rats as observed by light microscope and analysis of hematobiochemical parameters of blood are presented. Groups of 10 male and 10 female albino rats (Wistar strain) were treated with the test material at dose levels of 0.48 (low), 2.2 (medium), and 3.98 (high) mg/kg X d for 3 wk, followed by a 2-wk observation period. During application, a reduction in food intake and in body weight was recorded with all three treatments. However, gain in body weight and food intake resumed during the observation period and was marked with the high-dose treatment only. Symptoms like hypersalivation and frothing were noticed in both the sexes, as well as a relative decrease in liver weight and gross pathological alterations on microscopical examination of skin, lung, kidney, and testis; significant alterations in some hematobiochemical parameters of blood were observed.