Annual Meeting of the Japanese Society of Toxicology

A retrospective review has been performed of Acceptable Daily Intakes (ADI) for pesticide residues in Japan where dog studies have provided the pivotal data for their derivation. A set of 46 ADIs which are based on the results of dog toxicity studies (normally 1-year) were examined and reassessed under the assumption that the 1-year dog study had not been conducted , thus requiring the derivation of the ADI from an alternative toxicology study. A resulting ADI up to 2 times higher was not considered to be a real difference and was found in 36 of the 46 data sets (78.3%). An ADI 2-5 times higher was found in another 6/46 data sets (13%), but is potentially not a toxicologically
relevant difference or requiring additional studies, while for 3/46 data sets (6.5%) there may be a real difference. Only 1/46 data sets (2.2%) showed an ADI higher than 5 times.
The incidences of 3/46 plus 1/46 should not only be assessed within the specific data set investigated, but against the total of all registrations of conventional pesticides in Japan, a number exceeding 400 active substances. Accordingly, the absence of a 1-year dog study would not influence the ADI derivation in a relevant manner for more than 98% of these pesticides.
Therefore the standard requirement to conduct a 1-year dog study in addition to the 3-month study cannot be justified.

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Introduction : Reptile populations all around the world are decreasing. The dominant stressors are decrease of habitats, targeted harvesting and climate change. Environmental pollution could be a common factor weakening populations, yet we know little about the effect of xenobiotics on reptiles. Pyrene, as a representative of polycyclic aromatic hydrocarbons (PAHs), was choosen to study the metabolism in freshwater turtles, as disasters involving PAHs (oil spills) are one of the main causes of health and reproductive problems in water-living organism.
Materials and Methods:Red-eared sliders (Trachemys scripta elegans), Chinese pond turtles (Mauremys reevesii) and Chinese softshell turtles (Pelodiscus sinensis) were used. Pyrene exposure occurred thorugh oral feeding (4 mg/kg pyrene, dissolved in corn oil) or through water (250 μg/l). Exposed water was filtered, passed through a solid-phase cartridge, and eluded with methanol. Metabolites were determined by HPLC with FD equipped with an ODS column, and identified by an MS/MS system. Liver subcellular fractions were isolated from fresh samples, protein concentration were measured by BCA protein assay. EROD, UGT and SULT activity were measured.
Results and Discussion:Distinct metabolite distributions were measured for each species. The dominant metabolite in all three species was pyrene-1-sulfate. All enzyme activities were low compared to mammals (rat). Sulfate conjugation was the dominant phase II metabolic pathway in all three species.

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[Introduction]
In our previous work, positive correlations between CYP1A- dependent activities, protein expression and β-carotene (BC) accumulation in the ungulates were observed, however these cross-talks were poorly understood. Additionally, the regulatory effects of carotenoids on xenobiotics metabolizing enzymes (XMEs) had received little attention. Thus, the aim of the current study is to deeply investigate the constitutive response of AhR gene battery to the exposure to BC under various doses in the human hepatoma cell line (HEPG2) cells. Moreover, the possible regulatory mechanisms of these cross-talks between AhR and BC will be declared.
[Materials and Methods]
HEPG2 cell lines were treated with different concentrations of BC (0-10 µM) for 12-24h. The mRNA expression for phase I (CYP1A1 and 1A2), Phase II (UGT1A6 and NQO1) enzymes and AhR were examined using Real-Time PCR. Protein expression of AhR was investigated using western blotting. Rat H4IIE cells were transfected with h-XRE luciferase reporter plasmid and exposed to BC for 24h and dual- luciferase reporter assay was performed.
[Results and Discussion]
BC differentially modulated XMEs (Phase I and II enzymes) expression in dose-dependent fashion. In parallel, BC induced AhR mRNA, protein expression and luciferase activity. Thus, β-carotene differentially modulated AhR gene battery.

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