Extralabel use of penicillin in food animals.
Penicillin is one of the most commonly detected drug residues in tissues and milk, and is the antimicrobial for which information is most often sought through FARAD.
Animals↗
Biomedical subjects
Jim E Riviere
Publications and source records attributed to Jim E Riviere.
Surface coatings determine cytotoxicity and irritation potential of quantum dot nanoparticles in epidermal keratinocytes.
Quantum dot (QD) nanoparticles have potential applications in nanomedicine as drug delivery vectors and diagnostic agents, but the skin toxicity and irritation potential of QDs are unknown. Human epidermal keratinocytes (HEKs) were used to assess if QDs with different surface coatings would cause differential effects on HEK cytotoxicity, proinflammatory cytokine release, and cellular uptake. Commercially available QDs of two different sizes, QD 565 and QD 655, with neutral (polyethylene glycol (PEG)), cationic (PEG-amine), or anionic (carboxylic acid) coatings were utilized. Live cell imaging and transmission electron microscopy were used to determine that all QDs localized intracellularly by 24 hours, with evidence of QD localization in the nucleus. Cytotoxicity and release of the proinflammatory cytokines IL-1beta, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha were assessed at 24 and 48 hours. Cytotoxicity was observed for QD 565 and QD 655 coated with carboxylic acids or PEG-amine by 48 hours, with little cytotoxicity observed for PEG-coated QDs. Only carboxylic acid-coated QDs significantly increased release of IL-1beta, IL-6, and IL-8. These data indicate that QD surface coating is a primary determinant of cytotoxicity and immunotoxicity in HEKs, which is consistent across size. However, uptake of QDs by HEKs is independent of surface coating.
Cells, Cultured↗
Regression method of the hydrophobicity ruler approach for determining octanol/water partition coefficients of very hydrophobic compounds.
A regression method was developed for the hydrophobicity ruler approach, which is an indirect method for determining the octanol/water partition coefficients of very hydrophobic compounds. Two constants introduced into the mathematical model were obtained by regression of the absorption data sampled before the partition equilibrium. A water miscible organic solvent was used to increase the solubility of the very hydrophobic compounds in the aqueous solution so that the hydrophobicity scale was reduced and the equilibration was accelerated. Polydimethylsiloxane/methanol aqueous solution and a series of 21 polychlorinated biphenyls (PCBs) were used to demonstrate the regression method. The PCB compounds with known experimental logK(o/w) values served as reference compounds, while the PCB compounds without known logK(o/w) values were determined. The distribution coefficients (logK(p/s)), uptake and elimination rate constants were obtained from the two regression constants for each compound (reference or unknown). The correlation of the logK(p/s) values of the reference PCB compounds with their logK(o/w) values was linear (logK(o/w)=2.69logK(p/s)+0.76, R(2)=0.97). The logK(o/w) values were compared with literature values and suggested that some values from the literature far off the calibration line could be inaccurate. The critical experimental factors, the merits of the regression method were discussed.
Calibration↗
Trace analysis of fullerenes in biological samples by simplified liquid-liquid extraction and high-performance liquid chromatography.
Fullerene (C60) has several potential biomedical and industrial applications. While pure fullerene is not soluble in water, nanoparticles of the fullerene aggregates (nano-C60) can be prepared in water solutions. The concentration of nano-C(60) in biological media after systemic exposure could be very low and requires trace analytical methods to be developed for the toxicological and pharmacokinetic studies of the nanomaterial. A serious drop in extraction efficiency was observed when the concentration was under 0.5 microg/mL using traditional liquid-liquid extraction (LLE) protocols. The evaporation of the solvent extract to dryness was found to be the main reason for the efficiency drop and an improved evaporation method was proposed to overcome this problem. Optimal proportion of glacial acetic acid (GAA) was used to solublize the proteins and surfactants in the biological samples, so that the emulsion problem was eliminated during LLE. Magnesium perchlorate was used to destabilize the nano-C60 particles in the water solution and promoted the solvent extraction. A simplified LLE method was developed for high throughput while preserved the advantages of the traditional LLE. The developed method was used for trace analysis of fullerenes in protein containing media and tape-stripped skin samples. Under optimal experimental conditions, the detection limit was 0.34 ng/mL and the recovery was in the range of 94-100% (n=5) at a concentration of 10 ng/mL nano-C60 in the biological media.
Chromatography, High Pressure Liquid↗
Toxicity of jet fuel aliphatic and aromatic hydrocarbon mixtures on human epidermal keratinocytes: evaluation based on in vitro cytotoxicity and interleukin-8 release.
Jet fuels are complex mixtures of aliphatic (ALI) and aromatic (ARO) hydrocarbons that vary significantly in individual cytotoxicity and proinflammatory activity in human epidermal keratinocytes (HEK). In order to delineate the toxicological interactions among individual hydrocarbons in a mixture and their contributions to cutaneous toxicity, nine ALI and five ARO hydrocarbons were each divided into five (high/medium/low cytotoxic and strong/weak IL-8 induction) groups and intra/inter-mixed to assess for their mixture effects on HEK mortality and IL-8 release. Addition of single hydrocarbon to JP-8 fuel was also evaluated for their changes in fuel dermatotoxicity. The results indicated that when hydrocarbons were mixed, HEK mortality and IL-8 release were not all predictable by their individual ability affecting these two parameters. The lowest HEK mortality (7%) and the highest IL-8 production were induced with mixtures including high cytotoxic and weak IL-8 inductive ARO hydrocarbons. Antagonistic reactions not consistently correlated with ALI carbon chain length and ARO structure were evident and carried different weight in the overall mixture toxicities. Single addition of benzene, toluene, xylene or ethylbenzene for up to tenfold in JP-8 did not increase HEK mortality while single addition of ALI hydrocarbons exhibited dose-related differential response in IL-8. In an all ALI environment, no single hydrocarbon is the dominating factor in the determination of HEK cytotoxicity while deletion of hexadecane resulted in a 2.5-fold increase in IL-8 production. Overall, decane, undecane and dodecane were the major hydrocarbons associated with high cytotoxicity while tetradecane, pentadecane and hexadecane were those which had the greatest buffering effect attenuating dermatotoxicity. The mixture effects must be considered when evaluating jet fuel toxicity to HEK.
Aviation↗
Penetration of intact skin by quantum dots with diverse physicochemical properties.
Skin is the largest organ of the body and is a potential route of exposure to engineered nanomaterials, but the permeability of the skin to these nanomaterials is unknown. We selected commercially available quantum dots (QD) of two core/shell sizes and shapes and three different surface coatings to determine if QD could penetrate intact skin in a size- or coating-dependent manner. Spherical 4.6 nm core/shell diameter QD 565 and ellipsoid 12 nm (major axis) by 6 nm (minor axis) core/shell diameter QD 655 with neutral (polyethylene glycol), anionic (carboxylic acids) or cationic (polyethylene glycol-amine) coatings were topically applied to porcine skin in flow-through diffusion cells at an occupationally relevant dose for 8 h and 24 h. Confocal microscopy revealed that spherical QD 565 of each surface coating penetrated the stratum corneum and localized within the epidermal and dermal layers by 8 h. Similarly, polyethylene glycol- and polyethylene glycol-amine-coated ellipsoid QD 655 localized within the epidermal layers by 8 h. No penetration of carboxylic acid-coated QD 655 was evident until 24 h, at which time localization in the epidermal layers was observed. This study showed that quantum dots of different sizes, shapes, and surface coatings can penetrate intact skin at an occupationally relevant dose within the span of an average-length work day. These results suggest that skin is surprisingly permeable to nanomaterials with diverse physicochemical properties and may serve as a portal of entry for localized, and possibly systemic, exposure of humans to QD and other engineered nanoscale materials.
Animals↗
A time of change.
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Periodicals as Topic↗
Effect of formulation and route of administration on tissue residues and withdrawal times.
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Absorption↗
Predicting skin permeability from complex chemical mixtures.
Occupational and environmental exposure to topical chemicals is usually in the form of complex chemical mixtures, yet risk assessment is based on experimentally derived data from individual chemical exposures from a single, usually aqueous vehicle, or from computed physiochemical properties. We present an approach using hybrid quantitative structure permeation relationships (QSPeR) models where absorption through porcine skin flow-through diffusion cells is well predicted using a QSPeR model describing the individual penetrants, coupled with a mixture factor (MF) that accounts for physicochemical properties of the vehicle/mixture components. The baseline equation is log k(p) = c + mMF + a sigma alpha2(H) + b sigma beta2(H) + s pi2(H) + rR2 + vV(x) where sigma alpha2(H) is the hydrogen-bond donor acidity, sigma beta2(H) is the hydrogen-bond acceptor basicity, pi2(H) is the dipolarity/polarizability, R2 represents the excess molar refractivity, and V(x) is the McGowan volume of the penetrants of interest; c, m, a, b, s, r, and v are strength coefficients coupling these descriptors to skin permeability (k(p)) of 12 penetrants (atrazine, chlorpyrifos, ethylparathion, fenthion, methylparathion, nonylphenol, rho-nitrophenol, pentachlorophenol, phenol, propazine, simazine, and triazine) in 24 mixtures. Mixtures consisted of full factorial combinations of vehicles (water, ethanol, propylene glycol) and additives (sodium lauryl sulfate, methyl nicotinate). An additional set of 4 penetrants (DEET, SDS, permethrin, ricinoleic acid) in different mixtures were included to assess applicability of this approach. This resulted in a dataset of 16 compounds administered in 344 treatment combinations. Across all exposures with no MF, R2 for absorption was 0.62. With the MF, correlations increased up to 0.78. Parameters correlated to the MF include refractive index, polarizability and log (1/Henry's Law Constant) of the mixture components. These factors should not be considered final as the focus of these studies was solely to determine if knowledge of the physical properties of a mixture would improve predicting skin permeability. Inclusion of multiple mixture factors should further improve predictability. The importance of these findings is that there is an approach whereby the effects of a mixture on dermal absorption of a penetrant of interest can be quantitated in a standard QSPeR model if physicochemical properties of the mixture are also incorporated.
Algorithms↗
Aminoglycoside residues in food of animal origin.
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Aminoglycosides↗
Pre-treatment effects of trichloroethylene on the dermal absorption of the biocide, triazine.
Triazine is often added to cutting-fluid formulations in the metal-machining industry as a preservative. Trichloroethylene (TCE) is a solvent used for cleaning the cutting fluid or oil from the metal product. The purpose of this study was to examine the effect of TCE on the dermal absorption of triazine in an in vitro flow-through diffusion cell system. Skin sections were dosed topically with aqueous mixtures containing mineral oil or polyethylene glycol (PEG) spiked with (14)C-triazine. Some skin sections were simultaneously exposed to TCE while other skin sections were pre-treated with TCE daily for 4 days in vivo and then exposed to these mixtures in vitro. TCE pre-treatment almost doubled triazine permeability, but this pre-treatment had no effect on triazine diffusivity. The pre-treatment effects of TCE on triazine permeability appear to be more important in PEG-based mixtures than in the mineral oil-based mixtures. Simultaneous single exposure to TCE had little or no effect on triazine absorption. TCE absorption was significantly less than triazine absorption; however, cutting fluid additives had a more significant effect on TCE absorption than on triazine absorption. In summary, this study demonstrated that TCE pre-treatment can significantly alter the dermal permeability to triazine, and workers who are chronically exposed to this or similar cleansers may be at increased risk of absorbing related skin irritants.
Animals↗
Extralabel intramammary use of drugs in dairy cattle.
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Animals↗
Multi-walled carbon nanotube interactions with human epidermal keratinocytes.
Carbon nanotubes have widespread applications in multiple engineering disciplines. However, little is known about the toxicity or interaction of these particles with cells. Carbon nanotube films were grown using a microwave plasma enhanced chemical vapor deposition system. Human epidermal keratinocytes (HEK) were exposed to 0.1, 0.2, and 0.4 mg/ml of multi-walled carbon nanotubes (MWCNT) for 1, 2, 4, 8, 12, 24 and 48 h. HEK were examined by transmission electron microscopy for the presence of MWCNT. Here we report that chemically unmodified MWCNT were present within cytoplasmic vacuoles of the HEK at all time points. The MWCNT also induced the release of the proinflammatory cytokine interleukin 8 from HEKs in a time dependent manner. These data clearly show that MWCNT, not derivatized nor optimized for biological applications, are capable of both localizing within and initiating an irritation response in a target epithelial cell that composes a primary route of occupational exposure for manufactured nanotubes.
Cell Nucleus↗
Effect of vehicles and sodium lauryl sulphate on xenobiotic permeability and stratum corneum partitioning in porcine skin.
Dermal contact with potentially toxic agricultural and industrial chemicals is a common hazard encountered in occupational, accidental spill and environmental contamination scenarios. Different solvents and chemical mixtures may influence dermal absorption. The effects of sodium lauryl sulphate (SLS) on the stratum corneum partitioning and permeability in porcine skin of 10 agricultural and industrial chemicals in water, ethanol and propylene glycol were investigated. The chemicals were phenol, p-nitrophenol, pentachlorophenol, methyl parathion, ethyl parathion, chlorpyrifos, fenthion, simazine, atrazine and propazine. SLS decreased partitioning into stratum corneum from water for lipophilic compounds, decreased partitioning from propylene glycol and did not alter partitioning from ethanol. SLS effects on permeability were less consistent, but generally decreased permeability from water, increased permeability from ethanol and had an inconsistent effect on permeability from propylene glycol. It was concluded that, for the compounds tested, partitioning into the stratum corneum was determined by the relative solubility of the solute in the donor solvent and the stratum corneum lipids. Permeability, however, reflected the result of successive, complex processes and was not predictable from stratum corneum partitioning alone. Addition of SLS to solvents altered partitioning and absorption characteristics across a range of compounds, which indicates that partition coefficients or skin permeability from neat chemical exposure should be used with caution in risk assessment procedures for chemical mixtures.
Agrochemicals↗
Determination of the partition coefficients and absorption kinetic parameters of chemicals in a lipophilic membrane/water system by using a membrane-coated fiber technique.
The absorption kinetics of chemicals in a lipophilic membrane/water system was studied with a membrane-coated fiber (MCF) technique, in which the partition coefficient, membrane diffusivity and boundary layer adjacent to the membrane were taken into account. The cumulative amount permeated into the membrane was expressed as a function of absorption time in an exponential equation. Two constants were introduced into the model. Both of them were clearly defined by the physiochemical parameters of the system and were obtained by regression of the experimental data sampled over a limited time. The partition and diffusion coefficients, as well as the thickness of the boundary layer, were calculated from the two constants. The kinetic model adequately described the absorption kinetics of the MCF technique. All of the theoretical predictions were supported by the experimental results. The measured partition coefficients correlated well with the published octanol/water partition coefficient (R(2)=0.91). The thickness of the boundary layer was 5.2 microm in a solution stirred at 400 rpm. An inference of the kinetic model revealed that the contribution of the boundary layer to the absorption kinetics is significant for lipophilic chemicals by a lipophilic membrane. It suggested that the absorption rate of a very lipophilic compound could be controlled by the boundary layer even though the diffusivity of the compound in the membrane is lower than that in the solution. It was demonstrated that the MCF technique could be used to determine the partition, diffusion and permeation coefficients, as well as the thickness of the boundary layer in a lipophilic membrane/water system.
Absorption↗
NDELA and nickel modulation of triazine disposition in skin.
Cutting fluids can become contaminated with metals (e.g., nickel, Ni) and nitrosamines (e.g., N-nitrosodiethanolamine, NDELA) and there is concern that these classes of contaminants can modulate dermal disposition and ultimately the toxicity of cutting fluid additives, such as irritant biocides (e.g., triazine). Biocides are added to these formulations to prevent bacterial degradation of commercial cutting fluids. The purpose of this study was to assess the dermal absorption and skin deposition of 14C-triazine when topically applied to porcine skin in an in vitro flow-through diffusion cell system as aqueous soluble oil (mineral oil, MO) or aqueous synthetic (polyethylene glycol, PEG) mixtures. 14C-Triazine mixtures were formulated with NDELA and/or Ni, or with a combination of three additional cutting fluid additives; namely, 5% linear alkylbenzene sulfonate (LAS), 5% triethanolamine (TEA) and 5% sulfurized ricinoleic acid. Neither Ni nor NDELA was absorbed during these 8-h studies. However, 14C-triazine absorption ranged from 2.72 to 3.29% dose in MO and 2.29-2.88% dose in PEG with significantly greater triazine absorption in MO than PEG when all additives and contaminates were present. The difference between these two diluents was most pronounced when NDELA and/or Ni were present in cutting fluids. These contaminants also enhanced triazine deposition on the skin surface and skin tissues especially with PEG-based mixtures. In essence, the dermal disposition of irritant biocides could be dependent on whether the worker is exposed to a soluble oil or synthetic fluid when these contaminants are present. Workers should therefore not only be concerned about dermatotoxicity of these contaminants, but also the modulated dermal disposition of cutting fluid additives when these contaminants are present in cutting fluid formulations.
Alkanesulfonic Acids↗
Multivariate meta-analysis of pharmacokinetic studies of ampicillin trihydrate in cattle.
OBJECTIVE: To investigate the feasibility of using multivariate cluster analysis to meta-analyze pharmacokinetic data obtained from studies of pharmacokinetics of ampicillin trihydrate in cattle and identify factors that could account for variability in pharmacokinetic parameters among studies. SAMPLE POPULATION: Data from original studies of the pharmacokinetics of ampicillin trihydrate in cattle in the database of the Food Animal Residue Avoidance Databank. PROCEDURE: Mean plasma or serum ampicillin concentration versus time data and potential factors that may have affected the pharmacokinetics of ampicillin trihydrate were obtained from each study. Noncompartmental pharmacokinetic analyses were performed, and values of pharmacokinetic parameters were clustered by use of multivariate cluster analysis. Practical importance of the clusters was evaluated by comparing the frequency of factors that may have affected the pharmacokinetics of ampicillin trihydrate among clusters. RESULTS: A single cluster with lower mean values for clearance and volume of distribution of ampicillin trihydrate administered PO, compared with other clusters, was identified. This cluster included studies that used preruminant calves in which feeding was withheld overnight and calves to which probenecid had been administered concurrently. CONCLUSIONS AND CLINICAL RELEVANCE: Meta-analysis was successful in detecting a potential subpopulation of cattle for which factors that explained differences in pharmacokinetic parameters could be identified. Accurate estimates of pharmacokinetic parameters are important for the calculation of dosages and extended withdrawal intervals after extralabel drug administration.
Ampicillin↗
Development of a physiologic-based pharmacokinetic model for estimating sulfamethazine concentrations in swine and application to prediction of violative residues in edible tissues.
OBJECTIVE: To develop a flow-limited, physiologic-based pharmacokinetic model for use in estimating concentrations of sulfamethazine after IV administration to swine. SAMPLE POPULATION: 4 published studies provided physiologic values for organ weights, blood flows, clearance, and tissue-to-blood partition coefficients, and 3 published studies provided data on plasma and other tissue compartments for model validation. PROCEDURE: For the parent compound, the model included compartments for blood, adipose, muscle, liver, and kidney tissue with an extra compartment representing the remaining carcass. Compartments for the N-acetyl metabolite included the liver and the remaining body. The model was created and optimized by use of computer software. Sensitivity analysis was completed to evaluate the importance of each constant on the whole model. The model was validated and used to estimate a withhold interval after an IV injection at a dose of 50 mg/kg. The withhold interval was compared to the interval estimated by the Food Animal Residue Avoidance Databank (FARAD). RESULTS: Specific tissue correlations for plasma, adipose, muscle, kidney, and liver tissue compartments were 0.93, 0.86, 0.99, 0.94, and 0.98, respectively. The model typically overpredicted concentrations at early time points but had excellent accuracy at later time points. The withhold interval estimated by use of the model was 120 hours, compared with 100 hours estimated by FARAD. CONCLUSIONS AND CLINICAL RELEVANCE: Use of this model enabled accurate prediction of sulfamethazine pharmacokinetics in swine and has applications for food safety and prediction of drug residues in edible tissues.
Adipose Tissue↗