CRA

Are There Thresholds for Non-genotoxic and Genotoxic Carcinogens?

Little Pro on 2018-01-03 Views:  Update:2018-10-17

A carcinogen is a substance or agent capable of causing cancer. A carcinogen can be further classified into non-genotoxic carcinogen and genotoxic carcinogen.The threshold is the level of exposure below which there is no cancer risk. It is generally agreed that threshold exists for non-genotoxic carcinogens. However, there is some debate about wether there are also thresholds for genotoxic carcinogens. In this article, we will summarize the definition of non-genotoxic carcinogen and genotoxic carcinogens and try to give you a quick overview of whether there are thresholds for carcinogens from chemical risk assessment perspective. 

Definition of Non-genotoxic and Genotoxic Carcinogen

The key to differentiate a non-genotoxic carcinogen from a genotoxic carcinogen is to understand the Mode of Action (MoA) of carcinogenesis. Their definitions are listed as follows.

  • Genotoxic carcinogen: Chemical substances or agents causing tumours by interaction with the genetic material (eg, DNA, chromosomes). Such substances are usually both genotoxic and carcinogenic, and can induce gene mutations, structural chromosome mutations, and genome mutations. Genotoxicity
  • Non-genotoxic carcinogen: Chemical substances or agents causing tumors by non-genotoxic mechanism (eg, peroxisome proliferators, hormones and local irritants). Such substances do not have genotoxicity as a primary biological activity.

Overview of Thresholds for Carcinogens

Science has shown that there are are even thresholds for some genotoxic carcinogens. This has been recognized by many regulatory agencies, academics and chemical industry. A joint task force from the European Commission's Scientific Committee on Occupational Exposure Limits (Scoel) and Echa's Risk Assessment Committee (Rac) has agreed on the following approach towards the risk assessment of carcinogens. Mode of Action(MoA) is again becoming the key to decide whether health-based thresholds exist for carcinogens in chemical risk assessment. 

Category Mode of Action (MoA) Whether Thresholds Exist
Non-genotoxic Carcinogen

Non-genotoxic mechanism (eg, peroxisome proliferators, hormones and local irritants).

  • Genotoxicity is not a primary biological activity.
Yes
Genotoxic Carcinogen

Indirect genotoxicity: Genotoxicity is caused by indirect mechanisms that cause damage to DNA or chromosomes:

  • Toxic to non-DNA targets: interactions with proteins such as aneugens
  • Substances that overload the system/change metabolism and exceed natural protective mechanisms: ROS (reactive oxygen species).
Yes
Genotoxic Carcinogen Direct genotoxicity: Genotoxicity is caused by direct interaction of the respective substance or its metabolite with the DNA. No

Note: Sufficient evidence is needed to differentiate direct genotoxicants and indirect genotoxicants. 

Why Do Thresholds Matter?

Risk assessment approach for carcinogenic substances varies depending on whether there are health-based thresholds. For non-threshold carcinogens, It is usually assumed that even a very small dose may cause adverse effects. Thus Derived No Effect Level (DNEL) or reference concentration cannot be derived. Under REACH, only Derived Minimal Effect Level (DMEL) is calculated. For threshold carcinogents, OELs and DNELs can be derived using conventional approach for other systemic toxicants.

Reference

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 Tags: Topics - CRAToxicology and Health Risk Assessment

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