Mechanisms of Action Point Towards Combined PBDE/NDL-PCB Risk Assessment

Risk assessment of chemicals is usually conducted for individual chemicals whereas mixtures of chemicals occur in the environment. Considering that neuroactive chemicals are a group of contaminants that dominate the environment, it is then imperative to understand the combined effects of mixtures. The commonly used models to predict mixture effects, namely concentration addition (CA) and independent action (IA), are thought to be suitable for mixtures of similarly or dissimilarly acting components, respectively. For mixture toxicity prediction, one important challenge is to clarify whether to group neuroactive substances based on similar mechanisms of action, e.g., same molecular target or rather similar toxicological response, e.g., hyper- or hypoactivity (effect direction). We addressed this by using the spontaneous tail coiling (STC) of zebrafish embryos, which represents the earliest observable motor activity in the developing neural network, as a model to elucidate the link between the mechanism of action and toxicological response. Our objective was to answer the following two questions: (1) Can the mixture models CA or IA be used to predict combined effects for neuroactive chemical mixtures when the components share a similar mode of action (i.e., hyper- or hypoactivity) but show different mechanism of action? (2) Will a mixture of chemicals where the components show opposing effect directions result in an antagonistic combined effect? Results indicate that mixture toxicity of chemicals such as propafenone and abamectin as well as chlorpyrifos and hexaconazole that are known to show different mechanisms of action but similar effect directions were predictable using CA and IA models. This could be interpreted with the convergence of effects on the neural level leading to either a collective activation or inhibition of synapses. We also found antagonistic effects for mixtures containing substances with opposing effect direction. Finally, we discuss how the STC may be used to amend risk assessment.

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Risk Assessment of Mixtures: A Model Based on Mechanisms of Action and Interaction

Risk Analysis ◽

10.1007/978-1-4899-0730-1_30 ◽

1991 ◽

pp. 293-303 ◽

Cited By ~ 3

Author(s):

M. A. Clevenger ◽

R. M. Putzrath ◽

S. L. Brown ◽

M. E. Ginevan ◽

C. T. DeRosa ◽

...

Keyword(s):

Risk Assessment ◽

Mechanisms Of Action ◽

Model Based

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Mechanisms of Action of Chemical Carcinogens and Their Role in Structure–Activity Relationships (SAR) Analysis and Risk Assessment

Quantitative Structure-Activity Relationship (QSAR) Models of Mutagens and Carcinogens ◽

10.1201/9780203010822-7 ◽

2003 ◽

pp. 55-94

Keyword(s):

Risk Assessment ◽

Mechanisms Of Action ◽

Chemical Carcinogens ◽

Structure Activity Relationships ◽

Structure Activity ◽

Sar Analysis

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Assessing Combined Effects for Mixtures of Similar and Dissimilar Acting Neuroactive Substances on Zebrafish Embryo Movement

10.20944/preprints202103.0752.v1 ◽

2021 ◽

Author(s):

Afolarin Olaposi Ogungbemi ◽

Riccardo Massei ◽

Rolf Altenburger ◽

Stefan Scholz ◽

Eberhard Küster

Keyword(s):

Risk Assessment ◽

Mechanism Of Action ◽

Zebrafish Embryo ◽

Mixture Toxicity ◽

Mechanisms Of Action ◽

Concentration Addition ◽

Combined Effects ◽

Important Challenge ◽

Similar Mode ◽

Opposing Effect

Risk assessment of chemicals is usually conducted for individual chemicals whereas mixtures of chemical are occurring in the environment. Considering that neuroactive chemicals are a group of contaminants that dominate in the environment, it is then imperative to understand the combined effects from mixtures. The commonly used models to predict mixture effects, namely concentration addition (CA) and independent action (IA), are thought suitable for mixtures of similarly or dissimilarly acting components, respectively. For mixture toxicity prediction, one important challenge is to clarify whether to group neuroactive substances based on similar mechanisms of action, e.g. same molecular target or rather similar toxicological response, e.g. hyper- or hypoactivity (effect direction). We addressed this by using the spontaneous tail coiling (STC) of zebrafish embryos, which represents the earliest observable motor activity in the developing neural network, as a model to elucidate the link between mechanism of action and toxicological response. Two questions were asked: 1.) Can the mixture models CA or IA be used to predict combined effects for neuroactive chemical mixtures when the components share a similar mode of action (i.e. hyper- or hypoativity) but show different mechanism of action? 2.) Will a mixture of chemicals where the components show opposing effect directions result in an antagonistic combined effect? Results indicate that mixture toxicity of chemicals such as propafenone and abamectin as well as chlorpyrifos and hexaconazole that are known to show different mechanisms of action but similar effect directions were predictable using CA and IA models. This could be interpreted with the convergence of effects on the neural level leading to either a collective activation or inhibition of synapses. We also found antagonistic effects for mixtures containing substances with opposing effect direction. Finally, we discuss how the STC may be used to amend risk assessment.

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Mechanisms of Action of Chemical Carcinogens and Their Role in Structure-Activity Relationships (SAR) Analysis and Risk Assessment 2

Quantitative Structure-Activity Relationship (QSAR) Models of Mutagens and Carcinogens ◽

10.1201/9780203010822.ch2 ◽

2003 ◽

Cited By ~ 1

Author(s):

David Lai ◽

Yin-Tak Woo

Keyword(s):

Risk Assessment ◽

Mechanisms Of Action ◽

Chemical Carcinogens ◽

Structure Activity Relationships ◽

Structure Activity ◽

Sar Analysis

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Cancer Risk Assessment Strategies Based on Mechanisms of Action

Journal of the American College of Toxicology ◽

10.3109/10915818809019511 ◽

1988 ◽

Vol 7 (4) ◽

pp. 417-425

Author(s):

John H. Weisburger

Keyword(s):

Risk Assessment ◽

Cancer Risk ◽

Neoplastic Cell ◽

Mechanisms Of Action ◽

Cancer Risk Assessment ◽

In Vitro Tests ◽

Carcinogenic Effects ◽

Effect Level

The induction of cancer by chemicals is a complex process that involves a series of steps, proceeding from the neoplastic conversion of a normal cell, i.e., the discrete mechanistically distinct initiation of a neoplastic cell, through the steps involving promotion, development, and progression. Chemicals can act in each of these stages as initiators, cocarcinogens, promoters, or inhibitors of carcinogenesis. Chemicals must be classified as operating by genotoxic or epigenetic mechanisms. Appropriate short-term in vitro tests used as a battery can be applied to detect such properties. These abbreviated and economic tests have good qualitative decision-making potential, since they are based on mechanisms of action. Advances in molecular biology may provide additional tests to detect cancer risk. Quantitative data available from in vivo dose-response studies demonstrate that carcinogenic effects are dose dependent, and, therefore, a threshold or no-effect level probably exists that is low for potent carcinogens, especially genotoxins, and high for weaker ones, particularly epigenetic agents. A set of mechanism-oriented data must be acquired systematically to serve as basis for realistic and effective risk assessment and management.

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