Introduction to Threshold of Toxicological Concern (TTC) Approach in Chemical Risk Assessment

Little Pro on 2018-03-13

Threshold of Toxicological Concern (TTC) is a principle that refers to the establishment of a generic exposure level for all chemicals below which there would be no appreciable risk to human health. Once the threshold exposure level has been established, you simply need to compare the actual/predicted exposure level with the threshold value to determine if relevant risk is acceptable or not. The TTC approach has been used by regulatory authorities to assess the risks of favoring substances, impurities in food and pesticide metabolites.

Why Is the Threshold of Toxicological Concern (TTC) Approach Useful and Necessary?

There are many synthetic and natural chemical substances for which there are little or no toxicological data available. They may be found in our products (i.e, food, cosmetics)  or environment (i.e, ground water) either as constituents or impurities at very low concentrations . It is not always possible to generate toxicological data on them. To assess the risks of those substances, we need an approach that does not require extensive toxicological data. To address this problem, scientists have proposed the TTC approach. It can be used for an initial assessment of a low-level substance to determine whether a comprehensive risk assessment or additional toxicology testing is required.

Applicability of the TTC Approach

The TTC approach is not intended to replace the risk assessment of regulated chemical substances such as industrial chemicals, pesticide active ingredients or food additives. It is primarily used to assess low-level substances such as impurities and pesticide metabolites for which there is limited toxicology data.

In addition, the TTC approach is not applicable to high potency carcinogens (i.e. aflatoxin-like, azoxy- or N-nitroso-compounds), inorganic substances, metals and organometallics, proteins, steroids, substances that are known or predicted to bioaccumulate, nanomaterials, radioactive substances, and mixtures of substances containing both known and unknown chemical structures.

Threshold of Toxicological Concern (TTC)and Cramer Classification Scheme

The Cramer classification scheme (decision tree) is the best known approach to estimate the Threshold of Toxicological Concern for a chemical substance based on its chemical structure. In 1978, Cramer, Ford, and Hall, proposed the use of a decision tree that results in “fairly clear-cut separation” of chemicals into three classes based on toxicological data. Munro et al., (1996)  has further explored the relationship between structure and toxicity of many tested substances and proposed the following human health threshold values for 3 Cramer structural classes.

Cramer Class Description TTC (µg/day*)
I Substances of simple chemical structure with known metabolic pathways and innocuous end products which suggest a low order of oral toxicity. 1,800 (30 µg/kg bw/d)
II Substances that are intermediate. They possess structures that are less innocuous than those in Class 1 but they do not contain structural features that are suggestive of toxicity like those in Class 3. 540 (9 µg/kg bw/d)
III Substances with chemical structures that permit no strong initial impression of safety and may even suggest a significant toxicity. 90 (1.5 µg/kg bw/d)
  • For substances with genotoxic alerts, 0.15  µg/kg bw/d can be applied.
  • For anti-CHEs (OPs & carbamates),  0.3  µg/kg bw/d can be appliedj.

What it means: For a chemical substance belonging to Cramer Class I, an exposure level of less than 1,800ug per day does not lead to un-acceptable health risks even if there is limited toxicology data about the substance. Assuming the body weight of an adult person is 60kg, the threshold value can also be written as 30ug/kg bw/d.

Note*: Above threshold values only apply to repeated dose toxicity, reproductive and development toxicity. They do not apply to chemical substances with structure alerts for mutagenicity or carinogenicity.

How to Identify Threshold of Toxicological Concern (TTC) for Your Substances

To identify the threshold of toxicological concern for your substance, you must learn how to determine the Cramer class for your substance first. The most straightforward way is to use the following QSAR tools. We will write about them in our next tutorials. Please subscribe to our free newsletter to get updated. 

  • Toxtree (TT)
  • OECD QSAR Toolbox (TB)


Having Questions?

We do not provide consultancy services. If you have questions or need any help, please contact our sponsor. You may also find an expert in CSP business directory below. If you are a consultant, you may get yourself listed in CSP business directory (free) or sponsor this page to leave your contact info on this page..

 Tags: Topics - CRAToxicology and Health Risk Assessment