Biomedical subjects

Herbert S Rosenkranz

Publications and source records attributed to Herbert S Rosenkranz.

10 recordsLinked to original sources

PubMed2005

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"). These structure-activity relationship-based analyses indicate that high toxicity in rats (i.e. a low LD50 value) is not a good predictor of health effects in humans. In fact, it was found that high acute toxicity to minnows, as well as toxicity to cultured cells, showed significantly greater associations with the potential for health effects than rat LD50 values.

Animal Testing Alternatives↗

PubMed2004

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. The analyses indicate that if genotoxicants exceed non-genotoxicants, the performance of the SAR model can be improved if the dataset is supplemented with physiological chemicals which are assumed to be non-genotoxicants. On the other hand, if non-genotoxicants exceed genotoxicants, it was found that the predictive performance of the resulting SAR model is not improved by removal of genotoxicants from the dataset to achieve a ratio of genotoxicants/genotoxicants of unity. Overall, the present analyses did not result in the development of SAR models of greatly increased predictivity. Conceivably, for the particular datasets and SAR paradigm the limit of predictivity has been reached. The possibility of investigating the use of a "battery" of SAR paradigms should be considered.

Models, Biological↗

PubMed2003

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.

Environmental Pollutants↗

PubMed2003

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. Analyses of the properties of 10,000 agents representative of the "universe of chemicals" suggest that chemicals that have genotoxic potentials as well as exhibiting greater systemic toxicity are more likely to be carcinogens than non-genotoxicants or agents that exhibit lesser toxicity. Since "genotoxic" carcinogenicity is a hallmark of recognized human carcinogens, these findings are relevant to human cancer risk assessment.

Carcinogens↗

PubMed2003

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. The analyses revealed a statistically significant association between resistance to environmental biodegradation and the prevalence of chemical with the potential to induce systemic toxicity and cancer. On the other hand, there was no association between biopersistence and the potential for inducing toxicities unrelated to carcinogenesis, e.g. allergic contact dermatitis in humans and sensory irritation in mice.

Biodegradation, Environmental↗

PubMed2003

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. That commonality is compared to the frequency with which it is found among a population of 10,000 chemicals representing the "universe of chemicals". The similarities between the candidate chemicals and chemicals known to act by other recognized mechanisms are also determined. If the similarities between the candidate chemicals are significantly greater than for the non-related ones, the chemicals are assumed to act by a common mechanism. In that context, the putative non-genotoxic mechanism responsible for the carcinogenicity of genistein (GEN) and its relationship to the action of diethylstilbestrol is examined.

Animals↗

PubMed2003

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). However, within the data sets currently used to generate SAR models, there are limits to the complexity that can be handled. This may be the situation with regard to the modelling of systemic toxicity (for example, the LD50).

Animals↗

PubMed2003

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. lack of duplication. This introduces an element of uncertainty. Using two different data bases of fairly complex biological phenomena (allergic contact dermatitis in humans and the induction of mutations in Salmonella), it is demonstrated that the resulting SAR models can tolerate up to 20% ambiguity in the experimental data.

Algorithms↗

PubMed2003

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 6.9 A distance descriptor that spans the A and C rings and includes the 4-OXO and 7-hydroxyl moieties. The potency associated with that pharmacophore is determined by a series of structural modulators that can increase, decrease, or even abolish the COX-2-inhibiting potential associated with that pharmacophore. The second pharmacophore describes a para-substituted phenolic B ring that requires unsubstituted meta and ortho positions. Based upon this, it indicates that hydroxylation at the 4'-position and a free 5'-position are sufficient for COX-2-inhibiting activity. The potency associated with this pharmacophore is modulated by log P2 and by the molecular weight.

Antineoplastic Agents↗

PubMed2002

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. Structure-activity relationship (SAR) concepts can be of use in identifying possible health hazards associated with chemoprevention. Overall, SAR can be used (1) to predict the chemopreventative potential of a chemical and to understand its mechanism of action, (2) to evaluate the toxicological liabilities of such agents and (3) to design molecules with enhanced chemopreventative potency and decreased (or abolished) toxicity. While SAR techniques currently available are appropriate to achieve these aims, the primary block to their widespread deployment is lack of sufficient experimental data of acceptable quality to perform SAR modeling. The present report analyzes the current applicability of SAR methods to cancer chemoprevention.

Anticarcinogenic Agents↗