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180 Abstracts / Toxicology L

ncluding studies by subcutaneous route. All available informationas assessed using a dedicated decision tree based on a weight of

vidence approach. Depending on the quality of data and the degreef discrepancy between studies, each type of effect was qualifiedn terms of recognized, suspected, controversial or as no conclu-ive effects. The available data were presented by their windows ofxposure (pre natal, peri-natal). Results. Some effects were consid-red as recognised in animals, including: effects on neurogenesisfter pre or peri-natal exposure; effects on lipogenesis after pre-r peri- natal exposure or exposure in adulthood; development ofntraductal hyperplastic lesions after pre- or perinatal exposure andcceleration of architectural maturation of the mammary glands indulthood. Based on the limited human data, metabolism and car-iovascular diseases were considered as suspected while the effectsn brain behaviour and on breast were not conclusive. Conclusions.urther to this analysis, recognised effects in animals and suspectedffects in humans will be used for the risk assessment procedure,aking into account all routes of exposure to BPA.

oi:10.1016/j.toxlet.2012.03.647

29-13ehicles & excipients used in minipigs—Review of use inarketed drug products

iels-Christian Ganderup

Ellegaard Göttingen Minipigs, Denmark

Selection of suitable vehicles and/or excipients is critical in bothon-clinical and clinical studies as formulation impacts the intrin-ic characteristics of the final drug product, e.g., (extended) release,bsorption, distribution and (local) tolerance, to mention some.nappropriate selection of vehicles and/or excipients can have neg-tive impact on drug evaluation (which may be unwarranted) andonsequently delay or stop development. This type of informations available for mice, rats, rabbits, dogs and non-human primatesNHP), but information specific to minipigs is scarce.

More than forty marketed drug products (FDA/EMA dossiers)ave been reviewed and vehicles and excipients used are presented

n this poster. Data includes information on route of administration,osage, study duration, and (where possible) notable reactions.ublished literature on this topic is also included. This provides theon-clinical experimenter with a valuable tool in his or her work.

oi:10.1016/j.toxlet.2012.03.648

29-14eview of marketed drugs supported by the minipig ason-rodent species

iels-Christian Ganderup

Ellegaard Göttingen Minipigs, Democratic People’s Republic of Korea

Minipigs, like conventional pigs, are used as models of humanisease and in safety studies of new medicines, medical devices,ood additives and pesticides. This poster reviews the historical usef the minipig as a non-rodent species in regulatory toxicity testingo support new medicines and presents data on routes of adminis-ration, clinical indications as well as mechanism of action (where

f possible) for more than forty marketed drug products.

It also includes a qualitative assessment of the predictive valuef the minipig by comparing adverse reactions in clinical trials andinipig studies. The most readily available source of comprehen-

211S (2012) S43–S216

sive and unbiased information about licensed drugs is found in thepublicly available databases of major regulatory agencies, wherethere are extensive non-clinical and clinical data from companysubmissions and it is critical assessment by independent experts.

For the present analysis searches were made of two princi-pal databases covering medicines registered in the USA, namelyDrugs@FDA, and in the European Community EMA European Pub-lic Assess-ment Reports (EPARs); data mining and searches ofsaid databases was done using PharmaPendium®. Such informa-tion pertaining to minipigs has, to the authors knowledge, neverbeen published before, and is therefore seen as both new andground breaking and surely warrants rethinking of the potentialthis species holds as non-rodent species in safety assessment.

doi:10.1016/j.toxlet.2012.03.649

P29-15Haematology and biochemistry changes related to age inGöttingen minipigs

Andrew Makin, Jes T. Jensen, Signe Klastrup

CiToxLAB, Denmark

Minipigs are commonly used non-rodents in toxicology studies.We use Göttingen minipigs at a range of ages and developmentalstages from neonatal up to around two years of age depending onthe type of study. Minipigs develop rapidly. They are born withopen eyes and can walk. They wean at 4 weeks and are sexuallymature at 4 to 6 months. Despite maturing early, they continue togrow during the first 2 years of their lives. Therefore an animal atthe end of a chronic toxicity study is significantly bigger and moredeveloped than at the start. This is reflected by other changes thanjust increased size.

Findings in toxicology studies must be put into context usingboth concurrent control and historical data. We were interested tosee how some routine parameters measured in toxicology studieschange over time. There will always be results that need a deeperexplanation, which is where the background data is of value. Inour poster, we present a significant amount of control data fromminipigs covering a range of ages, highlighting changes that couldbe expected to be seen over time.

Our data indicates that values for certain parameters, e.g. redblood cells, change significantly over short times, especially inyounger animals. However, values for other parameters (e.g. serumprotein and creatinine) continue to change with age even in matureanimals. These results demonstrate that a database of age-matchedresults is invaluable in supporting interpretation of findings in tox-icology studies in the minipig.

doi:10.1016/j.toxlet.2012.03.650

P29-16Reducing dog use in one month toxicology studies withoutaffecting scientific quality

Sally Robinson 1, Kristian Konigsson 2, Hans Harlemann 1

1 United Kingdom, 2 AstraZeneca, Sweden

Assessing reversibility of treatment related changes is impor-

tant in risk assessment and embodied in regulatory guidance.Within AstraZeneca reversibility is incorporated into the onemonth toxicology studies.

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The one-month study design in dogs has previously included:ain phase 3M + 3F per group (control, low, mid, high) treated

or one month and Recovery 3M + 3F per group (control and high)reated for one month and left untreated for another month.

Control animals are fundamental for data that can only be col-ected once (e.g. pathology) providing information on backgroundhanges and a comparison for treated groups. For data collectedepeatedly in the same animals (e.g. ECG and Clinical pathology)ach animal is its own control. Since the purpose of the recoveryroups is to assess recovery from treatment related effects at theigh dose, we believe it is only necessary to compare high doseain animals with high dose recovery animals and that no control

ecovery group is needed.This approach is supported by (1) using mature animals to mini-

ize risk of age related drifts in background pathology and (2) usingcontrol slide set from recent studies that aids the interpretationf low incidence findings. Removing the recovery control grouprom one month studies reduces the number of dogs from 36 to 30.his approach was implemented in 2009 and has been applied in5 one month studies, across a range of therapy areas (using 150ewer dogs) and there have been no scientific or regulatory issues.roader applicability is being explored.

oi:10.1016/j.toxlet.2012.03.651

29-17oxicokinetic modelling to refine human risk assessment—Aase study (aminopyralid)

laire Terry 1, Alene T. Mccoy 2, David L. Rick 2, Shakil A. Saghir 2,ichael J. Bartels 2

Dow Agrosciences, United Kingdom, 2 The Dow Chemical Company,nited States

Purpose: During a developmental toxicity study of aminopyralid,n herbicide, in New Zealand White rabbits, maternal toxicity wasvidenced at 500 mg/kg/day by transient pharmacological effect,ncoordinated gait, and decreased body weight gains. The inco-rdination is thought to be associated with the high, transientaximum plasma concentrations (Cmax) achieved after oral gav-

ge dosing. Incoordination was deemed the critical effect and hasreviously been proposed as the driver for the Acceptable Oper-tor Exposure Level (AOEL) for human risk assessment in the EU.ethods: To better understand the potential risk of human expo-

ure to aminopyralid, a kinetic model of dermal absorption ofminopyralid was constructed. Blood concentrations after absorp-ion of aminopyralid via the dermal or oral routes were modelledsing a one-compartment open model with first-order absorption.esults and conclusions: Predicted Cmax at steady state after dermalpplication of 500 mg/kg/day was 23.11 �g/mL and daily systemicxposure (AUC24h) was 216 (�g h)/mL. Predicted Cmax at steadytate after oral administration of 500 mg/kg/day was 117.34 �g/mLnd daily systemic exposure (AUC24h) was 765 (�g h)/mL. Due tolower absorption by the dermal route, Cmax after dermal applica-ion of 500 mg/kg/day aminopyralid for 6 hours is 20% of Cmax viahe oral route.

In conclusion, modelling of aminopyralid plasma concentrationsn the rabbit showed that the pharmacological effects seen in theral dose study are not likely to occur in a study of dermal expo-ure at the same doses. This modelling supports a more appropriate

OEL to be set for aminopyralid.

oi:10.1016/j.toxlet.2012.03.652

211S (2012) S43–S216 S181

P29-18Pesticide safety management system in Ukraine

Mykola Prodanchuk, Olga Bobylyova, Nadii Nedopytanska, IgorLeposhkin, Georgii Prodanchuk

Medved’s Institute of Ecohygiene and Tox, Ukraine

The main principle of national policies on pesticide managementis the human and environmental health priority. Chemical safetiespertaining to pesticides are the responsibility of the Ministry ofEnvironment protection and the Ministry of Health of Ukraine.

Crop protection chemical safety is regulated more than 30Ukrainian Laws and directives, main of them are the Low aboutenvironmental protection; about providing sanitary and epidemicwell-being of population; about pesticides and agrochemicals.

Volumes of pesticides application in Ukraine consist more than36 000 ton on the 40 million “gectars” lands use for agriculture (gec-tar = 2,471 acres). The pesticides with state registration status onlyare allowed for use in Ukraine.

The priority directions of pesticides toxicological investigationsare the study of mechanisms of toxic, selective and combine action;ability to endocrine disruption; immunological action; the studyof aging sensibility to pesticides; evolving toxicogenomic of pes-ticides; the human health risk assessment; the improvement ofdiagnostics and treatment of acute and chronic poisons, antidotetherapy. The main institution in the problem of pesticides healthsafety in Ukraine is the Institute of Ecohygiene and Toxicologynamed by L.I.Medved.

One of the actual problems which have to solve is the bannedand obsolete pesticides accumulation.

Ukraine ratified the Rotterdam convention and the Stockholmconvention. The actual now is the harmonization of national chem-ical legislation to international requirements.

doi:10.1016/j.toxlet.2012.03.653

P29-19EEG correlates of reduced response inhibition during exposureto propionic acid

Stephanie Anja Juran 1, Christoph van Thriel 2, Stefan Kleinbeck 2,Michael Schaper 2, Michael Falkenstein 2, Anders Iregren 3,Gunnar Johanson 4

1 Karolinska Institutet/IMM, Sweden, 2 Leibniz Res Centre f Work Env,Dortmund, Germany, 3 Swedish Work Env Auth, Tox Risk Assessm,Sweden, 4 KI, IMM, Unit f Work Env Toxi, Stockholm, Sweden

We have previously demonstrated impaired behavioral accu-racy in human volunteers performing a response inhibition taskduring exposure to 10 ppm propionic acid (PA) (Hey et al., 2009).The aim of the present study was to investigate if these impair-ments could also be detected as deviations of neuronal activity inevent-related potentials (ERPs) a method allowing detailed inves-tigation of information processing leading to either a correct or anerroneous response.

Methods: 24 volunteers were whole-body exposed to PA at threelevels: 0.3 ppm (control condition), 5 (variable from 0 to 10) ppm,and 10 ppm (German and Swedish occupational exposure limit).Reaction times and accuracy were recorded three times during each

4-h exposure. ERPs representing motor inhibition and error pro-cessing were analyzed from EEG recordings from a subgroup of sixsubjects. Results: On the behavioral level, response accuracy in theERP subgroup showed a trend for impaired accuracy with increas-