2 . De Minimis and the Threshold of

Regulation

Alan M. Rulis

Food and Drug Administration

INTRODUCTION

This chapter addresses the concept of a "threshold of regulation" for

food additives . The Food and Drug Administration (FDA) has appreciated the need for such a concept since the early years after the passage of

the 1958 Food Additives Amendment to the Federal Food, Drug and

Cosmetic Act (the FD&C Act, or the Act) . The approach put forward in

this chapter is based upon the premise that, through an examination of

a sufficiently large sample of toxicological data from both classical

toxicological feeding studies and from carcinogenicity bioassays, some

global delimiters of risk and exposure can be determined to define levels

of human exposure and/or levels of migration of substances to food that

can be said to fall below some "threshold of regulation ." When this is

the case, the substance in question would not necessarily need to

undergo the rigors of the premarket safety evaluation requirements of

the Act . Inste2d, the particular use of the substance could be acceded to

by the FDA after an abbreviated review of pertinent information, thus

avoiding the need for the submission and agency approval of a food

additive petition covering the use of the substance . (Implicit in such a

process is the absence of any indication that the substance in question is

in fact a carcinogen or other potent toxin . Known carcinogens would

need to be handled in a considerably more formal manner, and would

be subjected to more formal risk assessment and risk management decisionmaking.)

THE PROBLEM

Section 201(s) of the FD&C Act defines a food additive as :

. . . 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 any food (including

29

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30 TOXICOLOGY

any substance intended for use in producing, manufacturing, packing,

processing, preparing, treating, packaging, transporting, or holding

food . . . . I

Because this broad definition includes food packaging and other

food-contact materials and their components that might migrate unintentionally into food, it is easy to see why the need has arisen for a

policy concerning a "threshold of regulation ." With the development of

ever more sensitive and discriminating analytical capabilities, the analyst today can confirm the presence in food, or in food-simulating solvents, of extremely small amounts of substances . In some cases, these

amounts may be as small as a few parts per billion (ppb) .

The FDA is often presented with situations in which a chemical

substance used or present in a food-contact material may indeed theoretically migrate to food, but is predicted to do so at levels that are so

low as to arguably not satisfy the above statutory definition . Often such

substances are not known to be carcinogens . Perhaps little else is known

about their toxic potential either. The question that often arises for

these very low level migrants is, "Is it necessary for the agency to request

and approve a full-blown petition allowing the presence of the substance in food?" Over the years, the agency has made many thresholdof-regulation decisions on a case-by-case basis, although some people

have cited inconsistencies in these decisions and some have called for a

more formal policy statement by the agency, indicating the principles

and procedures it would follow in granting threshold-of-regulation

approvals . If the agency wishes to continue to use its discretion not to

require a petition in certain cases, is there some consistent basis on

which this can be done, while still protecting the public health in the

(unlikely) event that the substance in question turns out to be a carcinogen or other potent toxin? (At exceedingly low exposure levels -say, less

than 10 ppb--it is likely that potential carcinogenesis would be almost

the only toxic phenomenon capable of producing any concern .)

Stating the problem another way, we may ask, "How can the agency

determine under a general policy that a given use of a food-contact

material or a component thereof, not presently known to be a carcinogen, does indeed not require full petition review and regulation, and

will, even in the worst case, present no unwarranted risk?" Furthermore, more, we might ask, "How can the agency build consistency and scientific credibility into the threshold-of-regulation decisionmaking process?" It is with one form or another of this problem, and with the above

questions, that the agency, the regulated industry, and the courts have

grappled for nearly three decades .~ Arguably, requiring the regulation

of low ppb levels of substances places significant and costly burdens on

both the agency and the affected industries, while the human exposure

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A.M. RULIS 31

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to such low levels of substances may have negligible public health significance . Conversely, however, even small exposures to highly toxic substances or to potent carcinogens might sometimes be found to produce

significant human risk . The agency must navigate carefully between

these two potentially unpleasant consequences .

Obviously, no simple solutions to this problem will materialize overnight . However, recent progress in understanding the global trends and

distributions of risk and exposure may help the agency to sufficiently

clarify the scope of available options, so that a consistent policy can

finally be achieved . This chapter addresses some areas of recent thinking about the problem at the FDA and offers some recommendations

for making further progress .

A PROBABILISTIC APPROACH

The complexities of the biological interactions of any chemical with a

living system are enormous . To construct a threshold-of-regulation policy that anticipates all potential adverse responses that a compound

may induce, including potential carcinogenesis, is clearly impossible .

Fortunately, however, the present toxicological literature contains an

enormous amount of data on the toxicity of chemical substances . The

premise of this chapter is that a proper summarization and analysis of

these data may provide important needed insights into the threshold-ofregulation question .

For example, Figure 1 displays potency data on a subset of 343 oral

carcinogens from animal studies recently compiled by Gold et al .y For

the purpose of the present discussion, "potency" is defined as the slope

of a straight line connecting the point representing TD,, dose (toxic dose

to 50% of the test animals) of Gold et al . with the point representing

zero risk and zero dose . (For a more complete description of the definition, refer to Flamm et al . 10 Figure 1 shows that when carcinogen

potencies are analyzed by grouping them into ranges and plotting them

as a probability distribution, they form, on a semilogarithmic scale, a

curve that is remarkably Gaussian (normal) in shape . The existence of

such a curve for carcinogen potencies demonstrates not only the well

known fact that chemical carcinogens present greatly different potencies (probabilities of inducing cancer per unit level of intake), but also

that a single chemical carcinogen selected at random can be predicted a

priori to have a potency that falls within fairly well defined limits . It

seems that such knowledge ought to be applicable to the threshold-ofregulation question . Therefore, let us now try to apply this knowledge

to the problem at hand, namely the delineation of options for determinhttp://legacy.library.ucsf.edu/tid/rdc05c00/pdf
32 TOXICOLOGY

Figure 1 . Histogram and nonlinear least squares best fit Gaussian to

the potencies of Gold et al .9

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ing exposures to chemicals that might be said to fall below a threshold of

regulation .

First, in order to be useful, the Gaussian distribution of Figure 1 must

be transformed into an exposure distribution at a constant assumed risk

of I x 10$ per lifetime . (This process has been previously described .10)

(A risk level of 1 x 10 e per lifetime has been chosen because it is the

upper bound level of risk identified by the agency recently as de

minimis for the purpose of regulating the carcinogen methylene chloride as a coffee decaffeinater.)" The transformation applicd to the

potency distribution of Figure 1 results in curve number 5 of Figure 2 .

We call such a curve a"risk equivalent exposure distribution ." It

describes the relative probability that a carcinogen selected at random

from the universe of known carcinogens will be one that presents a risk

of 1 x 10 e per lifetime at the exposure level indicated on the horizontal

axis across the top of Figure 2 . As can be seen, about half the area of

curve 5 falls on either side of the 1 ppb line . Therefore, at a human

dietary intake of 1 ppb, about half of all carcinogens are predicted,

under the very simplified assumptions of this analysis, to present a risk

of greater than 1 x 10 e per lifetime ; the other half, lower than 1 x

10-a .

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A.M . RULIS

Figure 2 . Relative probability distributions for various groupings of

toxicity data. Curves are arbitrarily vertically scaled and are

described in the key. Upper abscissas refer to various

measures of intake . "PP" refers to the "packaging factor"

defined in the text . Lower abscissa values are negative

base-10 logarithms of effect levels in mg/kglday for nonacute

data, mg/kg for acute data, and TD50s for the carcinogen

data of Gold et al? Below lower abscissa are minimum lethal

doses for selected toxins for comparison purposes .

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KEY: 1 18000 RTECS LD50s Rat/Mouse ; 2 130 LD5°s for Gold et al .

carcinogens; 3 PAFA LD50s (295 cpds) ; 4 PAFA LELS (159 cpds) ; 5

Risk-Equivalent Exposure Distribution 10~ Risk for 343 Gold et al .

carcinogens. Based on assumption of linear extrapolation from TD5°s.

33

A threshold-of-regulation level that precludes almost any measurable

lifetime risk from carcinogenesis (except for risk from substances like

aflatoxin B-1 or 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]), sayone part per trillion (ppt) in the human diet -would in all likelihood be

so low that it could not be reliably measured analytically, and certainly

could not be easily and consistently enforced . To insist on such a stringent level of risk protection would, in effect, preclude any reasonable

and practical threshold-of-regulation policy .

The use of a 5-ppb dietary level as a threshold of regulation presents

an interesting example, because this level has recently been suggested by

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some as an appropriate level to use for deciding on a threshold for

regulation .12 About 60% of the area under curve 5 of Figure 2 falls to

the right of the 5-ppb line . Therefore, it can be predicted on a probabilistic basis that should a substance permitted under a threshold-ofregulation decision unknowingly be a carcinogen, it would, under the

present analysis, have roughly a 60% chance of presenting greater than

a 1 x 10~ per lifetime level of risk at the 5-ppb level of exposure .

Some have suggested that an appropriate threshold-of-regulation

level of exposure would be the 5-ppb human dietary exposure as above,

but "modulated" by known classical (noncarcinogenic) toxicity information. For example, one could add to the 5-ppb requirement the

additional constraint that the LDso of the migrant be no lower than 105

times the threshold-of-regulation level (5-ppb) . In other words, any

candidate for a threshold-of-regulation decision whose LDso falls to the

right of about -1 on the abscissa of Figure 2 would be disqualified for

consideration at the 5-ppb exposure level on the grounds that its (noncarcinogenic) toxic potency is too high . Certain aspects of such an

approach have recently been put forward .12

In order to analyze this type of proposal, data on toxicity of numerous

chemical substances were compiled . The curves numbered 1, 2, 3, and

4 on the left of Figure 2 describe these data . Curve 1(arbitrarily scaled)

depicts a nonlinear least squares best fit of a Gaussian curve to data

compiled from 18,000 oral (rat or mouse) LDsos contained in the Registry of Toxic Effects of Chemical Substances (RTECS) . Curve 2 (arbitrarily scaled) represents a similar envelope of LDsos for 130 compounds

identical to the carcinogens of Gold et al . comprising curve 5 . Curves 3

and 4 (also arbitrarily scaled) derive from data analyzed in the FDA's

Priority-Based Assessment of Food Additives (PAFA) project ."-" Curve

3 represents the probability distribution of LDsqs for 295 regulated food

additives analyzed in the PAFA project . Curve 4 represents an envelope

of lowest effect levels from subehronic or chronic feeding studies on

food additives studied in PAFA .

As can be seen, the "realm" of classical toxicity (except for pesticides,

economic poisons, or some exquisitely toxic substances arrayed along

the abscissa for comparison) is fairly well delineated by these curves,

with no sizeable probability of such effects occurring in rodents at doses

lower than about I mg/kg/day (to the right of about 0 on the abscissa) .

(Such knowledge is actually not new at all, having been observed and

duly noted by Frawley in 1967, using a different data base .2)

The noteworthy point for our purposes, however, is that the requirement that the acute toxic dose of a substance be no less than five orders

of magnitude higher than the benchmark 5-ppb dietary intake level is

no requirement at all, because virtually all chemicals can meet that

criterion . To see this, just step five decades to the left of the 5-ppb arrow

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A.M. RULIS 35

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in Figure 2 . Analysis of relationships between acute toxicity and carcinogen potency in recent work in progress at the FDA reveals that use of

such comparisons is of dubious practical value when applied to

threshold-of-regulation questions where the acceptable upper bound

risk value is set at 1 x 10 ° or lower . Recently, Wilson et al .16 have dealt

with this relationship and have demonstrated its potential utility in the

decisionmaking process . They too, however, note that such an approach

is of limited value when the acceptable risk level is set at 1 x 10-e per

lifetime or Iower .1F

So far, we have shown how compilations of potency and toxicity data

can be used to rule out certain threshoid-of-regulation scenarios . They

can also be used to support other choices . For example, suppose we

define a threshold-oFregulation level to be 50 ppt in the human diet .

Such a level, although quite low, would correspond to a migration level

to food of 1 .0 ppb, assuming a 5% "packaging factor." (A "packaging

factor" may be defined as the weight fraction of the human diet likely to

be packaged in a given material .) One ppb, while on the borderline of

reliable analytical detection, is not outside the realm of measurability .

This level divides curve 5 of Figure 2 in such a way as to exclude about

85% of carcinogens that produce greater than I x 10-' per lifetime risk,

if held at that level of exposure. If we conservatively assume that one

out of five chemicals assented to by the agency under a threshold-ofregulation policy at this exposure level is unknowingly a carcinogen,

then on a purely probabilistic basis we can argue that 95 out of every

100 such threshold-of-regulation decisions will result in no more risk

than 1 x 10 6 per lifetime . Furthermore, that level of risk is a maximum, with the vast majority yielding far lower levels of potential risk .

SUMMARY AND RECOMMENDATIONS

A probabilistic approach has been described for analyzing large

amounts of toxicological data on numerous chemical substances . The

application of such an analysis to the problem of the threshold of regulation for food-contact materials was described .

While such an approach certainly does not address the immense biochemical complexity inherent in the interactions of individual chemical

substances with living systems, it may prove to be a useful tool for FDA

in evaluating the viability of options for, and in providing a scientific

basis of support for, choices of threshold-of-regulation migration levels .

Once the agency is able to support a given migration level or range of

levels as acceptable for a threshold of regulation, it will be in a better

position than ever before to make threshold-of-regulation judgments on

a consistent basis .

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Once the principles of such a policy have been established, it would

remain to devise appropriate procedures for implementing the policy . It

has been suggested . that the agency could make such threshold-ofregulation judgments based on a sufficient summary of both chemical

and toxicological information provided by an applicant . Certainly some

sort of abbreviated agency review of summary information may be an

important aspect of such procedures . In order to be able to efficiently

review its accumulated decisions over the years, the agency could keep

records of all threshold-of-regulation actions . Such accumulated decisions could form the basis for a data base of information on low level

migration of chemical substances to food .

It appears that there presently exists an adequate scientific basis of

data and information on which to construct a threshold-of-regulation

policy relating to food-contact substances . By applying this information

to the problem and implementing appropriate policies and procedures,

the agency will be in a position to better delineate the boundaries of the

food additive definition of the FD&C Act as it relates to food-contact

substances .

REFERENCES

1 . Federal Food, Drug and Cosmetic Act, as amended, (Title 21 U .S . Code) .

1958 . U.S . Government Printing Office, Washington, DC .

2 . Frawley, J .P . 1967 . Scientific Evidence and Common Sense as a Basis for

Food-Packaging Regulations . Food . Cosmet . Toxicol . 5 : 293-308.

3 . Checchi, A .A . 1959 . Developments Under the National Pure-Food Law

Affecting the Packaging Industry . Food Drug Cosmetic Law Journal 14:

527-533 .

4 . Checchi, A .A . 1959 . Food Additives Procedures and Policies . Food Drug

Cosmetic Law Journal, 14 : 591-596 .

5 . Rankin, W .B . 1959 . Incidental Food Additives . Food Drug Cosmetic Law

Journal 14 : 768-773, 777 .

6. Kirk, J .K . 1960 . Food Additive Developments . Food Drug Cosmetic Law

Journal 15 :755-760.

7 . Harvey, J .L . 1962. Food Additives and Regulations . Food Drug Cosmetic

Law Journal 17 : 272-281 .

8. DC Cir. 1979 . Monsanto v . Kennedy, 613 F. 2d 947 .

9 . Gold, L .S., et al . 1984. A Carcinogenic Potency Data Base of the Standardized Results of Animal Bioassays . Environ . Health Pers. 58 : 9-314 .

10. Flamm, W.G., Lake, L .R ., Lorentzen, R .J ., Bulis, A .M., Schwartz, P .S .,

and Troxell, T.C. Carcinogenic Potencies and Establishment of a Threshold of Regulation for Food Contact Substances . Submitted for Publication

in Risk Assessment .

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A.M. RULIS 37

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11 . Cosmetics : Proposed Ban on the Use of Methylene Chloride as an Ingredient of Aerosol Cosmetic Products . Dec. 18, 1985 . Federal Register 50 :

51551-51559.

12 . Threshold of Regulation for Packaging Materials Proposed . Dec . 2, 1985 .

Food Chem . News 29-30 .

13 . Rulis, A .M., Hattan, D .G., and Morgenroth, V.M. 1984 . FDA's PriorityBased Assessment of Food Additives: Preliminary Results . Regul . Toxicol .

Pharmacol . 4 : 37-56.

14 . Bulis, A .M ., and Hattan, D .C . 1985 . FDA's Priority-Based Assessment of

Food Additives : General Toxicity Parameters . Regul . Toxicol . Pharmacol .

5 : 152-174 .

15 . Hattan, D .C. and Rulis, A .M. 1986 . FDA's Priority-Based Assessment of

Food Additives : Specific Toxicity Parameters . Regul . Toxicol, Pharmacol .

6 : 181-191 .

16 . Zeise, L ., Wilson, R ., and Crouch, E . 1984 . Use of Acute Toxicity to

Estimate Carcinogenic Risk . Risk Analysis 4 : 187-199 .

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