etters

WTI

RS

1

C4

R

(as1PdAtdatptNdsporooraca

d

WRe

MC

1

U

chositentrv

t

ful for identifying chemical modes of action. In this regard, speciescomparisons are of great value for hazard assessment of humans.

doi:10.1016/j.toxlet.2012.03.136

Abstracts / Toxicology L

07-3he impact and role of NSAIDs on vulture populations in thendian subcontinent

ichard Cuthbert 1, Rhys E. Green 2, Vibhu Prakash 3, Mohiniaini 4, Mark A. Taggart 5

Royal Society for the Protection of Bird, United States, 2 University ofambridge, United States, 3 Bombay Natural History Society, India,Indian Veterinary Research Institute, India, 5 Environmentalesearch Institute, United Kingdom

Veterinary use of non-steroidal anti-inflammatory drugsNSAIDs) in South Asia has resulted in one of the most unexpectednd large-scale population decreases of wild bird populationsince the impacts of DDT and other persistent pesticides in the950s. NSAIDs became widely used in veterinary medicine in India,akistan and Nepal during the early 1990s and by the end of theecade large declines of three vulture species endemic to Southsia were observed. Research established that large quantities of

he NSAID diclofenac were being administered to livestock and thaticlofenac residues were present within vulture carcasses collectedcross South Asia. Clinical trials established diclofenac’s toxicityo vultures and testing of domesticated ungulate carcasses (therincipal food source of wild vultures) from across India revealedhat diclofenac contamination was present in >10% of carcasses.umbers of vultures, which used to number tens-of-millions, haveeclined dramatically with a population decline of >99.9% for onepecies. The loss of such numbers has had profound implications asrior to the declines these scavengers were the principal consumersf animal carcasses, providing a valuable ecosystem service andeducing the risk of human and zoonotic disease. The governmentsf India, Pakistan and Nepal banned veterinary use of the drugn domesticated ungulates in 2006 and testing of other NSAIDsevealed that another drug, meloxicam, was a safe and effectivelternative to diclofenac. Levels of diclofenac contamination withinarcasses have fallen in the last five years and vulture populationsre now showing the earliest signs of recovery.

oi:10.1016/j.toxlet.2012.03.804

07-4egulatory perspectives on pharmaceuticals in thenvironment

arlene Ågerstrand 1, Magnus Breitholtz 2, Sven Ove Hansson 3,hristina Rudén 3

Royal Institute of Technology (KTH), Sweden, 2 Stockholmniversity, Sweden, 3 Royal Institute of Technology (KTH), Sweden

Guidance documents recommend the use of standard ecotoxi-ity tests in regulatory risk assessments. These recommendationsave decreased the use of non-standard test data for several groupsf chemicals. This has increased the reliability of the data sincetrict reporting requirement enhance reliability, but it could havemplications for the relevance of the risk assessment. Standardests may not always be sensitive enough to measure the specificffects expected for instance from endocrine disrupting chemicals,anoparticles and pharmaceuticals. Bisphenol A is an illustra-ive example since three standard tests are preferred by several

isk assessors over 200 non-standard studies with lower effectalues.

Previous studies indicate that ecotoxicity studies published inhe open scientific literature are often insufficiently reported. This

211S (2012) S24–S34 S31

may be a major reason why they are often seen as less reliable in arisk assessment context. Several guidance documents recommendthat the method described by Klimisch et al. (1997) should be usedfor evaluating the reliability of data but the Klimisch criteria give astrong preference for standard tests.

We present a more comprehensive method for evaluating andreporting non-standard ecotoxicity data. Its aim is to enable anincreased use of non-standard data in risk assessments. As part ofthis work we clarify the definitions of “reliability” and “relevance”in order to promote the consistent use and application of these con-cepts in risk assessment procedures. Lastly we present examplesfrom environmental risk assessments of pharmaceuticals showinghow non-standard data can complement standard data to arrive atrobust and transparent risk assessments.

doi:10.1016/j.toxlet.2012.03.809

W8: CEFIC-LRI Innovative Science Awardee (2007–2010)

W08-1Human neurospheres as 3D cellular systems for developmentalneurotoxicity testing

Ellen Fritsche

IUF - Leibniz Research Institute, Germany

Neurospheres derived from fetal brains are three dimensional(3D) cell culture models consisting of neural progenitor cells (NPCs)which proliferate in culture and – under differentiating conditions –migrate and differentiate into neurons and glia cells. Neurospheresfrom human, mouse and rat origin mimic basic processes of braindevelopment: proliferation, migration and differentiation of pre-mature brain cells in vitro.

We tested the effects of methylmercury, methylazoxymethanol,valproic acid, lead, polychlorinated biphenyls, polybrominateddiphenyl ethers (PBDEs), TCDD, benzo(a)pyrene (B(a)P), chlor-pyrifos, parathion as well as the negative compounds glutamate,penicillin G and paracetamol on proliferation, migration, differen-tiation and viability of NPCs. The results indicate that neurospherescan distinguish between positive and negative compounds. More-over, studies comparing effects of compounds on human vs. rodentNPCs indicate that there are species-specific differences in suscep-tibility towards DNT substances.

Besides chemical screening mechanistic studies indicate thatPBDEs disrupt cellular thyroid hormone signaling causing migra-tion and differentiation defects of hNPCs. These substances exertlittle effects on mouse NPCs due to dissimilar thyroid hormonereceptor expression. Moreover, polycyclic aromatic hydrocarbonslike B(a)P selectively inhibit mouse neural migration by Aryl-hydrocarbon receptor (AhR) activation while, while mouse NPCproliferation is impaired by AhR inhibition by 3-methoxy-4-nitroflavone. Human neurospheres remain unaffected due to anabsent AhR expression.

Our data shows that neurospheres can be used for early DNTtesting in a medium-throughput system. Moreover, they are use-