Mode of action of carcinogenic nitrosamines and cumulative risk assessment

S70 Abstracts / Toxicology Letters 229S (2014) S40–S252

attenuated serum ALT (2168 ± 103 vs 5050 ± 445 U/L, p < 0.001),miR-122 and chemo/cytokine increases seen with APAP+PBS. Liverhistology and MPO revealed reduced neutrophil infiltration andactivity in anti-HMGB1 treated animals. No significant differenceswere seen between APAP+PBS and APAP+E2 for any parameter.

Our work is the first use of a humanized anti-HMGB1 antibodyto attenuate disease, and strongly suggests h2G7 has the potentialto be an important anti-inflammatory therapeutic.

http://dx.doi.org/10.1016/j.toxlet.2014.06.273

P-1.94Mode of action of carcinogenic nitrosaminesand cumulative risk assessment

Nathalie Ledirac 1,∗, Lisa Bertomeu 1, Marie-Charlotte Bernier 2

1 CEHTRA SAS, Bordeaux, France, 2 CEHTRA SAS, Paris, France

In the context of the DALMATIEN research project fundedby ANR (The French Research Agency), the degradation ofmonoethanolamine (MEA) in post-combustion CO2 capture wasinvestigated. Among the degradation products released in theatmosphere, several nitrosamines were identified. Their toxicolog-ical profiles and modes of action (MoA) were studied to evaluatethe relevance of assessing cumulative risks.

For each of these nitrosamines, available data on mammaliantoxicity were evaluated. The similarity of the MoA is not clearlysupported by a common target organ. The liver is the most fre-quent targeted organ, but esophagus and nasal cavity (NC) arealso affected. Nitrosopiperazine and dinitrosopiperazine targetthe NC in different strains of rats and mice. N-nitrosomorpholineinduces benign and malignant tumors in the liver in mice, rats andhamsters. Nitrosodiethanolamine targets the liver and the NC inrats when administered through drinking water. The metabolismwas clearly identified as a crucial and common step of the MoAleading to carcinogenicity. Nitrosamines can either be detoxifiedby denitrosation to simple amines and aldehydes or activated to adiazonium ion that can form DNA adducts. However, the formationof DNA adducts appeared to be poorly correlated to the observedcarcinogenicity and mutagenicity of nitrosamines. Based on thecurrent state of knowledge regarding the MoA of carcinogenicnitrosamines, independent actions were not clearly demonstratedand therefore a cumulative risk assessment and a general exposurelimit should be applied.

DALMATIEN: Degradation of Amines in Liquid Matrix andAnalysis: Toxicity or Innocuousness for ENvironment?

http://dx.doi.org/10.1016/j.toxlet.2014.06.274

P-1.95Gender-related pharmacokinetics oflobeglitazone following oral administration inrats

Jong-Hwa Lee ∗, Kyoung-Sik Moon, Eun ju Jeong, Sang-Joon Lee

Korea Institute of Toxicology, Daejeon, Republic of Korea

Lobeglitazone, a novel thiazolidinedione based activator forthe peroxisome proliferator-activated receptor, was recentlydeveloped and marketed for the treatment of diabetes. Follow-ing oral administration at the dose range of 0.1–10 mg/kg tomale and female rats, rats were exposed to lobeglitazone withdose-proportionality indicating linear pharmacokinetics. Gender

difference for lobeglitazone in the systemic exposure measured byAUC and Cmax was observed as thiazolidinedione compounds, suchas rosiglitazone, pioglitazone and troglitazone, have been demon-strated pharmacokinetic differences between male and female inrats. The AUC and Cmax for lobeglitazone were significantly higherin female rats than in male rats.

To confirm the mechanism of gender differences, rat liver micro-some experiments were performed in triplicate at six time pointsfrom 0 to 60 min using male and female rat liver microsome.Lobeglitazone was rapidly metabolized in males than in females,and lobeglitazone was remained with 3-folds in female rat livermicrosome that those of in male rat liver microsome. In addition,the CLint values for lobeglitazone in male rats was much higher thanthat in female rats.

http://dx.doi.org/10.1016/j.toxlet.2014.06.275

P-1.96Embryo-fetal development toxicokinetic studyof pyronaridine tetraphosphate in rats

Jong-Hwa Lee 1,∗, Kyung-Sik Moon 1, Lawrence Fleckenstein 2,Eun Ju Jeong 1, Sang-Joon Lee 1

1 Korea Institute of Toxicology, Daejeon, Republic of Korea,2 University of Iowa, Iowa City, IA, USA

In order to evaluate the maternal and fetal exposure to pyronar-idine during the embryo-fetal development of rats, pyronaridinetetraphosphate was administrated once a day by oral gavage topregnant rats from gestation day (GD) 6 to GD 15 at doses of 47,140 and 420 mg/kg/day. Maternal plasma samples collected on GDs5, 6, 10 and 15. Amniotic fluid was taken after Caesarean section onGD 15 to evaluate fetal exposure to pyronaridine. Quantification ofpyronaridine in maternal blood and amniotic fluid was achieved byhigh performance liquid chromatography (HPLC).

Pyronaridine whole blood concentration increased in a lin-ear fashion with respect to dose over the daily dose range of47–420 mg/kg/day. Mean pyronaridine concentrations were low inamniotic fluid on gestation day 15 compared to whole blood andwere 41.3, 78.2 and 154 ng/ml for the low, mid and high dose levels,respectively. Pyronaridine concentrations in amniotic fluid wereapproximately 4–7% of those in maternal whole blood indicatinglow placental permeability to the drug in rats. This study providesevidence of limited penetration of pyronaridine to amniotic fluid.

http://dx.doi.org/10.1016/j.toxlet.2014.06.276

P-1.97Aluminium intoxication and beer consumption:Effects in the levels of trace metals in mousebrain

Maria Jose González-Munoz 1, Isabel Meseguer 1, Carmen JoseMateos-Vega 1, Jose Benedí 2, Francisco Jose Sánchez-Muniz 3,Maria del Carmen Lobo-Bedmar 4,∗, Antonio Pena-Fernández 1

1 Departamento de Ciencias Biomédicas, Unidad Docente deToxicología, Facultad de Farmacia, Universidad de Alcalá, Alcalá deHenares, Madrid, Spain, 2 Departamento de Farmacología, Facultadde Farmacia, Universidad Complutense de Madrid, Madrid, Spain,3 Departamento de Nutrición, Facultad de Farmacia, UniversidadComplutense de Madrid, Madrid, Spain, 4 IMIDRA, Departamento deInvestigación Agroambiental, Alcalá de Henares, Madrid, Spain