Arturo Anadón

Toxicokinetics of permethrin in the rat.

The toxicokinetics of permethrin after single 460 mg/kg oral and 46 mg/kg intravenous doses were studied in male Sprague-Dawley rats. Serial blood samples after oral and intravenous dosage, and brain, medulla oblongata, sciatic nerve, and liver samples after oral administration were collected. Plasma, hypothalamus, cerebellum, frontal cortex, caudate putamen, hippocampus, medulla oblongata, sciatic nerve, and liver concentrations of permethrin and its metabolites, m-phenoxybenzyl alcohol and m-phenoxybenzoic acid, were determined by a high-performance liquid chromatographic assay. The permethrin plasma profile could be adequately described by a two-compartment open model. For permethrin, the elimination half-life (t1/2 beta) and the mean residence time from plasma were 8.67 and 11.19 hr after i.v. and 12.37 and 17.77 hr after po administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.058 liter/hr. After the single oral dose, permethrin was absorbed slowly with a Tmax of 3.52 hr. The maximum plasma concentration was 49.46 micrograms/ml. The oral bioavailability of permethrin was found to be 60.69%. The plasma concentration-time data for permethrin metabolites as well as the tissue concentration-time data for permethrin and its metabolites after an oral dose of permethrin were found to fit a one-compartment open model. The elimination half-life (t1/2el) of permethrin was greater for the hippocampus, medulla oblongata, frontal cortex, and sciatic nerve (23.10, 22.36, 13.86, and 16.27 hr, respectively) than for plasma (t1/2 beta, 12.37 hr). The maximum amounts of permethrin in cerebellum, hippocampus, caudate putamen, frontal cortex, hypothalamus, and sciatic nerve were about 1.5, 2, 2, 2.7, 4.8, and 7.5 times higher than in plasma, respectively, indicating an accumulation of pyrethroid by nervous tissue itself. Nervous tissue accumulation of permethrin was also reflected by the area under the concentration curve ratios of tissue/plasma (1.16, 3.71, 1.57, 4.27, 3.48, and 8.77, respectively). The metabolites of permethrin, m-phenoxy-benzyl alcohol and m-phenoxybenzoic acid, were detected in plasma and in all selected tissues for 48 hr after dosing, suggesting that a combination of metabolism by the tissues and diffusion into it from the blood may be present.

Risk assessment of coccidostatics during feed cross-contamination: Animal and human health aspects

Coccidiosis, an intestinal plasmodium infection, is a major infectious disease in poultry and rabbits. Eleven different coccidiostats are licensed in the EU for the prevention of coccidiosis in these animal species. According to their chemical nature and main biological activity, these compounds can be grouped as ionophoric (monensin, lasalocid sodium, salinomycin, narasin, maduramicin and semduramicin) or non-ionophoric (robenidine, decoquinate, nicarbazin, diclazuril, and halofuginone) substances. Coccidiostats are used as feed additives, mixed upon request into the compounded feed. During the technical process of commercial feed production, cross-contamination of feed batches can result in the exposure of non-target animals and induce adverse health effects in these animals due to a specific sensitivity of mammalian species as compared to poultry. Residue formation in edible tissues of non-target species may result in unexpected human exposure through the consumption of animal products. This review presents recent risk assessments performed by the Scientific Panel on Contaminants in the Food Chain (CONTAM) of the European Food Safety Authority (EFSA). The health risk to non-target species that would result from the consumption of cross-contaminated feed with coccidostats at levels of 2, 5 or 10% was found to be negligible for most animal species with the exception of salinomycin and monensin in horses because of the particular sensitivity for which toxicity may occur when cross-contamination exceeds 2% and 5% respectively. Kinetic data and tissue analyses showed that residues of coccidiostats may occur in the liver and eggs in some cases. However, the level of residues of each coccidiostat in edible animal tissues remained sufficiently low that the aggregate exposure of consumers would not exceed the established acceptable daily intake (ADI) of each coccidiostat. It could be concluded that technical cross-contamination of animal feeds would not be expected to adversely affect the health of consumers.

Coca and Poppy Eradication in Colombia: Environmental and Human Health Assessment of Aerially Applied Glyphosate

The production of coca and poppy as well as the processing and production of cocaine and heroin involve significant environmental impacts. Both coca and poppy are grown intensively in a process that involves the clearing of land in remote areas, the planting of the crop, and protection against pests such as weeds, insects, and pathogens. The aerial spray program to control coca and poppy production in Colombia with the herbicide glyphosate is conducted with modern state-of-the-art aircraft and spray equipment. As a result of the use of best available spray and navigation technology, the likelihood of accidental off-target spraying is small and is estimated to be less than 1% of the total area sprayed. Estimated exposures in humans resulting from direct overspray, contact with treated foliage after reentry to fields, inhalation, diet, and drinking water were small and infrequent. Analyses of surface waters in five watersheds showed that, on most occasions, glyphosate was not present at measurable concentrations; only two samples had residues just above the method detection limit of 25 microg/L. Concentrations of glyphosate in air were predicted to be very small because of negligible volatility. Glyphosate in soils that are directly sprayed will be tightly bound and biologically unavailable and have no residual activity. Concentrations of glyphosate plus Cosmo-Flux will be relatively large in shallow surface waters that are directly oversprayed (maximum instantaneous concentration of 1,229microgAE/L in water 30cm deep); however, no information was available on the number of fields in close proximity to surface waters, and thus it was not possible to estimate the likelihood of such contamination. The formulation used in Colombia, a mixture of glyphosate and Cosmo-Flux, has low toxicity to mammals by all routes of exposure, although some temporary eye irritation may occur. Published epidemiological studies have not suggested a strong or consistent linkage between glyphosate use and specific human health outcomes. An epidemiology study conducted in Colombia did not show any association between time to pregnancy in humans and the use of glyphosate in eradication spraying. The mixture of glyphosate and Cosmo-Flux was not toxic to honeybees. The mixture was, however, more toxic to the alga Selenastrum, the cladoceran Daphnia magna, fathead minnow, and rainbow trout than formulated glyphosate (Roundup) alone. Studies on the use of glyphosate in agriculture and forestry have shown that direct effects on nontarget organisms other than plants are unlikely. Indirect effects on terrestrial arthropods and other wildlife may be the result of habitat alteration and environmental change brought about by the removal of plants by glyphosate. Because of the lack of residual activity, recovery of glyphosate-treated areas in Colombia is expected to be rapid because of good plant growth conditions. However, return to the conditions of tropical old-growth forest that existed before clear-cutting and burning may take hundreds of years, not from the use of glyphosate but because of the clear-cutting and burning, which are the primary cause of effects in the environment. The risk assessment concluded that glyphosate and Cosmo-Flux did not present a significant risk to human health. In the entire cycle of coca and poppy production and eradication, human health risks associated with physical injury during clear-cutting and burning and the use of pesticides for protection of the illicit crops were judged to be considerably more important than those from exposure to glyphosate. For the environment, direct risks from the use of glyphosate and Cosmo-Flux to terrestrial mammals and birds were judged to be negligible. Moderate risks could occur in aquatic organisms in shallow surface waters that are oversprayed during the eradication program. However, the frequency of occurrence and extent to which this happens are unknown as data on the proximity of surface waters to coca fields were not available. Considering the effects of the entire cycle of coca and poppy production and eradication, clear-cutting and burning and displacement of the natural flora and fauna were identified as the greatest environmental risks and are considerably more important than those from the use of glyphosate for the control of coca and poppy.

Depletion study of enrofloxacin and its metabolite ciprofloxacin in edible tissues and feathers of white leghorn hens by liquid chromatography coupled with tandem mass spectrometry.

To ensure delivery of safe foods to consumers, withdrawal times for drugs must be respected according to the maximum residual limits established by regulatory agencies. Because of availability and price, feather meal is currently incorporated into animal feed as a protein source for farm species. Few data are available on residual drugs in feathers from treated animals. A depletion study was performed with laying hens treated intramuscularly with 5% enrofloxacin (Enromic) at 10 mg/kg body weight over 3 days. Thirty-three birds were treated and slaughtered at different times between 6 and 216 h after treatment; and samples of muscle plus skin, liver, kidney, and feathers were collected. High-performance liquid chromatography coupled with a tandem mass spectrometry method was validated before sample analysis to determine the decision limit, detection capability, recovery, and precision. Liver was the edible tissue with the slowest drug depletion. A withdrawal time of 6 days was calculated based on European Union maximum residual limits (100 microg/kg). A withdrawal time of 9 days was calculated based on Japan maximum residual limits (10 microg/kg). Enrofloxacin plus ciprofloxacin concentrations in feathers remained high through all sampling periods. Thus, feathers from treated animals should not be fed to food-producing animals.

Plasma and Tissue Depletion of Florfenicol and Florfenicol-amine in Chickens

Chickens were used to investigate plasma disposition of florfenicol after single intravenous (i.v.) and oral dose (20 mg kg-1 body weight) and to study residue depletion of florfenicol and its major metabolite florfenicol-amine after multiple oral doses (40 mg kg-1 body weight, daily for 3 days). Plasma and tissue samples were analyzed using a high-performance liquid chromatography (HPLC) method. After i.v. and oral administration, plasma concentration-time curves were best described by a two-compartment open model. The mean [ +/- standard deviation (SD)] elimination half-life (t1/2beta) of florfenicol in plasma was 7.90 +/- 0.48 and 8.34 +/- 0.64 h after i.v. and oral administration, respectively. The maximum plasma concentration was 10.23 +/- 1.67 microg mL-1, and the interval from oral administration until maximal concentration was 0.63 +/- 0.07 h. Oral bioavailability was found to be 87 +/- 16%. Florfenicol was converted to florfenicol-amine. After multiple oral dose (40 mg kg-1 body weight, daily for 3 days), in kidney and liver, concentrations of florfenicol (119.34 +/- 31.81 and 817.34 +/- 91.65 microg kg-1, respectively) and florfenicol-amine (60.67 +/- 13.05 and 48.50 +/- 13.07 microg kg-1, respectively) persisted for 7 days. The prolonged presence of residues of florfenicol and florfenicol-amine in edible tissues can play an important role in human food safety, because the compounds could give rise to a possible health risk. A withdrawal time of 6 days was necessary to ensure that the residues of florfenicol were less than the maximal residue limits or tolerance established by the European Union.

Prevention of overweight and obesity from a public health perspective

International organizations have raised awareness of the increasing prevalence of overweight and obesity worldwide and the impact on morbidity, mortality, quality of life, and cost of healthcare. The development and implementation of obesity prevention strategies requires the identification and understanding of determinant factors that can be influenced by effective large-scale action plans over time. Strategies aimed at the primary prevention of obesity in a population should be multifaceted and designed to actively involve stakeholders and other major parties concerned; in addition, multiple settings for implementation should be considered. In this paper, an overview is presented of the strategies currently in place for obesity prevention, particularly in Spain.

Pharmacokinetics of doxycycline in broiler chickens.

Doxycycline was given to two groups of eight chickens at a dose of 20 mg/kg of body weight, intravenously (i.v.) or orally. Plasma concentration was monitored serially for 12 h after each administration. Another group of 30 chickens was given 20 mg/kg orally every 24 h for 4 days, and plasma and tissue concentrations determined serially after the last administration. Concentrations of doxycycline were measured using high-performance liquid chromatography. Pharmacokinetic variables were calculated, using a two-compartment open model. The elimination half-life and the mean residence time for plasma were 6.03 +/- 0.45 and 7.48 +/- 0.38 h, respectively, after oral administration and 4.75 +/-0.21 and 2.87 +/-0.11 h, respectively, after i.v. administration. After single oral administration, doxycycline was absorbed rapidly, with T(max) of 0.35 +/- 0.02 h. Maximum plasma concentration was 54.58 +/- 2.44 mu/ml. Oral bioavailability of doxycycline was found to be 41.33 +/- 2.02%. Doxycycline was widely distributed in tissues and considerable concentrations were found following oral administration of 20 mg/kg on four successive days. The results indicate that doxycycline concentrations were cleared slowly and were at or below the accepted drug tolerance levels in the marker tissues within 5 days after dosing.

Toxicokinetics of glyphosate and its metabolite aminomethyl phosphonic acid in rats.

The toxicokinetics of glyphosate after single 100 mgkg(-1) intravenous (i.v.) and 400 mgkg(-1) oral doses were studied in rats. Serial blood samples were obtained after i.v. and oral administration. Plasma concentrations of glyphosate and its metabolite amiomethyl phosphonic acid (AMPA) were determined by HPLC method. After i.v. and oral administration, plasma concentration-time curves were best described by a two-compartment open model. For glyphosate, the elimination half-lives (T(1/2beta)) from plasma were 9.99 h after i.v. and 14.38 h after oral administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.995 l h(-1)kg(-1). After i.v. administration, the apparent volume of distribution in the second compartment (V(2)) and volume of distribution at steady state (V(ss)) were 2.39 and 2.99 l kg(-1), respectively, suggesting a considerable diffusion of the herbicide into tissues. After oral administration, glyphosate was partially and slowly absorbed with a T(max) of 5.16 h. The oral bioavailability of glyphosate was found to be 23.21%. Glyphosate was converted to AMPA. The metabolite AMPA represented 6.49% of the parent drug plasma concentrations. The maximum plasma concentrations of glyphosate and AMPA were 4.62 and 0.416 microg ml(-1), respectively. The maximum plasma concentration of AMPA was achieved at 2.42 h. For AMPA, the elimination half-life (T(1/2beta)) was 15.08 h after oral administration of glyphosate parent compound.

Metabolic characterization of cell systems used in in vitro toxicology testing: lung cell system BEAS-2B as a working example.

The bioactivation of pro-toxicants is the biological process through which some chemicals are metabolized into reactive metabolites. Therefore, in vitro toxicological evaluation should ideally be conducted in cell systems retaining adequate metabolic competency and relevant to the route of exposure. The respiratory tract is the primary route of exposure to inhaled pro-toxicants and lung-derived BEAS-2B cell line has been considered as a potentially suitable model for in vitro toxicology testing. However, its metabolic activity has not been characterized. We performed a gene expression analysis for 41 metabolism-related genes and compared the profile with liver- and lung-derived cell lines (HepaRG, HepG2 and A549). To confirm that mRNA expression was associated with the corresponding enzyme activity, we used a series of metabolic substrates of CYPs (CYP1A1/1B1, CYP1A2, CYP2A6/2A13 and CYP2E1) known to bioactivate inhaled pro-toxicants. CYP activities were compared between BEAS-2B, HepaRG, HepG2, and A549 cells and published literature on primary bronchial epithelium cells (HBEC). We found that in contrast to HBEC, BEAS-2B and A549 have limited CYP activity which was in agreement with their CYP gene expression profile. Control cell lines such as HepG2 and HepaRG were metabolically active for the tested CYPs. We recommend that similar strategies can be used to select suitable cell systems in the context of pro-toxicant assessment.

Permethrin-induced oxidative stress and toxicity and metabolism. A review

Permethrin (PER), the most frequently used synthetic Type I pyrethroid insecticide, is widely used in the world because of its high activity as an insecticide and its low mammalian toxicity. It was originally believed that PER exhibited low toxicity on untargeted animals. However, as its use became more extensive worldwide, increasing evidence suggested that PER might have a variety of toxic effects on animals and humans alike, such as neurotoxicity, immunotoxicity, cardiotoxicity, hepatotoxicity, reproductive, genotoxic, and haematotoxic effects, digestive system toxicity, and cytotoxicity. A growing number of studies indicate that oxidative stress played critical roles in the various toxicities associated with PER. To date, almost no review has addressed the toxicity of PER correlated with oxidative stress. The focus of this article is primarily to summarise advances in the research associated with oxidative stress as a potential mechanism for PER-induced toxicity as well as its metabolism. This review summarises the research conducted over the past decade into the reactive oxygen species (ROS) generation and oxidative stress as a consequence of PER treatments, and ultimately their correlation with the toxicity and the metabolism of PER. The metabolism of PER involves various CYP450 enzymes, alcohol or aldehyde dehydrogenases for oxidation and the carboxylesterases for hydrolysis, through which oxidative stress might occur, and such metabolic factors are also reviewed. The protection of a variety of antioxidants against PER-induced toxicity is also discussed, in order to further understand the role of oxidative stress in PER-induced toxicity. This review will throw new light on the critical roles of oxidative stress in PER-induced toxicity, as well as on the blind spots that still exist in the understanding of PER metabolism, the cellular effects in terms of apoptosis and cell signaling pathways, and finally strategies to help to protect against its oxidative damage.