The challenge of testing chemicals for potential carcinogenicity using multiple short-term assays: an analysis of a proposed test battery for hair dyes.

Recent reports of the association of hair dyes usage with increased bladder cancer risk in women with the slow NAT-2 acetylator phenotype have resulted both in attempts to identify the putative carcinogen as well as in devising batteries of tests that could be used to screen for such putative carcinogens in hair dye formulations, their intermediates and final products. Analytical studies have reported the presence of traces ( approximately 0.5 ppm) of the carcinogen 4-aminobiphenyl in some hair dye preparations.

Lack of predictivity of the rat lethality (LD50) test for ecological and human health effects.

The relationship between acute toxicity in rats (LD50 values) and indicators of potential health hazards in humans was investigated, based on a chemical population-based paradigm (i.e. the "chemical diversity approach").

SAR modelling of complex phenomena: probing methodological limitations.

The increased acceptance of the use of structure-activity relationship (SAR) approaches to toxicity modelling has necessitated an evaluation of the limitations of the methodology. In this study, the limit of the capacity of the MULTICASE SAR program to model complex biological and toxicological phenomena was assessed. It was estimated that, provided the data set consists of at least 300 chemicals, divided equally between active and inactive compounds, the program is capable of handling phenomena that are even more "complex" than those modelled up to now (for example, allergic contact dermatitis, Salmonella mutagenicity, biodegradability, inhibition of tubulin polymerisation).

SAR modeling of genotoxic phenomena: the consequence on predictive performance of deviation from a unity ratio of genotoxicants/non-genotoxicants.

SAR approaches to the study of genotoxic phenomena are finding increased applications. However, the data being modeled are frequently not considered optimal due to the small size of the dataset and an uneven distribution of genotoxicants and non-genotoxicants in the dataset. The effects of such imbalances on the performance of one SAR approach were investigated with respect to the modeling of the induction of unscheduled DNA synthesis in rat hepotocytes and of sister chromatid exchanges and chromosomal aberrations in cultural CHO cells.

Synergy between systemic toxicity and genotoxicity: relevance to human cancer risk.

The health risk manager and policy analyst must frequently make recommendations based upon incomplete toxicity data. This is a situation which is encountered in the evaluation of human carcinogenic risks as animal cancer bioassay results are often not available. In this study, in order to assess the relevance of other possible indicators of carcinogenic risks, we used the "chemical diversity approach" to estimate the magnitude of the human carcinogenic risk based upon Salmonella mutagenicity and systemic toxicity data of the "universe of chemicals" to which humans have the potential to be exposed.

Environmental odors and health hazards.

Using the recently developed and validated 'chemical diversity approach', the potential of chemicals, to be detected by the human olfactory system and to cause adverse health effects, was investigated. The analyses found no significant association between odor perceptibility and potential for inducing health effects.

SAR: flavonoids and COX-2 inhibition.

An analysis based upon structure-activity relationships (SAR) of the COX-2-inhibiting properties of flavonoids, a group of potential cancer chemopreventative agents, reveals that there is a dual structural basis for these activities. Each of these structural determinants (pharmacophores) alone is sufficient for activity. One of the pharmacophores is a 2D 6.

Environmental persistence of chemicals and their carcinogenic risks to humans.

A "chemical population"-based investigation of xenobiotics (i.e. a sample of 10,000 chemicals representative of agents in commerce, industry, and the environment, both synthetic and natural) that have the potential for ecotoxicity because of their persistence in the environment and their potential association with carcinogenic risks to humans was undertaken.

A data mining approach for the elucidation of the action of putative etiological agents: application to the non-genotoxic carcinogenicity of genistein.

A procedure designated "the virtual similarity index" (VSI) is described to determine the probability that two or more toxicants are related mechanistically. The approach is structure-activity relationship (SAR) based and generates the virtual toxicological profiles of the chemicals under investigation. It also determines the similarities between them.

SAR modeling: effect of experimental ambiguity.

The applicability of SAR (structure-activity relationship) techniques to data obtained using high throughput screening (HTS) and toxicogenomic techniques is explored. The reason for this study derives from the fact that for economical and time considerations HTS bioassays may consist of single determinations, i.e.

Structural concepts in cancer prevention.

The notion of developing cancer preventative strategies is attractive both from a public health and from a health economic viewpoint. However, as currently visualized, this may involve dietary supplementation of publicly available foods or the ingestion of specific supplements for prolonged periods of time. In view of the fact that the outcome of such preventative strategies may as yet not be known, it is essential that the strategy is devoid of risks.

A paradigm for determining the relevance of short-term assays: application to oxidative mutagenesis.

A simple substructure-based approach was developed to determine whether a short-term assay under development is related mechanistically to the endpoint it seeks to predict. Thus, substructures associated with mutagenicity in Salmonella are also present in carcinogens and agents active in other mutagenicity and genotoxicity assays. When applied to test results obtained with an Escherichia coli strain designed to identify oxidative mutagens, there was no significant association with either carcinogens or mutagens and genotoxicants detected by other systems.