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.     

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.     

Gulf War agents trigger discrete transcriptional changes in human neuronal cells

Reports on Gulf War illness (GWI) implicated the use of the pesticide permethrin (PER), and the insect repellent N,N-diethyl-m-toluamide (DEET), in its etiology, as well as pyridostigmine bromide (PB), which was given as a prophylactic treatment against nerve agent exposure. Using Affymetrix microarrays the genomic response of human neuronal SHSY-5Y cells to 10 days of exposure to these agents was characterized and profiles of gene modulation unique to each treatment were demonstrated. In particular, a significantly greater impact of PER was observed compared to the other treatments. The Ingenuity Pathway Analysis knowledgebase was used to analyze the genomic datasets and attribute functional consequences to the effects of related genes, which were significantly up- or down-regulated in response to different treatments. Canonical pathways shown to be significantly modulated at the genomic level in response to exposure included cellular mechanisms, which might contribute to the clinical presentation in GWI patients and thus be targeted for further investigation as potential targets for therapeutic intervention.     

The status of heavy metal levels in a Ramsar site,Kuala Gula bird sanctuary: the impact of the anthropogenic inputs

Distributions of Cd, Cu, Pb, and Zn in the surface sediments from two sites of the Kuala Gula Bird Sanctuary, Malaysia were monitored for a period of 6 months from October 2006 to March 2007. In December 2006, the concentration of Zn in one location was significantly (p??1) than the other metals at both sites, but in the oxidizable organic fraction it was highest at both sites during October; with mean concentrations of 18?mg?kg^?1 at both locations. In the acid-reducible fraction, high concentrations of Pb (2.3?mg?kg^?1) were detected at station 2 in February 2007, being highest among all four metals at both stations. The acid-reducible fraction found in Pb ranged from 0.10% to 3.1% in both stations. Percentages ranging from 51% to 96% were observed for all four metals in the resistant fraction throughout the sampling period. These results indicate low contributions from anthropogenic sources. The findings constitute a baseline data archive for future reference.     

Pharmacokinetics of [14C]-atrazine in rhesus monkeys,single-dose intravenous and oral administration

This is the first study regarding the pharmacokinetics of [¹⁴C]-atrazine conducted with rhesus monkeys. The animals received one dose (0.25 mg) intravenously (IV) or three doses (1, 10, or 100 mg) orally. Plasma, urine, and feces were collected at defined times up to 7 days post-dosing. Sample radioactivity was measured to determine the mass equivalent. IV administered [¹⁴C]-atrazine disappeared rapidly from blood, with an elimination half-life of about 5.5 ± 1.1 h. The pharmacokinetic profiles of [¹⁴C]-atrazine following oral administration at the three dose levels show that kinetic parameters such as AUC and C _max are linearly correlated with the dose. Seven days after dosing, urinary and fecal excretion of [¹⁴C]-atrazine reached 99% of total administered dose in the IV group and 91–95% in the three oral dose groups. In the IV-administered monkeys, approximately 85% of the dose was excreted in urine and 12% in feces. In three oral dose groups, urinary and fecal radioactivity recoveries approximated 57% and 21%, 58% and 25%, and 53% and 35%, respectively. More than 50% of the total urinary excreted radioactivity was found within the first 24 h after dosing. In conclusion, the principal elimination of [¹⁴C]-atrazine, IV and orally administered, is via urine. The oral bioavailability was 60% or higher. There was a significant linear correlation between administered oral dose and plasma concentration. Overall oral dose accountability ranged from 91% to 95%. Data generated may be useful in the risk assessment of human exposure to environmental atrazine contamination.     

Early murine immune responses from endotracheal exposures to biotechnology-related Bacillus strains

An immunology-based in vivo screening regime was used to assess the potential pathogenicity of biotechnology-related microbes. Strains of Bacillus cereus (Bc), Bacillus subtilis (Bs), Bacillus thuringiensis (Bt), and Bt commercial products (CPs) were tested. Balb/c mice were endotracheally instilled with purified spores, diluted CP, or vegetative cells (VC) (live or dead). Exposed mice were evaluated for changes in behavioral and physical symptoms, bacterial clearance, pulmonary granulocytes, and pulmonary and circulatory pyrogenic cytokines (interleukins (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α), as well as acute phase biomarkers (fibrinogen and serum amyloid A). Except for some differences in clearance rates, no marked effects were observed in mice exposed to any spore at 10⁶ or 10⁷ colony forming units (cfu). In contrast, live Bc or Bt VCs (10⁵ or 10⁶?cfu) produced shock-like symptoms (lethargy, hunched appearance, ruffled fur, and respiratory distress), and 11–200-fold elevations in pyrogenic cytokines at 2-h post-exposure. In the study, 4-h effects included increased lethargy, ocular discharge, and 1.5–4-fold rise in circulatory acute phase markers, but no indications of recovery. Bs VC did not produce any changes in symptoms or biomarkers. After 2 or 4?h of exposure to dead VC, increases of only plasma IL-1β and TNF-α (4.6- and 12.4-fold, respectively) were observed. These findings demonstrate that purified spores produced no marked effects in mice compared to that of metabolically active bacteria. This early screening regime was successful in distinguishing the pathogenicity of the different Bacillus species, and might be useful for assessing the relative hazard potential of other biotechnology-related candidate strains.     

Evaluation of reproductive and developmental toxicity of cypermethrin in male albino rats

The ever-increasing use of pesticides in the agricultural and public health has become a major cause of sterility in human and various other animals particularly in males. This study was sought to screen the toxic impacts of cypermethrin (synthetic pyrethroid) on reproduction and development. Twenty-four Wistar male rats divided into four groups were orally administered cypermethrin of daily doses 50, 75, or 100 mg?kg^?1 bwt per day for 45 days; and for developmental toxicity, 12 female rats were separated into two groups. Maternal rats (experimental) were administered cypermethrin (100?mg?kg^?1) by gavage daily from 6th to 17th day of gestation, and the control group was dosed only vehicle (olive oil). The body weights, fertility index, biochemical, enzymatic, hormonal, and histopathological parameters were the criteria used to evaluate the toxicity of cypermethrin. Study showed significant decline in the weight of testes, epididymises, seminal vesicles, and ventral prostate, and reduction in sperm counts both in epididymises and testes in chemical-treated animals. Pre- and post- fertility test showed 50%, 80%, and 100% negative results after treatment. A significant degenerative reduction in testicular glycogen and sialic acid was also noted. In contrast, protein and cholesterol levels of testes were significantly increased. In addition, acid phosphatase activity was significantly increased, while alkaline phosphatase, testosterone, leutinizing hormone (LH), and follicle stimulating hormone (FSH) levels were diminished. Histology of testes showed degenerative changes in seminiferous tubules. Cypermethrin exposure during gestation produced adverse effects markedly in females and fetuses.     

Male reproductive toxicity of organophosphorous compounds: a review

Fertility is declining in many countries and there has been substantial interest in the potential adverse effects of exposure to environmental hazardous chemicals, including pesticides on male reproduction. Organophosphorous compounds (organophosphates, OP) constitute a heterogeneous category of chemicals specifically designed for the control of pests or plant diseases. OP are known to produce reproductive toxicity, resulting in a decrease in the fertility levels of humans and animals. This review article mainly focused on toxicity of some OP such as acephate, chlorpyrifos, diazinon, dimethoate, fenitrothion, malathion, and monocrotophos especially dealing with reproductive toxicity in males. Furthermore, this review deals with mode of action and clinical syndromes of OP. Considerable lab studies on animals concluded that OP produce adverse effects on male reproductive system.     

Effects of β-cyclodextrin on adsorption and desorption of carbofuran in soils of divergent texture

Laboratory studies were conducted to determine the adsorption/desorption equilibrium of carbofuran between four divergently textured soils and distilled water and an aqueous solution of 0.01?mol?L^?1 β-cyclodextrin using a batch equilibrium technique. The determined adsorption isotherms for silt loam soils were of L-shaped, for sandy loam soil S-shaped, in agreement with a Freundlich isotherm. In the presence of β-cyclodextrin, the adsorption of carbofuran to the four soils was lower than with distilled water. Positive hysteresis was observed in all soils with distilled water, negative hysteresis when using a solution of β-cyclodextrin as desorbent. The results indicate the potential use of β-cyclodextrin for remediation of pesticide-contaminated soils.