Chemical Categories for Health Hazard Identification: A Feasibility Study

doi:10.1006/rtph.2001.1468

Regulatory Toxicology and Pharmacology

Volume 33, Issue 3, June 2001, Pages 313-318

https://doi.org/10.1006/rtph.2001.1468 Get rights and content

Abstract

The use of chemical categories has been suggested in order to lower the number of chemicals tested in the High Production Volume (HPV) Chemical Challenge Program. In this investigation we examined the reliability of using organic chemical categories to classify chemicals as either toxic or nontoxic for individual toxicological effects as well as for panels of such endpoints. The analyses indicate that chemical categories are unable to consistently identify groups of chemicals with similar toxic responses either for a multiplicity of endpoints or for single effects. Our analyses suggest that if chemical categories are to be used to identify health hazards, that computer-based SAR approaches appear to be superior to arbitrary chemical categories for predicting specific toxicological effects but they are not, at this time, useful for defining the overall toxicity.

References (26)

J. Ashby et al.
Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP
Mutat. Res.
(1991)
A.R. Cunningham et al.
Identification of ``genotoxic'' and ``non-genotoxic'' alerts for cancer in mice: The carcinogenic potency database
Mutat. Res.
(1998)
S.G. Grant et al.
Modeling the mouse lymphoma forward mutational assay: The Gene-Tox program database
Mutat. Res.
(2000)
G. Klopman et al.
Prediction of carcinogenicity/mutagenicity using MULTICASE
Mutat. Res.
(1994)
G. Klopman et al.
Toxicity estimation by chemical substructure analysis: The Tox II Program
Toxicol. Lett.
(1995)
W.-L. Yang et al.
Structural basis of the in vivo induction of micronuclei
Mutat. Res.
(1992)
Ennever, F. K., Rosenkranz, H. S., Lave, L. B., and Omenn, G. S.1990. Value-of-information analysis of testing...
Development of Chemical Categories in the HPV Challenge Program.
(1999)
Guidance for Meeting the SIDS requirements.
(1999)
HPV Challenge Program Guidance Documents.
(1999)

The Use of Structure–Activity Relationships (SAR) in the High Production Volume Chemicals Challenge Program.

(1999)

J. Gómez et al.

Structural determinants of developmental toxicity in hamsters

Teratology

(1999)

Cited by (10)

Review of the toxicity of chemical mixtures: Theory, policy, and regulatory practice
2006, Regulatory Toxicology and Pharmacology
An analysis of current mixture theory, policy, and practice was conducted by examining standard reference texts, regulatory guidance documents, and journal articles. Although this literature contains useful theoretical concepts, clear definitions of most terminology, and well developed protocols for study design and statistical analysis, no general theoretical basis for the mechanisms and interactions of mixture toxicity could be discerned. There is also a poor understanding of the relationship between exposure-based and internal received dose metrics. This confounds data interpretation and limits reliable determinations of the nature and extent of additivity. The absence of any generally accepted classification scheme for either modes/mechanisms of toxic action or of mechanisms of toxicity interactions is problematic as it produces a cycle in which research and policy are interdependent and mutually limiting. Current regulatory guidance depends heavily on determination of toxicological similarity concluded from the presence of a few prominent constituents, assumed from a common toxicological effect, or presumed from an alleged similar toxic mode/mechanism. Additivity, or the lack of it, is largely based on extrapolation of existing knowledge for single chemicals in this context. Thus, regulatory risk assessment protocols lack authoritative theoretical underpinnings, creating substantial uncertainty. Development of comprehensive classification schemes for modes/mechanisms of toxic action and mechanisms of interaction is needed to ensure a sound theoretical foundation for mixture-related regulatory activity and provide a firm basis for iterative hypothesis development and experimental testing.
A paradigm for determining the relevance of short-term assays: Application to oxidative mutagenesis
2002, Mutation Research - Fundamental and Molecular Mechanisms of 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. There was, however, a significant association between alerts for oxidative mutagenesis and chemicals capable of inducing allergic contact dermatitis (ACD) in humans.
Probing chemical induced cellular stress by non-Faradaic electrochemical impedance spectroscopy using an Escherichia coli capacitive biochip
2011, Analyst
Open source tools for read-across and category formation
2010, Issues in Toxicology
How can structural similarity analysis help in category formation?
2007, SAR and QSAR in Environmental Research
Computational Tools for Regulatory Needs
2006, Computational Toxicology: Risk Assessment for Pharmaceutical and Environmental Chemicals

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Regulatory Toxicology and Pharmacology

Abstract

References (26)

Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP

Mutat. Res.

Identification of ``genotoxic'' and ``non-genotoxic'' alerts for cancer in mice: The carcinogenic potency database

Mutat. Res.

Modeling the mouse lymphoma forward mutational assay: The Gene-Tox program database

Mutat. Res.

Prediction of carcinogenicity/mutagenicity using MULTICASE

Mutat. Res.

Toxicity estimation by chemical substructure analysis: The Tox II Program

Toxicol. Lett.

Structural basis of the in vivo induction of micronuclei

Mutat. Res.

Development of Chemical Categories in the HPV Challenge Program.

Guidance for Meeting the SIDS requirements.

HPV Challenge Program Guidance Documents.

The Use of Structure–Activity Relationships (SAR) in the High Production Volume Chemicals Challenge Program.

Structural determinants of developmental toxicity in hamsters

Teratology

Cited by (10)

Review of the toxicity of chemical mixtures: Theory, policy, and regulatory practice

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

Probing chemical induced cellular stress by non-Faradaic electrochemical impedance spectroscopy using an Escherichia coli capacitive biochip

Open source tools for read-across and category formation

How can structural similarity analysis help in category formation?

Computational Tools for Regulatory Needs

Regular ArticleChemical Categories for Health Hazard Identification: A Feasibility Study

Abstract

Mutat. Res.

Mutat. Res.

Mutat. Res.

Mutat. Res.

Toxicol. Lett.

Mutat. Res.

Development of Chemical Categories in the HPV Challenge Program.

Guidance for Meeting the SIDS requirements.

HPV Challenge Program Guidance Documents.

The Use of Structure–Activity Relationships (SAR) in the High Production Volume Chemicals Challenge Program.

Structural determinants of developmental toxicity in hamsters

Teratology

Regular Article
Chemical Categories for Health Hazard Identification: A Feasibility Study