How Are Proposed Food Additives Tested for Toxicity?

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1. General Principles
2. Types of Toxicity Studies
3. Determination of Tolerance Level

Some general principles:

• Laboratory animals are good models for assessing toxicity of substances in humans
• Species differences are kept in mind
• Scientists also consider the probable amount of the additive that will be consumed, and the cumulative effect of the additive in the diet.
• Also, an additive may not be used to deceive a consumer by changing the food to make it appear other than it is. For example, preservatives that contain sulfites are prohibited on meats because they restore the red color, giving meat a false appearance of freshness. (The U.S. Department of Agriculture regulates meats, but depends on the FDA regulation to prohibit sulfites in meats.)

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Types of Animal Studies

Classification of Toxicological Tests

• Acute Oral Toxicity Study
  • Single exposure, or multiple doses within 24 hours
  • To determine adverse effects from acute (short term) exposure
  • Rodent species (rat or mouse) usually used
• Short-term Feeding Studies
  • Duration less than one month, usually 28 days
  • Determination of dose range to be tested in longer-term studies
  • Dermination of target organs of the test chemical
• Subchronic Oral Toxicity Studies
  • Duration 90 days to 12 months
  • At least 3 dose levels
    • 20 rodents each sex per dose group, or
    • 4 dogs each sex per dose group
  • Provide information on toxic effects on target organs from daily dose throughout time period
• Chronic Oral Toxicity Studies
  • Longer than one year duration
  • Determine most chronic effects and dose-response relationships
  • Often can assess carcinogenic potential of the proposed food additive
• Developmental Toxicity and Teratogenicity Studies (Oral)
  • Rodent species
  • Multigenerational, to determine effects on reproduction, and offspring
  • Effects on gonadal function, estrous cycles, mating behavior, conception, and partutition are assessed.
  • Incidence of congenital malformations (birth defects) is assessed.
  • Can often be combined with chronic feeding studies and carcinogenesis bioassay
• Carcinogenesis bioassay
  • Two species
  • Observe test animals over life span for the development of cancer
  • Oral, dermal, and inhalation routes of administration

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Determination of Tolerance Levels

• Tolerance level = maximum level of additive allowed in food
• When the level at which no adverse effect occurs in animals has been determined from feeding studies described above, this is called the NOEL (No Observed Effect Level).
  • Also called NOAEL (no observed adverse effect level)
  • Determined from subchronic studies
  • = the highest dose in mg/kg body weight that results in no detectable damage to the animal.
• RfD (Reference dose) is the maximum daily dose (mg/kg body weight) of additive considered acceptable for humans over a lifetime. A lifetime is considered = 70 years.
• A safety factor is applied to the NOEL to determine the RfD
• The safety factor may range from 100-1,000, depending on species and individual susceptibility to toxicity.
• For substances with potential severe toxicity, a safety factor of 1,000 must be applied.
• RfD = NOEL/Safety Factor
• MPI = maximal permissible intake per day
  • MPI (mg/day) = RfD (mg/kg) X 60 kg (adult body weight)
• MPL = maximal permissible level in food (also called tolerance level)
  • MPL = MPI/food factor
  • Food Factor represents an estimation of the amount of that food in the diet.
• The RfD is usually well above the Estimated Daily Intake (EDI) of a food additive.(EDI = the probable level of consumer exposure to the additive, expressed in grams per person per day)

  Click here for an FDA web site that gives detailed examples of how EDI is determined

  Example: Brilliant Blue

  • The synthetic food color additive "Brilliant Blue" was tested on two species of animals
  • A No Observable Effect Level (NOEL) of 1,000 milligrams per kilogram body weight (mg/kg) was determined
  • The Reference Dose (RfD) = NOEL/Safety Factor = 1,000/100 = 10 mg/kg body weight
  • Using food consumption survey data, it was found that the person with the highest intake would consume 5.4 mg/kg body weight
  • The Maximal Permissible Intake per day (MPI) = RfD X 60 kg (adult body weight) = 10 mg/kg X 60 kg = 600 mg.
  • If Brilliant Blue were to be added to hard candy, and it is estimated that a person eats 1 gram (gm) of candy per day, the MPL or tolerance would be 600 mg of Brilliant Blue per gram of candy.

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Prepared Summer 1997 by Bernadene Magnuson, Ph.D.
University of Idaho, Dept. of Food Science and Toxicology - EXTOXNET FAQ Team.