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Estimating Potential for Harm: The Threshold of Toxicological Concern


Whether it’s a man-made or a naturally occurring chemical, we don’t always have a lot of data on its potential toxicity.  Some of these chemicals can occur at very low levels in nature or in products.  But given our ever-increasing ability to measure very low amounts of chemical exposure we have a need to be able to make judgements about potential for harm and prioritizing which chemicals need further toxicity studies.  So how does a toxicologist go about prioritizing which of these kinds of chemicals need additional study?

With this Tox Topic we introduce you to a concept called The Threshold of Toxicological Concern (TTC).  The TTC is a science-based approach for helping to guide which chemicals should have a high priority for additional study versus those that can be presumed to present no appreciable human health risk.  It uses the knowledge gained from many years of testing chemicals for toxicity and relies on applying that knowledge to other chemicals based on their properties and the amount of exposure expected.  It also recognizes that all chemicals have a safe level of exposure below which there is no significant risk to human health.

Basics of the Approach

Risk assessment of chemicals typically relies on dose-response toxicity data and estimates of human exposure.  One of the things toxicologists have learned is that even though there are is a huge diversity of chemicals, there are actually comparatively fewer ways in which they cause harm.  This allows chemicals to be grouped based on their chemical structure and other key properties, as well as the type of harm they cause.  Once grouped in this way toxicologists have been able to gain important insights into the amounts that it takes to cause harm, and importantly, the amount of exposure below which there is expected to be no significant chance of causing harm.  In other words, they have been able to define Thresholds of Toxicological Concern.

It is important to recognize that this approach can’t be used for all chemicals.  For example, this approach should not be used for chemicals that accumulate in the body over time, for so-called heavy metals, and nanomaterials.  There are other exceptions and to learn more the reader should consult the references provided.  While the TTC was originally developed in the context of chemical exposure via food, it has also been applied to exposure via inhalation and the skin (e.g. cosmetics).

Chemical Classes

The basis of the TTC approach is to establish classes (groupings) of chemicals that have similar properties and toxicity.  Compiled information on those classes is then used to derive levels of human exposure below which no harm is expected over a lifetime of exposures.  This is directly analogous to the process of establishing safe amounts of exposure using dose-response studies and determining doses below which no harm occurs for a single chemical.  When this approach was first described in the scientific literature it resulted in 3 classes of chemicals that were given the names Cramer Class I, II and III after one of the senior authors on the paper.  In later years, additional classes of chemicals have been added.  In the most recent review of the use of the TTC approach in food safety assessment, the European Food Safety Authority lists the following 5 classes of chemicals and their corresponding thresholds of toxicological concern.


TTC values                                                                                TTC                                     TTC

                                                                                            ug/person per day         ug/kg bw per daya


DNA-reactive mutagens and/or carcinogens                           0.15                                   0.0025

Organophosphate and carbamate insecticides                         18                                       0.3

Category III                                                                                      90                                      1.5

Category II                                                                                        540                                    9.0

Category I                                                                                          1,800                                 30


a The average human body weight is estimated to be 70 kg (about 154 pounds).

One of the things immediately apparent from the values in the table is that there are significant differences in the estimated thresholds of safe exposure levels among chemicals.  For chemicals that have a likelihood of causing the kind of harm that can lead to cancer, the level of exposure that causes concern is much, much lower (over 10,000 times lower) than the least concerning class of chemicals.


The TTC is an excellent tool to help prioritize when there is a need for additional toxicity studies on chemicals for which limited data may exist and the potential for exposure is clear.  These values will be continually refined as the database on which they are derived grows.  It is also important to note that there are other factors that will help determine testing priorities, such as how commonly something is used and the frequency and amount of estimated exposures.

The bottom line is that when you hear that some chemicals have never been tested, you can feel confident that this doesn’t mean that there is no data-based perspective on the potential for harmful effects to occur.  Tools like the TTC make it possible for toxicologists to understand the potential for harmful effects even when specific data on a chemical may not exist.


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