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Abstracts / Toxicology L

te by the same mode of action, dose addition is the appropriateype of data analysis. This means that one toxicant drives theffect up on the sublinear curve of the other. If the observed effects induced via different pathways, response addition is appro-riate; two dose-response curves follow each other sequentially.urves of dose addition and response addition embrace an “enve-

ope of additivity”. Synergistic or antagonistic interaction can beostulated only if the mixture effect is outside this area. Thisituation was investigated experimentally with (i) the Ames testnd (ii) in vitro micronucleus tests, using binary combinationsf different DNA-alkylating agents, the topoisomerase-II inhibitorenistein, and gamma irradiation. Results showed not only differ-nt types of dose-response relationships and combination effects,uch as supradditivity, dose addition, response addition, and antag-nism, but also mixed effects. We conclude that knowledge of theose-response curves of all components of a mixture is crucial toostulate synergism or antagonism and that an in-depth mecha-istic knowledge is required for appropriate data interpretation.

oi:10.1016/j.toxlet.2009.06.093

09-03se of Cramer classes and additive models of mixture toxicity:pplication to real world mixtures and an assessment of factors

hat minimize the potential for synergy

aul Price 1,∗, Heli Hollnagel 2

The Dow Chemical Company, TERC, Midland, United States, 2 Dowurope GmbH, EH&S/TERC, Horgen, Switzerland

ramer classes and the Munro et al. (1996) database (hereaftereferred to as CC), are part of the TTC and conservatively predicthronic toxicity based on structure. In this paper CC are used forroviding the noncancer toxicity estimates for mixture componentshat have missing toxicity data. Without such data, it is not possibleo use additive or other models of mixture toxicity. In this presen-ation, we report on an assessment of mixtures in a series of 48urface water samples. These samples contained detectable levelsf from 2 to 23 chemicals and a total of 44 chemicals were foundn one or more of the samples. Toxicity data were found for 31 ofhe 44 chemicals and CC were used for the remaining 13 chem-cals. A screening additive model was used to assess the toxicityf the mixtures. The resulting estimates of mixture toxicity wereufficient to determine that the mixtures were unlikely to pose aisk to human health. Use of the CC was shown to result in 4 to000 fold overestimates of mixture toxicity. This suggests that thepproach is most appropriate for use in screening assessments. Inddition, the additive models constrained exposures to all mixtureomponents to doses below their chronic standards and for mostomponents the doses were more than 100 fold below their stan-ards. This constraint limits the potential for interaction betweenixture components and thus the possibility of synergy.

eference

unro, I.C., Ford, R.A., Kennepohl, E., Sprenger, J.G., 1996. Food Chem. Toxicol. 34,829–867.

oi:10.1016/j.toxlet.2009.06.094

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189S (2009) S37–S56 S51

09-04ritical analysis of literature on low dose synergy for use of TTC

n screening chemical mixtures for risk assessment

lan Boobis,ESI Risk Assessment Methodology Mixtures Project ILSI Healthnd Environmental Sciences Institute (HESI), Risk Assessmentethodology Technical Committee, Mixtures Project, Washington,C

Imperial College London, Experimental Medicine and Toxicology,ondon, United Kingdom

cientists need a better understanding of the consequences ofo-exposures to substances at environmentally relevant concen-rations. As it is not possible to test all combinations, a defaultssumption of dose or response additivity, as appropriate, has beensed for the joint toxicity assessment of chemicals. From a safetyerspective, it is essential to know whether synergistic interac-ions can occur at these low exposure levels. A literature searchas conducted to identify studies of synergism, with emphasis onoses close to the individual chemicals’ NOAELs or LOAELs. Theearch identified 204 chemicals by in-depth critical review of 90eferences. A quantitative estimate of low dose synergy was foundn only a few studies. Calculations of interaction magnitude werencluded in 11 articles. While the range of reported values is quite

ide, these values are not directly comparable because definitionsnd quantification of synergy differed across the studies. Methodsaried in terms of the null hypothesis, response measured, point ofeparture (POD), and whether the slope of the dose-response curveas considered. Nevertheless, the magnitude of any low dose syn-

rgy reported was generally relatively modest. It is anticipated thathis analysis will help in developing an approach for quantitativeisk assessment of chemical mixtures, including use of a Thresh-ld of Toxicological Concern for screening and prioritization. Prioro this, it is recommended that: synergy be defined in terms ofeparture from dose additivity; uniform procedures be developedor assessing synergy at low exposures; and POD for calculatingynergy be standardized.

oi:10.1016/j.toxlet.2009.06.095

orkshop 10: Photosensitization: What Makes the Difference?

10-01hysicochemical behaviors of photosensitizing drugs

ranscisco Boscá

Universidad Politécnica de Valencia, Instituto de Tecnología QuímicaPV-CSIC/Departamento de Química, Valencia, Spain

he absorption of light by a drug generates electronically excitedtates (singlet or triplet states). In both multiplicities, very fastnternal conversion leads to the lowest excited states (S1 and1, respectively). These states, which have typically lifetimes ofanoseconds for S1 and microseconds for T1, live long enough that ahemical reaction competes with internal conversion to the groundtate (S0). These excited states are electronic isomers of the ground

tate and can show a different chemistry.

The competition between the chemical reactions and physicalecay to the S0 depends in a complex way on the structure andn conditions. Efficiency and photoproduct distribution of a pho-ochemical reaction can change significantly even among closely