Reduced Erythrocyte Counts Research Articles

Iron citrate Synthesit: impact on blood parameters in non-iron deficient models

Iron's significance extends beyond treating anemia, impacting various disorders. However, studies on iron-fortified diets in healthy subjects are limited. To evaluate the effects of Synthesit iron citrate on biochemical, hematological parameters, and body weight in aged rhesus macaques, and its safety in SHK-line mice. An experimental study involved SHK mice and rhesus macaques receiving Synthesit iron citrate, with blood parameters, histology, hematopoietic stem cells, and biochemistry monitored over 30 days (14 mice) and six weeks (8 macaques). The study shows increased hematopoietic cell types and mitosis index, with significant increases in Myelokaryocyte count (32.4%), megakaryocyte count (3.7-fold), myeloblast count (1.7-fold), mononuclear cell count (2.5-fold), erythroblast count (4-fold), and reticulocytes (13.3%). In macaques, supplementation initially reduced erythrocyte count, followed by recovery, while thrombocyte count increased initially but decreased post-supplementation. Leukocyte analysis showed varied responses, with a decrease in monocyte and lymphocyte but an increase in neutrophil percentage. Biochemical analyses revealed improvements in glucose (baseline: 4.36 ± 0.32 mmol/l vs day 43: 3.30 ± 1.06 mmol/l), cholesterol (baseline: 4.563 ± 0.799 mmol/l vs day 29: 2.84 ± 0.88 mmol/l), and triglyceride levels (baseline: 1.49 ± 0.63 mmol/l vs day 29: 0.70 ± 0.34 mmol/l). The novel study reveals the effects of iron citrate synthesis in non-iron deficient models into the blood parameters which has metabolic potential. In conclusion, Synthesit® iron citrate supplementation exhibits promising effects on hematopoiesis and metabolic parameters in murine and primate models.

Wnt/β-Catenin-Signaling Modulates Megakaryopoiesis at the Megakaryocyte-Erythrocyte Progenitor Stage in the Hematopoietic System.

The bone marrow (BM) hematopoietic system (HS) gives rise to blood cells originating from hematopoietic stem cells (HSCs), including megakaryocytes (MKs) and red blood cells (erythrocytes; RBCs). Many steps of the cell-fate decision remain to be elucidated, being important for cancer treatment. To explore the role of Wnt/β-catenin for MK and RBC differentiation, we activated β-catenin signaling in platelet-derived growth factor b (Pdgfb)-expressing cells of the HS using a Cre-lox approach (Ctnnb1BM-GOF). FACS analysis revealed that Pdgfb is mainly expressed by megakaryocytic progenitors (MKPs), MKs and platelets. Recombination resulted in a lethal phenotype in mutants (Ctnnb1BM-GOFwt/fl, Ctnnb1BM-GOFfl/fl) 3 weeks after tamoxifen injection, showing an increase in MKs in the BM and spleen, but no pronounced anemia despite reduced erythrocyte counts. BM transplantation (BMT) of Ctnnb1BM-GOF BM into lethally irradiated wildtype recipients (BMT-Ctnnb1BM-GOF) confirmed the megakaryocytic, but not the lethal phenotype. CFU-MK assays in vitro with BM cells of Ctnnb1BM-GOF mice supported MK skewing at the expense of erythroid colonies. Molecularly, the runt-related transcription factor 1 (RUNX1) mRNA, known to suppress erythropoiesis, was upregulated in Ctnnb1BM-GOF BM cells. In conclusion, β-catenin activation plays a key role in cell-fate decision favoring MK development at the expense of erythroid production.

Viral Bronchiolitis Findings in Children at the Pediatric Clinic of Clinical Center of the University of Sarajevo

Bronchiolitis is a relatively common respiratory condition, usually presenting in the first two years of life. It is followed by audible phenomena, due to inflammatory airway obstruction. Common symptoms are nasal discharge, cough, tachypnoea, fever, and cyanosis. The cause is viral, most commonly respiratory syncytial virus. Bronchitis leads to respiratory acidosis and leads to accumulation of carbon dioxide. We analyzed 83 patients with a diagnosis of bronchiolitis at the discharge from the Pediatric clinic of the Clinical Center of the University of Sarajevo. We observed the relationships between acid-base status parameters, blood work parameters, age, and weight and placed them into groups based on whether they had any co¬morbidities or not. Patients without comorbidities showed significant differences in age, body temperature, and leukocyte count compared to patients with comorbidities. We also noted significant correlations be¬tween age, weight, hemoglobin level, hematocrit, erythrocyte count, pCO2, pH, and HCO3 which led to a conclusion that it is likely that in young children with bronchiolitis, the issue is not in the elimination of CO2 through lungs. Rather, it is the transport of CO2 to the lungs due to reduced erythrocyte count and so we believe, that if proven feasible, bronchiolitis could be treated with pure erythrocyte trans.

Rusfertide (PTG-300) treatment in phlebotomy-dependent polycythemia vera patients.

7003 Background: Polycythemia (PV) patients with hematocrit (HCT) levels > 45% are at an increased risk of thrombosis and are treated with therapeutic phlebotomy (TP) alone or in combination with cytoreductive agents. Current therapies are not effective in reaching a HCT < 45% or uniformly tolerated. Rusfertide (PTG-300) is a hepcidin mimetic being developed as a non-cytoreductive option to consistently control HCT at < 45% in PV patients. Methods: We report results from two Phase 2 trials investigating the activity of rusfertide in PV patients. The first (NCT04057040) was conducted in patients with excessive erythrocytosis despite TP (3 or more in the 6 months prior to enrolling) ± cytoreductive therapy with a HCT < 45% at study entry. This study comprised 1) a 28-week open-label dose finding phase; 2) a 12-week double-blind randomized (1:1) withdrawal; and 3) a 3-year open-label extension with all subjects receiving rusfertide. Rusfertide doses,10-120 mg, were self-administered SQ weekly and adjusted monthly to maintain HCT < 45%. The second study (NCT04767802) enrolled poorly controlled PV patients with HCT > 48% at study entry despite TP ± hydroxyurea. Rusfertide dosing was initiated as 40 mg twice weekly and reduced to once weekly dosing when HCT < 45% was reached. Results: As of December 2021, 63 subjects were enrolled in Study 1. TP alone was the most common treatment (n = 30). The mean number of TP in the 28 weeks prior to enrollment was 4.63 and was 0.43 after treatment. On rusfertide, patients consistently maintained HCT < 45%, essentially eliminating TP, had normalization of serum ferritin, MCV values and iron deficiency. Rusfertide-treated patients also reported a statistically significant improvement in symptom burden at week 28. 20 subjects were enrolled in Study 2. TP with hydroxyurea was the most common treatment (n = 12). Mean HCT was 50.7% pre-treatment and mean time to reach HCT < 45% without TP was 4.79 weeks with persistently well controlled HCT thereafter. Rusfertide significantly reduced erythrocyte counts by ̃1.2x106/μL within 8 weeks of treatment. In both trials rusfertide did not result in changes in the number of WBC; clinically not meaningful transient increases in platelet numbers were noted. Rusfertide was well tolerated, with mostly grade 1-2 adverse events (AE). The most common AEs were injection site reactions. These were typically transient, manageable with topical therapies, and did not lead to study withdrawal. Conclusions: Rusfertide, when added to standard therapy, demonstrated robust activity in managing PV patients with sub-optimally controlled erythrocytosis in 2 trials, enrolling patients with HCT < 45% (Study 1), and HCT > 48% (Study 2). Taken together, these data show that the non-cytoreductive rusfertide, is a promising novel agent for PV patients which leads to sustained HCT control < 45%. A pivotal Phase 3 study is scheduled to begin in 2022. Clinical trial information: NCT04057040 and NCT04767802.

Effects of Hyperhomocysteinemia on the Platelet-Driven Contraction of Blood Clots.

Hyperhomocysteinemia (HHcy) is associated with thrombosis, but the mechanistic links between them are not understood. We studied effects of homocysteine (Hcy) on clot contraction in vitro and in a rat model of HHcy. Incubation of blood with exogenous Hcy for 1 min enhanced clot contraction, while 15-min incubation led to a dose-dependent suppression of contraction. These effects were likely due to direct Hcy-induced platelet activation followed by exhaustion, as revealed by an increase in fibrinogen-binding capacity and P-selectin expression determined by flow cytometry. In the blood of rats with HHcy, clot contraction was enhanced at moderately elevated Hcy levels (10–50 μM), while at higher Hcy levels (>50 μM), the onset of clot contraction was delayed. HHcy was associated with thrombocytosis combined with a reduced erythrocyte count and hypofibrinogenemia. These data suggest that in HHcy, platelets get activated directly and indirectly, leading to enhanced clot contraction that is facilitated by the reduced content and resilience of fibrin and erythrocytes in the clot. The excessive platelet activation can lead to exhaustion and impaired contractility, which makes clots larger and more obstructive. In conclusion, HHcy modulates blood clot contraction, which may comprise an underappreciated pro- or antithrombotic mechanism.

Systemic deficiency of mouse arachidonate 15-lipoxygenase induces defective erythropoiesis and transgenic expression of the human enzyme rescues this phenotype.

Arachidonic acid 15-lipoxygenases (ALOX15) are lipid peroxidizing enzymes, which has previously been implicated in the maturational breakdown of intracellular organelles and plasma membrane remodeling during reticulocyte-erythrocyte transition. Conventional Alox15-/- mice are viable, develop normally but do not exhibit a major defective erythropoietic phenotype. To characterize the putative in vivo relevance of Alox15 for red blood cell development, we explored the impact of systemic inactivation of the Alox15 gene on mouse erythropoiesis. We found that Alox15-/- mice exhibited reduced erythrocyte counts, elevated reticulocyte counts and red cell hyperchromia. The structure of the plasma membrane of Alox15-/- erythrocytes is altered and a significant share of the red cells was present as echinocytes and/or acanthocytes. An increased share of the Alox15-/- erythrocytes cells were annexin V positive, which indicates a loss of plasma membrane asymmetry. Erythrocytes of Alox15-/- mice were more susceptible to osmotic hemolysis and exhibited a reduced ex vivo life span. When we transgenically expressed human ALOX15 in Alox15-/- mice under the control of the aP2 promoter the defective erythropoietic system was rescued and the impaired osmotic resistance was normalized. Together these data suggest the involvement Alox15 in the maturational remodeling of the plasma membrane during red cell development.

Chlorpyrifos mediated oxidative damage and histopathological alterations in freshwater fish Oncorhynchus mykiss in Northern Pakistan

The intensive applications of chlorpyrifos (CPF) in agricultural production have resulted in lethal effects on the environment, particularly on aquatic fauna. Thus, present study was aimed to assess the haematological responses, antioxidant enzymes (superoxide dismutase [SOD] and catalase [CAT]) activity, acetylcholinesterase enzyme (AChE) inhibition and histopathological alterations in liver and gill tissues of cold-water fish rainbow trout (Oncorhynchus mykiss) in their native habitat, when exposed to CPF. In total, 240 fingerlings were subjected to various CPF concentrations (0, 2, 4 and 6 μg/L) for acute and sub-lethal toxicity tests. Results revealed that increasing CPF concentration and exposure time have resulted in reduced erythrocyte count, haemoglobin concentration and haematocrit level; however, leucocyte count was increased. Additionally, decrease in AChE activity was also observed with increasing concentration. CPF concentrations at lowest exposure duration induced slight increase of SOD and CAT activity while the high exposure durations (14 and 21 days) exhausted the activity of antioxidant enzymes. Structural damages produced by CPF in liver tissues were hyperaemia, dilated central veins, sinusoids and degenerative changes, while the lesions observed in gill tissue were curling of secondary lamella, cell degeneration, cell necrosis, narrowing of water channels, hyperplasia, oedematous changes, fusion of secondary lamella and sloughing.

Altered erythropoiesis and decreased number of erythrocytes in children with neuroblastoma.

Neuroblastoma (NB) is a pediatric tumor presenting at diagnosis either as localized or metastatic disease, which mainly involves the bone marrow (BM). The physical occupancy of BM space by metastatic NB cells has been held responsible for impairment of BM function. Here, we investigated whether localized or metastatic NB may alter hematopoietic lineages’ maturation and release of mature cells in the periphery, through gene expression profiling, analysis of BM smears, cell blood count and flow cytometry analysis.Gene ontology and disease-associated analysis of the genes significantly under-expressed in BM resident cells from children with localized and metastatic NB, as compared to healthy children, indicated anemia, blood group antigens, and heme and porphyrin biosynthesis as major functional annotation clusters. Accordingly, in children with NB there was a selective impairment of erythrocyte maturation at the ortho-chromic stage that resulted in reduced erythrocyte count in the periphery, regardless of the presence of metastatic cells in the BM. By considering all NB patients, low erythrocyte count at diagnosis associated with worse survival. Moreover, in the subset of metastatic patients, low erythrocyte count, hemoglobin and hematocrit and high red cell distribution width at follow-up also associated with worse outcome.These observations provide an alternative model to the tenet that infiltrating cells inhibit BM functions due to physical occupancy of space and may open a new area of research in NB to understand the mechanism(s) responsible for such selective impairment.

Association of aggressive periodontitis with reduced erythrocyte counts and reduced hemoglobin levels

Studies have shown that erythrocyte counts and hemoglobin levels are reduced in patients with chronic periodontitis, suggesting that this condition may be associated with anemia of chronic disease. Although increased leukocyte counts have been reported in aggressive periodontitis, very little is known about the effects of aggressive periodontitis on erythrocyte counts. The present study was undertaken to determine whether generalized aggressive periodontitis is associated with reduced erythrocyte counts and reduced hemoglobin levels. The present study was conducted as a case-control study in which 64 patients with generalized aggressive periodontitis were categorized as cases and 58 periodontally healthy individuals were categorized as controls. Erythrocyte parameters (such as erythrocyte count, hemoglobin concentration, and hematocrit and erythrocyte indices) and clinical parameters (such as gingival index, plaque index, probing depth, clinical attachment level and percentage of severe sites) were recorded. Significant differences were observed between cases and controls in mean erythrocyte count (4.45±0.6×10(6) erythrocytes/μL and 4.78±0.56×10(6) erythrocytes/μL respectively, p=0.002) and hemoglobin level (12.43±1.83g/dL and 13.53±1.64g/dL, respectively, p=0.001). Other erythrocyte parameters, such as hematocrit, mean corpuscular volume and mean corpuscular hemoglobin, were also significantly lower among cases compared with controls. Logistic regression analyses showed that generalized aggressive periodontitis was significantly associated with lower erythrocyte counts (p=0.032) and a lower hemoglobin concentration (p=0.017). The findings of the present study suggest that patients with generalized aggressive periodontitis tend to have lower erythrocyte counts and lower hemoglobin levels compared with periodontally healthy controls. This suggests that generalized aggressive periodontitis, like chronic periodontitis, may be associated with a risk for anemia of chronic disease.

Renal dysplasia and nephrosclerosis in calves

Renal dysplasia and nephrosclerosis in six calves, which were aged three to six months and from different farms in western Scotland and north-west England, was characterised clinically by stunted growth...

Blood parameters in brook trout Salvelinus fontinalis (Mitchill, 1815), affected by columnaris disease

Mass death of farmed brook trout Salvelinus fontinalis reared in raceway culture on a commercial fish farm was recorded in May. The condition was caused by natural infection with external signs of Flavobacterium columnare. Haematological analyses were carried out from peripheral blood from 10 fish from each group. Anaemia was characterized by a reduced erythrocyte count and lower haemoglobin levels; the values of mean corpuscular volume and mean corpuscular haemoglobin were higher and the values of mean corpuscular haemoglobin concentration were decreased. Clinical chemistry analyses in blood plasma indicated decreased levels of total protein, glucose and total calcium and an increase in the urea level. Among the four enzymes analysed, a catalytic activity reaching multiples of the normal level was found in alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase. The catalytic concentration of alkaline phosphatase was decreased. Electrophoretic analyses of the plasma protein indicated a reduced level of albumin. The moribund fish had a higher hepatosomatic index and their condition coefficient after Fulton and after Clark was also higher.

Aeromonas Causes Severe Skin Lesions in Rainbow Trout (Oncorhynchus mykiss): Clinical Pathology, Haematology, and Biochemistry

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Increased erythrocyte volume in car repair painters and car mechanics.

The biological effect of occupational long term low level exposure to organic solvents was studied in 17 car repair painters and 28 car mechanics, and compared with a control group consisting of 46 healthy men not exposed to organic solvents. The erythrocyte count (RBC) was significantly decreased for both the painters and the mechanics compared with the control group, and a significant increase in the mean erythrocyte volume (MCV) was seen in painters. The mode in size distribution of the erythrocytes (MAXRBC) was shifted towards larger cell volumes for both painters and mechanics. When data from painters and mechanics were combined, the exposed group showed a significantly reduced erythrocyte count (RBC), an increased mean erythrocyte volume (MVC), and an increased mean platelet volume (MPV) compared with the controls. Exposure measurements in combination with analysis of haematological parameters may be a tool for early detection of cellular changes in the blood caused by exposure to solvents, before the appearance of clinical symptoms.

Some selected peripheral blood and haemopoietic system indices in wistar rats with chronic vanadium intoxication

1. 1. Wistar rats of both sexes received vanadium in drinking water in the amount of 23–29 mg/kg body weight in the form of ammonium metavanadate (AMV) for a period of 2, 4 and 8 weeks. 2. 2. Animals treated in this way ate less food and drank less AMV solution as compared with the amount of water consumed by the controls; they suffered from diarrhoea, and owing to this the increment in body weight was reduced. 3. 3. Vanadium decreased erythropoiesis and maturation of red blood cells, which was expressed by a reduced erythrocyte count and haemoglobin level and increased reticulocyte and polychromatophilic erythrocyte count in the peripheral blood. 4. 4. The composition percentage of the bone marrow cells and the peripheral blood leukocyte count did not undergo noticeable changes under the influence of vanadium.

Chronic toxicity and oncogenicity studies of ethylene glycol in rats and mice

These studies were performed to assess the chronic toxicity and oncogenicity of ethylene glycol (EG) in rats and mice. Groups of 130 Fischer 344 rats and 80 CD-1 mice per sex were fed diets yielding approximate dosages of 1.0, 0.2, or 0.04 g/kg/day of EG. Two separate control groups in each study received no EG. Mortality rate was increased in high-dose male rats all of which died by 475 days. The following effects were also observed in high dose male rats: reduced body weight gain, increased water intake, increased blood urea nitrogen and creatinine, reduced erythrocyte count, reduced hematocrit and hemoglobin, increased neutrophil count, increased urine volume, reduced specific gravity and pH. Urinary calcium oxalate crystals and increased kidney weight were seen in all high-dose rats. Uric acid crystals were seen in the urine of high-dose female rats at 18 and 24 months. Histopathologic changes in high-dose male rats included tubular cell hyperplasia, tubular dilation, peritubular nephritis, parathyroid hyperplasia, and generalized soft tissue mineralization. Fatty change of the liver was seen in high- and intermediate-dose female rats. No clinical signs, or gross or microscopic evidence of toxicity was seen in mice at the dosages used. Water intake and clinical pathologic parameters were not measured in the mouse study. In these studies there was no evidence of an oncogenic effect of EG in rodents.

The haematological assessment of bacterial infection in rainbow trout, Salmo gairdneri Richardson

The pH, pCO2 and pO2 values for diseased fish did not differ significantly from those values for healthy fish, but fish treated with terramycin showed a highly significant rise in pCO2 with a corresponding fall in pO2. Haematocrit values, as well as haemoglobin and total plasma protein concentrations were significantly lower in diseased fish while treated fish showed a significant rise in total plasma protein. Glucose concentrations fell very significantly in diseased fish and showed a significant increase in treated fish.The plasma electrolytes, sodium, potassium and chloride, were significantly reduced in diseased fish and potassium levels also fell in treated fish. Diseased fish showed very significantly reduced erythrocyte counts. Of the three parameters MCV, MCH and MCHC, only the values for MCH in diseased fish differed significantly from those for healthy fish.

Zur Interaktion von Nickel mit Eisen, Kupfer und Zink

Studies were carried out investigating the role of nickel as an essential element in the growth of rats. Reduced levels of iron, copper and zinc were found in the liver, spleen and kidneys during Ni deficiency. These findings could be reproduced in 2 generations of 30-day and 50-day-old rats. Reduced rates of Fe storage during Ni deficiency were, in some cases, even noted of the Fe supply was raised to a level of as high as 100 mg Fe per kg of the diet. This accounted for the diminished haemoglobin values, the reduced erythrocyte count and reduced hematocrite found under conditions of Ni deficiency.

Experimental visceral larva migrans in monkeys. I. Clinical, hematological, biochemical and gross pathological observations on monkeys inoculated with embryonated eggs of the dog ascarid, Toxocara canis.

Nine Macaca monkeys were inoculated experimentally with 100, 000 to 400, 000 embryonated eggs of Toxococara canis. Of them, four belonged to Macaca fascicularis, one to M. nemestrina, two to M. cyclopis, and two to M. fuscata. Six infected monkeys, Nos. 1 to 3, 5, 6 and 9, which suffered from a mild invasion of the CNS by larvae of T. canis, showed no clinical abnormality, except mild or moderate inappetence and depression for several weeks together with occasional mild coughing. The remaining three infected monkeys, Nos. 4, 7 and 8, harbored considerable numbers of viable larvae not only in the thoracic and abdominal viscera but also in the CNS, and began to develop such clinical signs as anorexia, weakness and coughing 4 to 7 days after infection. Severe neurological signs that terminated in paralysis were also noted in these three animals on the 8th to 16th days. The postmortem examination of them revealed parasitic granuloma formation and focal tissue destruction with hemorrhage at numerous sites on the cut surfaces of the brain and spinal cord. From these results, it should be emphasized that the severe neurological disorders resulted from the CNS damage which had been caused by the invasion of T. canis larvae in the brain and spinal cord. Hematological findings of the infected animals included transiently reduced erythrocyte counts and marked eosinophilia. The latter appeared soon after inoculation, increased to a high degree between the 2nd and the 4th week, and declined as the infection progressed. Analysis of their blood plasma also showed increased globulin concentrations, reduced albumin values, and decreased albumin/globulin ratio, in addition to elevated plasma transaminase levels. No important changes were found in any other parameter.

Clinico-pathological studies on naturally-occurring bovine fascioliasis in the Sudan.

An investigation was made of the pathological, haematological and biochemical aspects of naturally-occurring bovine fascioliasis in the Sudan. 228 animals infected with Fasciola gigantica and 25 non-infected controls were used in the study. The infected cattle revealed emaciation, typical liver pathology, and, occasionally, lesions in the lung and the pancreas. Analysis of their sera also showed reduced albumin values, increased globulin concentrations and decrease albumin/globulin ratio, in addition to increased arginase activity. The serum iron concentration, on the other hand, was decreased, while the total iron binding capacity increased and the resultant iron saturation values reduced. Haematological findings in the infected animals included reduced erythrocyte counts, decreased haematocrit values, increased mean corpuscular volumes, eosinophilia and decreased neutrophil, lymphocyte and monocyte counts. Other parameters were similar in infected and control cattle.

Oral toxicity and metabolism of diuron ( N-(3,4-dichlorophenyl)- N′,N′-dimethylurea) in rats and dogs

Diuron ( N-(3,4-dichlorophenyl)- N′,N′-dimethylurea) has a relatively low order of acute oral toxicity in the rat. The LD 50 (14-day) for males was 3·4 g/kg. Ten daily doses of 1 g/kg were not lethal but growth depression was observed. In both studies, increased erythropoiesis was indicated histologically. Skin irritation and sensitization tests in guinea-pigs proved negative. 90-Day feeding studies in rats disclosed no growth depression at a dietary level of 400 ppm or less; slight in males at 2000 ppm; marked in both sexes at 2500 ppm and higher. Slight anaemia and enhanced erythropoiesis were observed at 250 ppm in females and in both sexes at 2500 ppm and above. An abnormal blood pigment, identified as sulphaemoglobin was detected at 2000 ppm and higher. Feeding studies on two dogs revealed no effect at 160 ppm for 1 month but slight growth retardation and a moderate anaemia were induced by 2-month feeding of increasing dietary levels commencing at 400 ppm and terminating at 2400 ppm. 2-Yr feeding studies were conducted on rats and dogs at dietary levels of 0, 25, 125, 250 and 2500 ppm. No effect was seen at the 25, 125 or 250 ppm levels in either species with the exception of a trace of abnormal blood pigment in some animals on 125 or 250 ppm diuron and of a trend towards reduced erythrocyte counts in dogs on 250 ppm. At the highest level of 2500 ppm the principal findings in both species were growth retardation, slight anaemia, presence of abnormal blood pigment, enlargement of spleen (occasionally in rats) and of liver (dogs) and increased erythropoiesis with splenic haemosiderosis. No histological changes were seen at any level and there was no evidence of carcinogenicity. In a three-generation reproduction study in rats maintained on 0 or 125 ppm diuron, no untoward findings were obtained. In metabolic studies in rats and dogs fed 25–2500 ppm diuron for 9 months–2 yr, tissue residue levels were proportional to the dietary intake of diuron but no tissue storage occurred. Excretion occurred in both faeces and urine. N-(3,4-Dichlorophenyl)urea was the predominant metabolite in the urine; small amounts of N-(3,4-dichlorophenyl)- N′-methylurea, 3-4-dichloraniline, 3,4-dichlorophenol and unchanged diuron were also detected.