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U.S. Department of Health and Human Services

Animal & Veterinary

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Risk Standard for Food Additives

SLIDE 1: CVM Workshop on the use of Antimicrobial Drugs in Food Animals January 23, 2001

FDA’s Risk Standard for Food Additives and FDA’s Threshold of Regulation for Food Contact Substances

Mitchell A. Cheeseman


SLIDE 2: Summary

  • Standard of Review
  • Standard of Safety
  • Threshold of Regulation
    • Legal basis/ History
    • Scientific basis


SLIDE 3: Standard of Review

“Fair evaluation of the data . . .”


SLIDE 4: House of Representatives, Report No. 2284, “Food Additives Amendment of 1958”

Committee on Interstate & Foreign Commerce, 85th Congress, 2nd Session, July 28, 1958

“The committee feels that the Secretary’s findings of fact and orders should not be based on isolated evidence in the record, which evidence in and of itself may be considered substantial without taking account of the contradictory evidence of equal or even greater substance . . . .”


SLIDE 5: Standard of Safety

The petitioner has the burden to demonstrate a “reasonable certainty of no harm” from the intended use of the additive
This requires that the FDA assess whether it has received adequately documented answers to appropriate questions of probative value.



Legislative History of the FD&C Act

The concept of safety used in this legislation involves the question of whether a substance is hazardous to the health of man or animal. Safety requires proof of a reasonable certainty that no harm will result from the proposed use of an additive.

It does not -- and cannot -- require proof beyond any possible doubt that no harm will result under any conceivable circumstance.



  • It is NOT an academic inquiry or academic research
  • It is NOT a search for “complete knowledge”
  • It is NOT intended to ensure, nor is it possible to ensure, safety
    with absolute certainty: (“Reasonable Certainty of No Harm
    rather than “Certainty of No Theoretical Possibility of Harm”)
  • Does NOT weigh risks and benefits



  • It DOES, in fact, ensure safety
  • It IS a consensus decision made under uncertainty that provides a fair evaluation of all the data of record …
    • That must protect the public health
    • That is made in the absence of complete knowledge
    • That will withstand scientific, procedural, and legal challenge from all sides
    • Where the residual uncertainty is not out-of-line with what has been previously tolerated in the context of all previous similar safety decisions


SLIDE 9: Food Additive Definition

The term “food additive” means any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of food.


SLIDE 10: Threshold of Regulation Proposals

  • Frawley 1967
    Dietary Conc. of 100 ppb
  • Ramsey 1969
    Migration of 50 ppb
  • SPI 1977
    Migration not detectable (50 ppb)
  • FDA 1993
    Dietary Conc. of 0.5 ppb


SLIDE 11: FDA’s Threshold of Regulation

  • Threshold for review not approval
    • 0.5 ppb in the diet
    • No specific testing required
    • Compound must not be known to be a carcinogen (Delaney)
    • No technical effect in food


SLIDE 12: Problems with Establishing a Threshold of Regulation Policy

  • Uncertainty in the amount of flexibility FDA has in interpreting the food additive definition of section 201(s) of the FD&C Act.
  • Absence of data showing that substances present in the daily diet at concentrations at or below the proposed threshold level would not pose safety concerns.


SLIDE 13: Monsanto v. Kennedy

613 F. 2d 947
(D.C. Cir. 1979)

The Monsanto court held that “… the Commissioner may determine, based on the evidence before him that the level of migration into food of a particular substance is so negligible as to present no public health or safety concerns…”


SLIDE 14: Dietary Concentrations at Which Noncarcinogenic Toxic Effects Occur

  • Frawley, 1967
    • 1000 ppb (220 Chronic studies)
  • Rulis, 1990
    • 1000 ppb (18,000 acute studies)
  • Cheeseman, et al., 1998
    • 98.1% > 500 ppb (3,306 reproductive toxins)
    • 99.9% > 500 ppb (2,542 subchronic studies)


SLIDE 15: The Problem of Carcinogenic Risk

  • Can we be reasonably certain that an untested compound is unlikely to be both:
    • A carcinogen
    • Potent enough to be of concern at a given dietary concentration?


SLIDE 16: A Probabilistic Approach

  • Use a database of compounds of known carcinogenic potency that is representative of unknown compounds. (Gold CPDB)
  • Perform a probabilistic analysis of the doses equivalent to a negligible risk level. (I.e., one in one million U.B.)


SLIDE 17: Threshold of Regulation

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