From a regulatory point of view, the main objective of acute toxicity testing is to classify chemicals according to their intrinsic toxicity. This is conventionally conducted on the basis of the animal LD50 methods however, this test has been widely criticised. Moreover, conventional toxicity testing focuses on single chemicals and often human exposures are to more than one chemical. This research study had two main objectives. The first was to investigate the accuracy of selected in vitro tests for predicting the acute toxic action of chemicals in rodents and humans, and in predicting the Globally Harmonised System of Classification and Labelling of Chemicals (GHS) categories. The second was to explore the relevance of in vitro tests in determining the nature of toxicological interactions (i.e. additive, antagonistic and synergistic) among binary and ternary chemical mixtures. A battery of cytotoxicity tests (MTS, NRU, LDH and ATP) assays were used to determine the toxicity of 21 chemicals spread across the GHS categories where mercuric chloride (GHS category 1) was the most toxic chemical and glycerol (GHS unclassified) the least toxic. Significant differences for the majority of test chemicals were found among all assays, highlighting the need for a battery of in vitro tests measuring different endpoints. The NRU assay was found to be a more sensitive measure of toxicity for most chemicals and predicted all of the GHS categories. In general, in vitro IC50 values correlated well with in vivo rodent (LD50); human acute toxicity (LDL0 and LC) data and published in vitro data. In addition, in vitro NOEC values correlated well with published TLV. Selected assays (MTS, NRU) were applied to binary (15) and ternary (5) chemical mixtures. Mixtures were prepared at mixture ratios proportional to the potency of individual components. Experimental data was used to assess the predictive capabilities of two approaches (mathematical model and concentration addition) commonly used by regulatory agencies which assume additive effect. However, all three interactions (antagonism, synergism and additivity) where observed in this study. These results suggest that these interactions cannot be excluded from toxicological risk assessments. The methods developed and information obtained from this study provide a comprehensive comparison between selected in vitro assays for assessing the toxicity of chemicals and their mixtures.
| Identifer | oai:union.ndltd.org:ADTP/215389 |
| Date | January 2006 |
| Creators | Azzi, Rola, Safety Science, Faculty of Science, UNSW |
| Publisher | Awarded by:University of New South Wales. School of Safety Science |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Rola Azzi, http://unsworks.unsw.edu.au/copyright |
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