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of therapeutic strategies for neurodegenerative diseases, such asAlzheimer’s and Parkinson’s.

Abstracts / Toxicology L

27-13cute organophosphorus poisoning in humans: A PK model forhlorpyrifos

acqueline M. Anderson 1, Klas J. Petersson 2, Lena E. Friberg 2,ranz Worek 3, Horst Thiermann 3, Nicholas A. Buckley 1

University of New South Wales, Australia, 2 Uppsala University,weden, 3 Bundeswehr Institute of Pharmacology, Germany

Organophosphorus (OP) pesticide poisoning is an importantroblem in South Asia. Acute poisoning from OP’s in Sri Lankaesulted in 853 deaths in 2007 with incidence increasing. Charac-erization of the dose-concentration-response relationship woulde useful to understand the time-course of acute poisoning. How-ver, accurate information on dose amount and time of ingestions generally lacking. In this analysis we aimed to develop PK andKPD models of one OP, chlorpyrifos (CPF), in acute poisoning.

A PK model for CPF and its metabolites was developed usingONMEM VII. The model was derived from acute poisoning data

rom patients (n = 72; 7 Female, age 15–65 years, 2–8 samples perubject). Reported volumes ingested ranged from 10 to 350 ml.PF, chlorpyrifos oxon (CPO), Cholinesterase [acetylcholinesteraseAchE) and butyrlcholinesterase (BChE)] were measured.

A 2-compartment model for CPF with first order absorptioninetics and one compartment disposition for the active metabo-ite CPO best described the data. Dose uncertainty was accountedor by allowing each individual’s dose to deviate from the median57.5 ml) using reported volume intake as a covariate on the rela-ive bioavailability parameter. For CHL, absorption was fixed, 1.64h), Cl 0.9 (L/h), Vd 7.39 (L), Vp 33.9 (L) and Q 1.65 (h). Proportionalesidual error was 37%. Estimated dose was on average 30 ml lesshan reported.

The validated PK model characterized the observed concen-rations of 0.1–19 nM well with reasonable estimates of the doseange. The PD model is under development and will incorporateholinesterase inhibition, an important biomarker, and survivalata.

oi:10.1016/j.toxlet.2012.03.784

27-14hildren nearby organic plantation have lower levels ofhlorpyrifos metabolites

erna van Wendel de Joode 1, Douglas Barraza 1, Clemensuepert 1, Ana María Mora 1, Leonel Córdoba 1, Mattias Öberg 2,atharina Wesseling 1, Donna Mergler 3, Christian Lindh 4

Universidad National, Costa Rica, 2 Karolinska Institutet, Sweden,University of Quebec at Montréal, Canada, 4 Lund Universityospital, Sweden

Due to concern of neurodevelopmental effects, the U.S. EPAanned residential use of chlorpyrifos in 2001. Meanwhile, in Costaica, chlorpyrifos-treated bags are increasingly used to protectanana and plantain fruits from insects and to fulfill product stan-ards. The purpose of this study was to evaluate children’s exposureo chlorpyrifos in villages situated nearby banana plantations andlantain farms in Costa Rica.

Two villages where chlorpyrifos-treated bags were used in

earby banana plantations and plantain farms and one villageith organic production were investigated, inhabited by indige-ous Ngäbe and Bribri. In total, 140 children donated urine samples,f which 40 on more than one occasion.

211S (2012) S43–S216 S173

Urinary 3,5,6-trichloro-2-pyridinol (TCPy) levels were mea-sured as a biomarker for chlorpyrifos exposure.

Children from the banana and plantain villages had statisti-cally significant higher urinary TCPy concentrations than childrenfrom the referent village; 2.6 and 2.2 versus 1.3 �g/g creatinine,respectively. Estimated median values of the absorbed daily doseof children from the banana and plantain villages were about0.1 �g/kg/day, compared to 0.05 �g/kg/day from the organic vil-lage.

In conclusion, Children living nearby plantations withchlorpyrifos-treated bags are exposed to chlorpyrifos. For part ofthese children, their estimated daily intake exceeded the referencedose established by U.S. EPA and every second value indicated anintake above the chronic population adjusted dose. Interventionsto reduce chlorpyrifos exposure are likely to improve children’senvironment and health in tropical regions.

doi:10.1016/j.toxlet.2012.03.785

P27-15Neuroprotective effects of memantine in the models ofexcitotoxicity

Ramesh Gupta 1, Snjezana Zaja-Milatovic 2, Dejan Milatovic 2

1 Murray State University, United States, 2 Vanderbilt University,United States

Purpose: Exposure to chemicals of various classes induce excito-toxicity, oxidative/nitrosative damage, and neurodegeneration bymultiple mechanisms. The present investigation was undertaken toexamine whether NMDA receptor antagonist memantine providesantioxidative, antinitrosative, and neuroprotective effects in exci-totoxicity models induced by kainic acid (KA) or anticholinesterase(anti-AChE) diisopropylphosphorofluoridate (DFP) or carbofuran.

Methods: DFP or carbofuran (1.25 mg/kg, sc) treated rats, andKA (1 nmol/5 �l, icv) treated mice were evaluated for excitotox-icity, quantitative changes in oxidative/nitrosative biomarkers,high-energy phosphates (HEPs), and morphometric changes indendritic system of hippocampal pyramidal neurons. Protection ofexcitotoxicity-induced injury was assessed in animals pretreatedwith memantine 30 min prior to KA/anti-AChE exposure.

Results and conclusions: Excitotoxicity signs occurred within30 min. At this time, significant increases in biomarkers of oxidativedamage (F2-isoprostanes, 1.5–2-fold; F4-neuroprostanes, >2-fold),nitrosative damage (citrulline, 3–6-fold increase), and declines inHEPs (ATP, ∼50%; PCr, ∼60%) occurred in the cerebrum. Brainregional heterogeneity (cortex, amygdala, and hippocampus) forcitrulline in both control and treated rats was noteworthy. Hip-pocampal neurons showed significant reductions in dendriticlength and spine density (>60%) in treated animals. Memantinepretreatment in rats (18 mg/kg, ip) or mice (5 mg/kg, ip) attenu-ated DFP-, carbofuran-, or KA-induced changes in F2-Isoprostanes,F4-neuroprostanes, citrulline, HEPs and morphometry of CA1hippocampal neurons. These findings suggest that memantinesignificantly protects neuronal oxidative/nitrosative damage andrescues neurons from neurodegeneration in excitotoxicity inducedby anti-AChE or KA. Elucidation of memantine’s multiple neuro-protection mechanisms will be instrumental in the development

doi:10.1016/j.toxlet.2012.03.786