Feasibility of metabolic parameter estimation in pharmacokinetic models of carbon tetrachloride exposure in rats1

Carbon tetrachloride (CCl₄) is a toxic chemical that was once used in degreasers and detergents, and some remnants of the chemical may be present in the water supply. Physiologically-based pharmacokinetic (PBPK) modeling can assist in understanding resulting internal doses of CCl₄ after exposure, but the pharmacokinetic parameters describing the metabolism of CCl₄ are not well characterized. The goal of this study was to provide insights into how to more accurately estimate these values in rats using PBPK modeling and data from previous studies. Three different PBPK models were constructed to describe CCl₄ exposure in rats via inhalation, oral ingestion, and venous injection. Each of these models was compared to data, and sensitivity analysis was performed for each model to determine whether the available data could be used to accurately determine the metabolic parameters of interest. These parameter sensitivities were so low that optimization to the available data yielded physiologically unrealistic results. Model sensitivities were analyzed for different doses and routes of exposure in order to find experimental conditions that would allow for greater identifiability of the metabolic parameters. Data were simulated from these models at optimal conditions with varying levels of noise from a normal distribution. Optimizations were then performed to confirm that the original values could be obtained. The experiments developed are left as suggestions for investigators who wish to further pursue estimating these metabolic parameters.     

Nickel in the muscle tissues of freshwater fish from north eastern Poland should not cause human health concerns

Excessive intake of nickel (Ni) is known to produce adverse health effects in humans, including carcinogenicity and allergenicity. The main route of exposure for humans is diet, including fish. There is, however, little information concerning Ni content in freshwater fish in Poland. The aim of the study was to determine the concentrations of Ni in meat tissues of three fish species from north eastern Poland and assess toxic potential to healthy and susceptible sub-groups of individuals. The settings for the study lakes span a range of anthropogenic influence from protected areas to a basin with a town and several villages and another one influenced by a pesticide tomb leakage. Fish were netted and kept frozen until analysis. After defrosting, the fish were filleted and minced. The ashed samples were dissolved in nitric acid and analyzed for Ni by flame atomic absorption spectrometry. Roach meat contained 6.6–23 µg kg^?1 Ni, bream 9.5–178 µg kg^?1, and carp 16.5–139 µg kg^?1. These concentrations are low, indicating that the fish were not excessively contaminated with the metal. Consuming a 250 g portion of fish would result in an average nickel intake of 4 µg for roach, <10 µg for bream, and <20 µg for carp. These values represent only 0.4–2% of the maximum level that is likely to pose a risk of adverse effects as established in the USA. Consumption of fish from the study region need not necessarily pose a health threat.     

Biochemical evaluation of hepatotoxicity in mice due to administration of artemether

Effects of artemether administration on liver and selected biochemical parameters were evaluated. Eighty albino mice were divided into four equal groups. Group 1 was given water which served as control, while groups 2, 3, and 4 were given 1.2, 2.4, or 4.8 mg kg^?1 body weight artemether intramuscularly for five consecutive days. On day 6 all mice were sacrificed by cervical dislocation and blood was collected for analysis of alanine and aspartate transaminases, alkaline phosphatase, copper, and total proteins. Liver tissues were prepared for histological studies. It was found that the serum alanine and aspartate transaminase and alkaline phosphatase activities were higher in groups treated with artemether compared to control. The serum concentrations of copper and total proteins were lower than control. The histological features of liver tissues after administration of artemether showed histopathological alterations. These findings showed that artemether administration may have reversible adverse effects on mouse hepatocytes.     

Evaluation of vitamin E and calcium effects on fluoride toxicity-induced fertility impairment

Chronic fluoride (Fl) toxicity is a serious public health problem globally where drinking water contains more than 1 ppm of Fl. Sodium fluoride (NaF) produced male reproductive system toxicity. The aim of the present study was to evaluate the amelioration of Fl toxicity-induced fertility impairment by vitamin E and calcium during the withdrawal period. The study was carried out on 70 adult male albino rats divided into five main groups: group I control; subdivided into group Ia (maintained on standard diet and water ad libitum for 60 days) and group Ib (maintained on standard diet and water ad libitum for 120 days), group II was administered NaF and subdivided into group IIa (administered NaF for 60 day and sacrificed) and group IIb (administered NaF for 60 day then maintained on standard diet and water ad libitum for a further 60 days), and treated groups III, IV, and V were administered NaF. Rats were maintained during withdrawal from NaF, on vitamin E (10 mg kg^?1 day^?1 for 60 days), calcium (50 mg kg^?1 day^?1 orally for 60 days), and both vitamin E and calcium, respectively. The duration of NaF administration was 60 days at a dose 20 mg kg^?1 day^?1 for all treated groups. The following parameters were determined: body and organ weights, sperm motility, sperm morphology, sperm viability, fertility test, and hormone assays: testosterone, in vitro testosterone production, luteinizing hormone, and follicular stimulating hormone. The combined administration of vitamin E and calcium during withdrawal from NaF showed significant improvement from chronic FL-induced toxicity on male reproductive organs.     

An assessment of the air pollution data from two monitoring stations in Kuwait

This article assesses the air pollution data from two monitoring stations in Kuwait. The measurements cover major pollutants, i.e., CO, CO₂, methanated and non-methanated hydrocarbons, NO _x , SO₂, O₃, and particulate matter (PM10). The data also includes meteorological parameters, i.e., solar intensity, temperature, wind speed, and wind direction, and has been collected over a period 4 years, from 2001 to 2004. Data analysis includes the assessment of annual hourly averages and 1-h maxima. Typical pollutant concentration trends, similar to those previously reported for Kuwait and for other locations around the world, are observed except for particulate matter measurements, which have higher values because of proximity to the desert. Emissions of nitrogen oxides show a consistent increase over the years. This is caused by the increase in the number of motor vehicles and the expansion in power generation and industrial activities. The data collected is a subset of the air quality criteria, as defined by the US EPA (United States Environmental Protection Agency).     

Toxicological effects of mouse diet contaminated with tributyltin on the immune and neurological systems of C57BL/6 mice

Organotin compounds, widely used as antifouling agents, are known to bioaccumulate in the food chain. Among organotin compounds, tributyltin (TBT), a toxic and widespread contaminant, has become a serious factor in environmental pollution and is suspected of being immunotoxic in animals. The purpose of this study was to assess the effects of 80 µg of TBT per kilogram of body weight (kg bw), provided in food, on the immune and neurological systems of C57Bl/6 mice. Data showed that TBT increased the proliferation of T and B lymphocytes in both adult and juvenile female and juvenile male mice, but that it decreased the proliferation of both T and B lymphocytes in adult male mice. The macrophages activity in female and male juvenile mice was higher than in adults of both sexes. The natural killer cytotoxic activity was also increased in juvenile and adult males and females compared to the control groups. In the brain, we observed the presence of TBT in the hippocampus, the striatum, the cortex, and the cerebellum in both the male and female groups. The highest levels were observed in the cortex of females and males, while the lowest levels were found in the cerebellum. TBT also induced an increase in the levels of the antioxidant glutathione (GSH) in the striatum, the hippocampus and in cortical structures but not in the cerebellum where the levels of TBT are lower. Our findings indicate that TBT modulated the immune and nervous systems causing endocrine and nervous perturbations.     

Adsorption and movement of carbaryl in soils: A verification of cosolvent theory and comparison of batch equilibrium and soil thin layer chromatography results

Batch equilibrium and soil thin layer chromatography (TLC) techniques were used to investigate the influence of different volume fractions of organic cosolvents (acetone and methanol) on the adsorption and movement of carbaryl in four different types of Indian soils. L-shaped isotherms were obtained for both the cosolvent–water mixtures at all f _s values and were in close agreement with the Freundlich equation. Higher adsorption was observed on F.R.I. soil (FSL) followed by Alampur soil (ASL), Kalai soil (KL), and Bhoran soil (BSL) at all f _s values for both the cosolvent systems as was anticipated from the K and K _D values. The K and K _D values also confirmed that carbaryl adsorption was higher in methanol–water mixture than acetone–water mixture and decreased with increasing f _s values. The frontal R _f values obtained from soil TLC studies were inversely proportional to the K and K _D values for both the cosolvent systems. The higher K and K _D values and lower R _f values in methanol–water mixtures relative to acetone–water mixtures for all the soils indicated that acetone had a greater potential for ground water contamination compared to methanol. The adsorption data were used to evaluate the cosolvent theory for describing adsorption of carbaryl in acetone–water and methanol–water mixtures. The aqueous phase partition coefficients, K _DW (mol g^?1), normalized with respect to f _oc for carbaryl was evaluated by extrapolating f _s → 0.     

Biochemical assessment of lead,phenol, and benzene-contaminated water on the heart and blood of Albino rats

A study was performed to evaluate the effect of contaminated water on the tissues of Rattus novergicus (albino rats). Test rats were given water contaminated with lead (0.015 µg L^?1 tap water), phenol (0.05 mL L^?1 tap water), and benzene (0.05 mL L^?1 tap water), while control rats were given tap water over a period of 65 days after which the activity of selected enzymes of the heart and serum was assayed, and hematological parameters and serum lipid profiles were also determined. Generally, a significant (p < 0.05) drop in the activity of the enzymes was observed in the heart of test rats relative to the control rats. However, the serum activities increased significantly in the test group compared to the control group (p < 0.05). The concentrations of serum cholesterol, low-density lipoprotein (LDL), and triglycerides of the test rats were found to be significantly higher than those of the control rats (p < 0.05). Concentrations of hemoglobin, red blood cell count, and packed cell volume of test rats were observed to be significantly lower than those of the control rats (p < 0.05). The experimental results indicated that consumption of water contaminated with lead, phenol, and benzene may damage the heart, increase the risk of atherosclerosis as reflected by the serum lipid profile, and anemia as suggested by abnormal hematological properties.     

Absence of metallothionein 3 expression in breast cancer is a rare but favorable marker that is under epigenetic control

Cadmium (Cd²⁺), a known carcinogen, mimics the effects of estrogen in the uterus and mammary gland suggesting its possible involvement in the development and progression of breast cancer. This lab showed through analysis of a small set of archival human diagnostic specimens that the third isoform of the classic Cd²⁺ binding protein metallothionein (MT-3) is not expressed in normal breast tissue, but is expressed in some breast cancers and that expression tends to correlate with a poor disease outcome. The goals of this study were to verify that overexpression of MT-3 in a large set of archival human diagnostic specimens tends to correlate with poor disease outcome and define the mechanism of MT-3 gene regulation in the normal breast epithelial cell. The results showed that MT-3 was expressed in approximately 90% of all breast cancers and was absent in normal breast epithelium. The lack of MT-3 staining in some cancers correlated with a favorable patient outcome. High frequency of MT-3 staining was also found for in situ breast cancer suggesting that MT-3 might be an early biomarker for breast cancer. The study also demonstrated that the MCF-10A cell line, an immortalized, non-tumorigenic model of human breast epithelial cells, displayed no basal expression of MT-3, nor was it induced by Cd²⁺. Treatment of the MCF-10A cells with the demethylation agent, 5-aza-2′-deoxycytidine, or the histone deacetylase inhibitor, MS-275, restored MT-3 mRNA expression. It was also shown that the MT-3 metal regulatory elements are potentially active binders of protein factors following treatment with these inhibitors suggesting that MT-3 expression may be subject to epigenetic regulation.