Comparative Pharmacokinetics of High and Low Doses of the Herbicide Propanil in Mice.

We have documented that the herbicide propanil is immunotoxic in mice, and our in vitro tissue culture experiments largely recapitulate the in vivo studies. Laboratory studies on environmental contaminants are the most meaningful when these studies are conducted using concentrations that approximate levels in the environment. Many techniques to measure the distribution and pharmacokinetics (PK) on compounds rely on techniques, such as liquid scintillation counting (LSC) of radio-labeled starting compound, that require concentrations higher than environmental levels. The aim of this study was to compare tissue PK after exposure to propanil concentrations more relevant to levels of exposure to agricultural workers and the general population to concentrations previously reported for laboratory studies. To this end, we conducted a study to measure propanil distribution in three immune organs, using ultrasensitive accelerator mass spectrometry (AMS). We used two doses: the lower dose modeled levels expected in the environment or long-term occupational exposure to low doses, while the higher dose was to model the effects of an accidental exposure. Our results showed that the distribution and PK profiles from these two different concentrations was markedly different. The profile of the high dose (concentration) exposure was indicative of saturation of the detoxifying capability of the animal. In contrast, at the lower environmentally relevant concentration, in vivo concentrations of propanil in spleen, liver, and blood dropped to a very low level by 720 min. In conclusion, these studies highlight the differences in PK of propanil at these two doses, which suggests that the toxicity of this chemical should be re-investigated to obtain better data on toxic effects at doses relevant for humans.

Subcellular localization of the amide class herbicide 3,4-dichloropropionanilide (DCPA) in T cells and hepatocytes.

3,4-Dichloropropionanilide (DCPA), or propanil, a post-emergent herbicide used on rice and wheat crops in the United States, is immunotoxic in vivo and in vitro. Although it has been documented that DCPA exerts differential effects on specific immune cell types and is toxic to the liver, the way in which DCPA modulates intracellular functions leading to these effects is less understood. In this study, Jurkat T cells and hepatocytes from C57Bl/6 mice were exposed to 100 microM DCPA for 1.5 h. Following incubation, subcellular fractions of each cell type were isolated. DCPA, when present, was removed from each cell fraction by liquid-liquid extraction. The extraction product was then analyzed for the presence of DCPA using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The cellular uptake of DCPA was monitored by detection of the molecular ion and product ion of DCPA. The analyses demonstrate that DCPA, a lipophilic compound, localizes primarily in the cytosol of T cells and hepatocytes. These results indicate that DCPA is able to cross the plasma membrane and is accessible to intracellular immunomodulatory effectors.

Clinical outcomes and kinetics of propanil following acute self-poisoning: a prospective case series.

BACKGROUND: Propanil is an important cause of death from acute pesticide poisoning, of which methaemoglobinaemia is an important manifestation. However, there is limited information about the clinical toxicity and kinetics. The objective of this study is to describe the clinical outcomes and kinetics of propanil following acute intentional self-poisoning. METHODS: 431 patients with a history of propanil poisoning were admitted from 2002 until 2007 in a large, multi-centre prospective cohort study in rural hospitals in Sri Lanka. 40 of these patients ingested propanil with at least one other poison and were not considered further. The remaining 391 patients were classified using a simple grading system on the basis of clinical outcomes; methaemoglobinaemia could not be quantified due to limited resources. Blood samples were obtained on admission and a subset of patients provided multiple samples for kinetic analysis of propanil and the metabolite 3,4-dichloroaniline (DCA). RESULTS: There were 42 deaths (median time to death 1.5 days) giving a case fatality of 10.7%. Death occurred despite treatment in the context of cyanosis, sedation, hypotension and severe lactic acidosis consistent with methaemoglobinaemia. Treatment consisted primarily of methylene blue (1 mg/kg for one or two doses), exchange transfusion and supportive care when methaemoglobinaemia was diagnosed clinically. Admission plasma concentrations of propanil and DCA reflected the clinical outcome. The elimination half-life of propanil was 3.2 hours (95% confidence interval 2.6 to 4.1 hours) and the concentration of DCA was generally higher, more persistent and more variable than propanil. CONCLUSION: Propanil is the most lethal herbicide in Sri Lanka after paraquat. Methylene blue was largely prescribed in low doses and administered as intermittent boluses which are expected to be suboptimal given the kinetics of methylene blue, propanil and the DCA metabolite. But in the absence of controlled studies the efficacy of these and other treatments is poorly defined. More research is required into the optimal management of acute propanil poisoning.

Fluorescent Pseudomonas isolates from Mississippi Delta oxbow lakes: in vitro herbicide biotransformations.

Fluorescent pseudomonads were a major component [log (10) 4.2-6.1 colony-forming units mL-1] of the culturable heterotrophic gram-negative bacterioplankton observed in three Mississippi Delta oxbow lakes in this study. Pure cultures of fluorescent pseudomonads were isolated from three Mississippi Delta oxbow lakes (18 per lake), using selective media S-1. Classical physiological tests and Biolog GN plates were used in criteria for taxonomic identification. Most isolates were identified as biotypes of Pseudomonas fluorescens 55% (II), 7% (III), and 25% (V). About 7% of the isolates were identified as P. putida and 7% as non-fluorescent Pseudomonas-like. Cell suspensions of these isolates were tested for their ability to metabolize/co-metabolize six 14C-radiolabeled herbicides (2,4-dichlorophenoxyacetic acid (2,4-D), cyanazine, fluometuron, metolachlor, propanil, and trifluralin) that are commonly used for crop production in this geographical area. Almost all (53 of 54) isolates transformed trifluralin via aromatic nitroreduction. Most isolates (70%) dechlorinated metolachlor to polar metabolites via glutathione conjugation. About 60% of the isolates hydrolyzed the amide bond of propanil (a rice herbicide) to dichloroaniline, with the highest frequency of propanil-hydrolyzing isolates observed in the lake from the watershed with rice cultivation. All propanil-hydrolyzing isolates were identified as P. fluorescens biotype II. No metabolism of cyanazine or fluometuron was observed by any isolates tested, indicating little or no potential for N-dealkylation among this group of bacterioplankton. No mineralization of 2,4-D labeled in either the carboxyl or ring position was observed. These results indicate that reductive and hydrolytic pathways for herbicide co-metabolism (aromatic nitroreduction, aryl acylamidase, and glutathione conjugation) are common in Mississippi Delta aquatic fluorescent pseudomonads; however, the potential for certain oxidative transformations (N-dealkylation, cyano group oxidation) may be rare in this group of bacterioplankton.

Distribution and elimination of the herbicide propanil in the channel catfish (Ictalurus punctatus).

1. The uptake, elimination and tissue distribution of total radioactivity derived from the herbicide, [14C]propanil (3,4-dichloropropionanilide) and its metabolites were examined in individual farm-raised Channel Catfish which were exposed for 24 h to water containing 1 ppm of 14C-propanil under static conditions. Uptake and elimination of total radioactivity was monitored in individual animals over time in respective exposure (24 h) and depurating (144 h) aquaria. 2. Maximal uptake was reached between 8 and 12 h with approx. 38% of the absorbed radioactivity remaining in the animal after 144 h of depuration. Whole body depuration of radioactivity was biphasic with alpha and beta half-lives of 20 and 444 h, respectively. 3. Tissue distribution of total radioactivity was monitored at various time points in 12 tissues and bile over 48 h. Intestine, abdominal fat and liver possessed the greatest levels of radioactivity per gram of tissue over time. Radiolabel was shown to slowly increase in bile and intestine indicating biliary excretion as a possible pathway of metabolite elimination. 4. Bile possessed approx. 104 nmol (23%) of the remaining radioactivity in fish after 48 h. Other whole tissues possessing > 10% of radiolabel after 48 h were blood (83.5 nmol, 19% of the administered dose) and muscle (190 nmol, 43%).