News from CRIS: Everyday Toxicology - Reference Dose

January 23, 2024

How do regulators determine how much of an ingredient is safe in a product?

Many factors determine an ingredient’s safety. We know regulators look at many endpoints to determine how much of an ingredient is safe for people to consume, even vulnerable populations. Once the factors are determined, the Reference Dose is established.

What is a Reference Dose in toxicology and ingredient safety?

The Reference Dose (RfD) estimates the daily exposure to ingredients humans, including sensitive populations like children, can likely be exposed to without increasing our risk of adverse health effects over our lifetime.

You’ll see it written out as milligrams of the ingredient (e.g., chemical) per kilogram of body weight per day (mg/kg/day).

How are Reference Doses determined?

Traditionally, researchers conduct studies that measure how a person, animal, or organism responds to an ingredient or substance by giving them specific doses or amounts of the ingredient and observing how the organism responds.

Often, researchers used animal models to help develop safety thresholds. These research models are called “in vivo,” meaning in living organisms.

New Approach Methodologies (NAMs) are changing how scientists conduct research. Advancements in research techniques and computational modeling allow researchers to use, under certain circumstances, safety data from studies that are not conducted in an intact organism, termed “in vitro,” meaning in glass models.

In vitro research involves using cells, tissues, or biological samples that researchers have isolated from living animals or humans to build models that may be more applicable to human exposure and human biology while reducing the need for laboratory animals.

Using the data researchers gather from traditional and new approach methodologies, scientists and regulators can determine safe levels of exposure by deriving a Reference Dose (RfD).

What is an uncertainty factor? Why does it matter?

Humans are not laboratory animals. We may not respond the same way to a chemical as a laboratory animal. Current data relies heavily on information derived from animal studies.

Additionally, humans are individuals and may react differently to ingredients based on each person’s unique makeup.

Humans are not all one specific size, shape, or makeup. For example, children’s bodies are developing and may be more sensitive to an ingredient.

These are examples of uncertainties in what a safe level of exposure is, and to compensate for the above variables, regulators use additional safety factors to ensure that even vulnerable populations will be protected when determining a Reference Dose.


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