Center for Research on Ingredient Safety

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.

How do researchers and regulators calculate a safe level for an ingredient?

Traditionally, scientists use threshold data to determine the highest dose an animal can be safely exposed to a compound. Then, researchers will use the data derived from animal studies and apply it to humans to create a safety margin.

Since animal and human biological systems are sometimes different, researchers must ensure that humans are not negatively impacted more than animals. To do this, they calculate a safe dose for humans by dividing the animal safety dose typically by a default of 100 (10-fold reduction for the uncertainty of extrapolating across different animal species and 10-fold reduction due to the uncertainty of differences in sensitivity between individual people), if not more.

For example, a safe dose for animals may be 100mg/kg/day. So, using the same uncertainty factors, the safe dose for humans would be 1mg/kg/day.

The calculation generates a conservative estimation of safe exposure that considers vulnerable populations like children. It does not necessarily guarantee adverse effects for any dose above the established human threshold.

Why does a Reference Dose matter?

Researchers and regulatory agencies need Reference Dose (RfD) data to establish a safety buffer for chemical ingredient exposure, over a lifetime.

The RfD allows regulatory bodies to set limits on exposure to potentially hazardous substances found in our environment, food, and consumer products. This includes chemical ingredients like food additives, preservatives, pesticides, and more.

How do Reference Doses (RfD) impact food and ingredient safety?  

Reference Doses (RfD) are critical elements of the risk assessment process.

The risk assessment process involves regulatory agencies, including the U.S. Food and Drug Administration, U.S. Environmental Protection Agency, Consumer Product Safety Commission, and more, to use RfD and other data to generate safe levels of exposure to chemicals we may contact regularly.

The agencies use different terms to describe these numbers, but their core purpose is to prevent harmful levels from entering our daily lives. These terms can include:

• Acceptable Daily Intake
• Reference Dose
• Minimal Risk Levels
• Permissible Exposure Levels
• Threshold Limit Values
• Recommended Exposure Levels
• Health Advisories

The good news.

Reference Doses are essential to ensuring the foods and products we use are safe. By providing uncertainty factors that are calculated to derive the Reference Dose, we can safely use and consume food, beverages, and products on the market.  

If you have any questions about foods and ingredients, please reach out to us via email or submit your idea to us at go.msu.edu/cris-idea