Problems Associated with the Use of Chemical Class Controls in Absence of Information on the Underlying Mechanism

Oesch, Franz

doi:10.1007/978-1-4684-4334-9_4

Cited by 1 publication

(2 citation statements)

References 8 publications

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“…Firstly, in some instances, such as with benz(a)anthracene derivatives, many methylated analogues are much morepotent carcinogens (Oesch 1982), or, the conjugation reaction can even be a prerequisite for the formation of the ultimate reactive carcinogen, such as with the aromatic amines or with 1,2-dibromoethane, where the reaction with glutathione leads to a reactive brominated sulfur mustard.…”

Section: Answer To Ouestion 1: Sensitivity For Organic Compound Is Vementioning

confidence: 99%

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Structural Characteristics of Compounds That can be Activated to Chemically Reactive Metabolites: Use for a Prediction of a Carcinogenic Potential

Lutz

1984

Archives of Toxicology

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Abstract. Many mutagens and carcinogens act via covalent interaction of metabolic intermediates with DNA in the target cell. This report groups those structural elements which are often found to form the basis for a metabolism to such chemically reactive metabolites. ~mpounds which are chemically reactive per se and which do not require metabolic activation form group 1. Group 2 compri~es of olefins and aromatic hydrocarbons where the oxidation via an epoxide can be responsible for the generation of reactive species. Aromatic amines, hydrazines, and nitrosamirres form group 3 requiring an oxidation of a nitrogen atom or of a carbon atom in alpha position to a nitrosated amine. Group 4 compounds are halogenated hydrocarbons which can either give rise to radicals or can form an ·olefin (group 2) upon dehydrohalogenation. Group 5 compounds depend upon some preceding enzymatic activity either not available in the target cell or acting on positions in the molecule which are not directly involved in the subsequent formation of electrophilic atoms. Examples for each group are taken from the "List of Chemieals and Irrdustrial Processes Associated with Cancer in Humans" as compiled by the International Agency for the Research on Cancer, and it is shown that 91% of the organic carcinogens would have been detected on the basis of structural elements characteristic for group 1-5. As opposed to this very high sensitivity, the specificity ( the true negative fraction) of using this approach as a short-term test for carcinogenicity is shown to be bad because detoxification pathways have so far not been taken into account. These competing processes are so complex, however, that either only very extensive knowledge about pharmacokinetics, stability, and reactivity will be required or that in vivo systems have to be used to predict, on a quantitative basis, the darnage expected on the DNA. DNA-binding experiments in vivo are presented with benzene and toluene to

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Section: Answer To Ouestion 1: Sensitivity For Organic Compound Is Vementioning

confidence: 99%

“…These classes were meant to reflect a presumption of low, moderate, or serious toxicity, and the authors claimed that so far the procedure had not resulted in any underestimation of toxicity. The analysis reported by Ashby (1978) and by Oesch (1982) revealed a much more complicated situation as soon as quantitative assessments are attempted.…”

mentioning

confidence: 99%

Structural Characteristics of Compounds That can be Activated to Chemically Reactive Metabolites: Use for a Prediction of a Carcinogenic Potential

Lutz

1984

Archives of Toxicology

View full text Add to dashboard Cite

show abstract

Problems Associated with the Use of Chemical Class Controls in Absence of Information on the Underlying Mechanism

Cited by 1 publication

References 8 publications

Structural Characteristics of Compounds That can be Activated to Chemically Reactive Metabolites: Use for a Prediction of a Carcinogenic Potential

Structural Characteristics of Compounds That can be Activated to Chemically Reactive Metabolites: Use for a Prediction of a Carcinogenic Potential

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