Toxicity modelling

A Review of Exposure, Bioaccumulation, and Toxicity Models Paquin, Farley, Santore, Kawadas, Mooney, Winfield, Wu, Di Toro 2003... 

Rosenbaum R, Bachmann TM, Gold LS, Huijbregts MAJ, Jolliet O, Juraske R, Koehler A, Larsen HF, MacLeod M, Margni M, McKone TE, Payet J, Schuhmacher M, van de Meent D, Hauschild MZ (2008) USEtox the UNEP-SETAC toxicity model recommended characterisation factors for human toxicity and freshwater ecotoxicity in life cycle impact assessment. Int J Life Cycle Assess 13 532-546... 

Fig. 11. The molecular connectivity-QSAR toxicity model for PAHs...

Zebrafish embryo assay results were compared to the ToxCast in vitro assay features from the predictive model of developmental toxicity (50). A majority of the features were significant between the zebrafish data and predictive models, despite the fact that the zebrafish assay did not correlate with global developmental toxicity defined by species-specific ToxRefDB data. The top 15 chemicals predicted to be developmental toxicants and bottom 15 chemicals predicted not to be developmental toxicants varied in their endpoint responses and logP values. Padilla et al. (35) noted that chemical-physical characteristics could limit the amount of chemical seen by the embryo due to poor solubility or poor uptake. This may be the reason that a majority of the bottom 15 chemicals with no zebrafish embryo activity had logP values less than 1.0. The bottom 15 chemicals with zebrafish embryo activity could almost exclusively be characterized by the negative predictors of the species-specific developmental toxicity models, which may be indicating that these predictors have differing roles between mammalian and zebrafish development. 

Benigni, R., Andreoli, C., Cotta-Ramusino, M., Giogi, R, and Gallo, G., The electronic properties of carcinogens and their role in SAR studies of noncongeneric chemicals, Toxicity Modeling, 1, 157-167, 1995. 

Aryl Hydrocarbon Receptor, and is the basis of the 2378-TeCDD TEQ additive toxicity model. Concentrations of AHR PCDD/Fs increased an order of magnitude downstream from the confluence of the Tittabawassee River, and increased a further order of magnitude in the lower reaches of the river, presumably because these were depositional zones. 

Liao, C.M. and Lin, M.C. (2001) Acute toxicity modeling of rainbow trout and silver sea bream exposed to waterborne metals, Environmental Toxicology 16 (4), 349-360. 

Tietge, J.E., Hockett, J.R. and Evans, J.M. (1997) Major ion toxicity of six produced waters to three freshwater species application of ion toxicity models and TIE procedures, Environmental Toxicology and Chemistry 16 (10), 2002-2008. 

To address the quality limitations for extrapolation, the available experimental data on observed mixture effects were evaluated with care, and a pragmatic approach for mixture extrapolation was followed. Although mechanistic understanding was often not the purpose of the experiments, the extrapolation approach is based upon mechanistic principles, that is, regarding the choice between mixture toxicity models. Conceptual considerations on biases and mathematical characteristics of the models were included (see Section 5.3.3). 

We have reviewed current conceptual and modeling approaches in mixture eco-toxicology as well as current experimental evidence to derive practical risk assessment protocols for species and species assemblages. From the review of conceptual approaches in mixture ecotoxicology, it appears that there is a difference between a mechanistic view of joint action from a compound mixture and a probabilistic perspective on combined toxicity and mixture risk. A mechanistic view leads to emphasis on the distinction of modes of action and physicochemical properties first, then on the choice of the appropriate joint toxicity model, followed by a comparison of the models prediction with experimental observations. A probabilistic orientation leads to the observation that concentration addition often yields a relatively satisfactory quantitative prediction of observations for the integral level of effects as observed in individual organisms or populations. In these applications, concentration addition is frequently connected with a slight bias to conservatism, especially for compounds with different modes of action (Backhaus et al. 2000,2004 Faust et al. 2003). 

This chapter proposes the use of SSD and mixture toxicity models in ecological risk assessment of species assemblages by calculating the multisubstance potentially affected fraction of species on the basis of measured or predicted (biologically active) concentrations of toxic compounds in the environment. The msPAF method has been scrutinized for its conceptual basis. To address this scrutiny, we cite the human toxicology work of Ashford (1981) as a cross-link. 

Paquin PR, Santore RC, Farley K, Di Toro DM, Wu KB, Mooney KG, Winfield RP. 2003. Metals in aquatic systems a review of exposure, bioaccumulation, and toxicity models. Pensacola (FL) SETAC Press, 168 p. 

As discussed previously, relevant animal models and predictability of safety have become significant issues. Recent experience with developing ERT for Niemann-Pick disease has highlighted the potential risk of relying on standard toxicity models and not identifying the most relevant test species. 

Type of endpoint. The type of endpoint recording is essential for the application of different types of mixture toxicity models. Endpoints measured at only 1 point in time may only be used to derive concentration-response-related parameters, such as ECx or LCx or NOECs. Continuous recording or at least repeated recording of responses may allow for time series analysis. Time-related responses may, for example, be used for the derivation of kinetic parameters by applying pharmacokinetic/dynamic models (like the PBPK models in human toxicology see, e.g., Krishnan et al. 1994) or... 

Although the MPTP model is nearly perfect once developed, it is a toxic model that occurs suddenly after the introduction of the toxin, whereas PD is a progressive disease. Nevertheless the elucidation of the action of MPTP on the mitochondrial respiratory chain, more precisely on the step between I and II has led to the search to the search for agents with neuroprotective abilities in the mitochondrial respiratory chain. 

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