Aflatoxin control—How a regulatory Agency managed risk from an unavoidable natural toxicant in food and feed

REGULATORY

Aflatoxin

TOXICOLOGY

AND

Control-How an Unavoidable

PHARMACOLOGY

9,109-

130 (1989)

a Regulatory Agency Managed Risk from Natural Toxicant in Food and Feed’

DOUGLAS L. PARK*.’ AND LEONARD

SToLowf

*Department of Nutrition and Food Science, University ofArizona, Tucson, Arizona 85 721. and j13208 Bellevue St., Silver Spring, Maryland 20904

Received January 9.1988

The control by the Food and Drug Administration (FDA) of aflatoxin, a relatively recently discovered, unavoidable natural contaminant produced by specific molds that invade a number of basic food and feedstuffs,provides an example of the varying forces that affect risk assessment and management by a regulatory Agency. This is the story of how the FDA responded to the initial discovery of a potential carcinogenic hazard to humans in a domestic commodity, to the developing information concerning the nature of the hazard, to the economic and political pressures that are created by the impact of natural forces on regulatory controls, and to the restraints of laws within which the Agency must work. This story covers four periods: the years of discovery and action decisions on the basis of meager knowledge and the fear of cancer; the years oftinkering on paper with the regulatory process; the years of digestion of the accumulating knowledge, and the application of that knowledge to actions forced by natural events; and an audit of the current status of knowledge about the hazard from aflatoxin, and proposals for regulatory control based on that knowledge. o 1989 Academic PKSS. I~C.

THE

THEORETICAL COMPONENTS ANALYSIS AND MANAGEMENT

OF RISK

The manner in which the Food and Drug Administration (FDA) has managed the risk from aflatoxin can be examined and critiqued in relation to a theoretical ideal. The ideal process is usually divided into the following components: hazard evaluation, exposure determination, risk determination, and management of risk. A hazard evaluation provides a description of the expected lesion and of the dose/ response relationship. Ideally, the test animal should be the target animal. The most important target animal for a public health agency is man, but domestic animal welfare also comes within the regulatory jurisdiction of the FDA. Since experimentation with humans is not generally a viable option, and unless the target animal is some ’ This paper was sponsored by the IUPAC Commission on Food Chemistry ’ To whom correspondence and reprint requests should be addressed. 109 027%2300/89 $3.00 Copyright Q 1989 by Academic Press, Inc. All rights ofreproduction in any form reserved.

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PARK AND STOLOF’F

species of livestock, laboratory animals must be used. A determination must be made, usually by comparative toxicology, whether the test animal is a proper surrogate for the target animal, and a scaling factor must be established for translation of the dose/ response data from test to target species. When the toxic agent is a recently recognized component of the environment, the laboratory data must be examined in relation to epidemiological evidence of past exposure to the agent. After development of suitable analytical and sampling procedures, a determination must be made of the geographic and temporal distribution of the toxic agent in each major commodity subject to contamination. Combined with commodity consumption data, this information can lead to an estimate of exposure to the toxic agent by various human and animal populations. The method development and the surveys by which such data are accumulated are usually more costly in time and resources than is generally acknowledged. With dose/response, scaling, and exposure data in hand, an estimate of risk to the exposed population can be made. For a newly recognized natural toxicant, regardless of the theoretical basis for calculation, the risk based on laboratory data must be compared to the observed risk from epidemiological data. When the two approaches produce divergent results, comparative toxicology observations may shed light on the reasons for the difference and lead to a rational conclusion. Risk management decisions are usually made with an inadequate knowledge of all the foregoing factors. Decisions can be forced by societal or political pressures, economic necessity, or legal mandates, and can be molded by the same factors. The management plan can take the form of maximum tolerated levels that are legally enforced, educational programs leading to voluntary compliance by industry, and research programs leading to a better understanding of how and where the toxicant occurs, with prevention of the occurrence or removal of the toxicant as the ultimate goals. Risk analysis and management should be an evolving process as more and better knowledge is acquired. AFLATOXIN

DISCOVERED

( 196 1- 1969)

The events leading up to the first FDA actions in regard to aflatoxin have been fairly well chronicled (Bauer and Parker, 1984; Fischbach, 1984; Stoloff, 1972, 1976a, 1980a). When in 196 1 the information was first transmitted to FDA scientists from colleagues in England that a mold-produced toxin (mycotoxin) had been isolated from peanut meal and then from peanuts, the Agency was busy with the implementation of the 1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetics Act. Major resources of the Division of Toxicology of the Bureau of Biological and Physical Sciences had been assigned to develop protocols to be recommended for use by industry to determine whether proposed food additives were safe for their intended purposes, and the Division of Food was involved in the compilation of a list of those additives that were generally recognized as safe (GRAS). Although not addressed directly by these activities, cancer was a subliminal topic, as evidenced by the Delaney Amendment to the Food Additives amendment. Major producers of consumer peanut products in the United States had also been alerted at about the same time as the FDA to the potential of a toxin in peanuts. Peanut products manu-

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facturers and the FDA independently followed the research developments closely, because initial tests had indicated that the toxin could be a hepatocarcinogen. Manufacturers and the FDA, also independently, started to develop analytical capability for the toxin and to look for it in U.S.-produced peanuts. By 1963 the evidence was clear; the toxin, now characterized as four related compounds named aflatoxins B, , B2, G, , and G2, was confirmed as a potent hepatocarcinogen to rats, and aflatoxins were found in U.S.-produced peanuts and peanut meal. (More related compounds, including mammalian metabolites, were subsequently characterized, but for the sake of brevity the term “aflatoxin” will be used generically in those situations where specificity is not required for understanding.) The major manufacturers of consumer peanut products in the United States, recognizing the potential for harm to the public, and to themselves from adverse publicity, took the initiative in starting a cooperative industry-Department of Agriculture (USDA)-FDA effort to develop practical analytical methods and to use whatever methods were available to determine the sources and extent of aflatoxin contamination of peanuts. This effort resulted in the creation of a continuing voluntary agreement between the Secretary of Agriculture and peanut growers and shellers for inspection of in-shell peanuts for evidence of possible aflatoxin contamination, and certification of each lot of raw shelled peanuts as either positive or negative for the presence of aflatoxin. Because peanuts were, and still are, under the price support regulations and commodity marketing orders of the USDA, and because price and marketing support were made contingent on growers’ and shellers’ acceptance of the aflatoxin testing portion of these documents, essentially 100% of the U.S. peanut crop has been tested for aflatoxin since the institution of the program in 1964: but good contamination data were not available until 1967 when research had progressed to the state where sampling and testing procedures could be specified and approved laboratories established. The continuing data from these laboratories, summarized each year by the Peanut Administrative Committee, an industry-appointed body that oversees the certification program, have provided a comprehensive picture of aflatoxin in raw shelled peanuts. These data can be translated into anticipated aflatoxin levels in consumer peanut products by introducing a factor for aflatoxin removed or destroyed in processing (ca. 55%). These calculated levels can be checked against data from more limited surveys of consumer peanut products on the market (Stoloff, 1980a). In 1967 the potential for harm to humans from aflatoxin was still an unknown (Peers, 1967). The FDA took the position that in the absence ofadequate information on which to base a safe level of aflatoxin in food, and to ensure a continued supply of food in those situations where some contamination with aflatoxin was unavoidable. administrative guidelines would be established consistent with what could bc achieved practically by use of the then available agronomy, technology. and analytical methodology. The 1964 USDA marketing agreement for peanuts provided for removal to USDA custody of all lots of raw peanuts with detectable aflatoxin: the method for aflatoxin then available had a detection limit around 100 ppb. The following year, with improvements in analytical methodology and at FDA insistence. the limit was dropped to 50 ppb. By 1968, the FDA felt sufficiently confident of the analytical method that had been developed to train chemists in selected FDA district laboratories in the technique and to issue a formal administrative action guideline of

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30 ppb total aflatoxins in peanut products. With no information available on the relative carcinogenic potency of the several aflatoxins, the sum of all measurable aflatoxins was used for the guideline. The following year the peanut marketing agreement contained the 30 ppb level of aflatoxins as the cutoff point for a negative certificate. But by then the FDA had dropped the administrative guideline to 20 ppb, an action that was based on a year of experience with the analytical method and the limitations of the method then in use for confirmation of atlatoxin identity, a necessary consideration for any contemplated legal action. A decision had been made to justify seizure actions for aflatoxin contamination under Section 402(a)( 1) of the Food, Drug, and Cosmetic Act. The general provisions of the act prohibit interstate commerce of an adulterated food, and Section 402(a)( 1) defines a food to be adulterated if it contains an added poisonous or deleterious substance which may render it injurious to health. Under this section, the FDA needs to demonstrate only the presence of the poisonous substance; there is no need to prove the substance harmful at the level encountered; the controlling word is “added.” The FDA, however, must still prove to the satisfaction of the court adjudicating the issue the identity of that which is being measured. The methods for confirmation of identity (Stoloff, 1980b) that in 1969 were considered necessary to provide this proof could not be applied with confidence to commodities with less than 20 ppb aflatoxins, When the FDA action level was dropped to 20 ppb, the peanut shellers argued that is was impractical for them to meet this cutoff point. To maintain the voluntary system of 100% inspection, the FDA compromised with a level of 25 ppb for raw shelled peanuts. The rationalization for this compromise was that peanuts are not usually consumed raw, and that further processing into consumer products, on which FDA surveillance would be concentrated, would lower the concentration to well below the 20 ppb level. It is evident that FDA risk assessment and management actions during this 19651969 period were a mixture of prudence and pragmatism. It was prudent to assume in the absence of evidence to the contrary that a carcinogen for rats was also a carcinogen for humans. With limited data on incidence and level of contamination, the practical approach was to concentrate research on analytical methodology and surveillance; and with limited resources and experience for handling a natural contaminant problem, it was wise to encourage and nurture voluntary control efforts. The legal framework selected provided a basis for flexible action, and the administrative guidelines that were established maintained sufficient pressure for corrective action by industry without jeopardizing the availability of an important commodity at reasonable prices. THE GLASNOST

PERIOD

( 1974- 1978)

In 1974 the FDA General Counsel convinced the Commissioner that the temper of the times required an open presentation and discussion of FDA regulatory actions through publication of proposals in the Federal Register, including invitations for comment. One result of this policy was a proposal to control unavoidable poisonous or deleterious substances in food through application of Section 406 of the Food, Drug, and Cosmetic Act. This section allows the Commissioner to set a tolerance “at

AFLATOXIN

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a level necessary for the protection of the public health, taking into account the extent to which the substance can not be avoided.” The first, and only, proposal of rules under this policy included mercury in fish, lead in evaporated milk, and aflatoxins in shelled Peanuts and peanut products used as human food (Food and Drug Administration, 1974). For management of risk there is a considerable difference between a tolerance under Section 406 and a guideline under Section 402(a)( 1). Under Section 406, setting a tolerance requires an extensive protocol, including public comment, and once a tolerance is set, a change requires that the same cumbersome procedure be followed. Under 402(a)(l), as then interpreted by FDA, guidelines could be set and changed, as needed, by executive directive. Under Section 406, the legal charge for seizure action is that the level of contaminant exceeds the tolerance. The technical proof involves the validity of the sample, and the accuracy of the analysis. Under 402(a)( 1), the level affects only the Agency, as a trigger for action. The technical proof involves the identity of the substance, and its potential for harm. The state of knowledge at this period of time concerning the hazard from, and exposure to, aflatoxin has been presented in the Section 406 tolerance proposal (Food and Drug Administration, 1974), and in a number of reviews (Campbell and Stoloff, 1974; Stoloff, 1976a,b; Wessel and Stoloff, 1973; Wogan, 1973). From 1964 to 1974, probably related to increased interest in and funding for cancer research, and easy access to adequate quantities of relatively pure aflatoxin, the annual publication of research findings on aflatoxin toxicology had increased about fourfold, peaking to 88 in 1973. In this IO-year period the FDA had acquired 527 separate publications on this topic. The hepatocarcinogenicity of aflatoxin to more species than the rat had been demonstrated, including some preliminary findings with nonhuman primates, and a dose/response relationship had been established for one strain of rat. But some species proved to be resistant to aflatoxin carcinogenesis and were used in studies of comparative metabolism after a number of mammalian metabolites of aflatoxin had been isolated and characterized. Differences in metabolic rates and patterns between species were noted. To test the thesis that aflatoxin might be related to liver cancer in humans, a number of epidemiological studies in areas of Africa and Asia where liver cancer was prevalent had been completed. A general correlation was noted between the incidence of liver cancer and the current levels of exposure to aflatoxin, but some problems with the studies were also noted. The conclusion in the tolerance proposal from this evidence was “while it is not certain that aflatoxins are a cause of primary liver cancer in the United States, . . . [t]he observations of severe carcinogenic effects in experimental animals and positive correlations between dietary aflatoxins and primary human liver cancer seen in other parts of the world are sufficient justification to regard aflatoxins as poisonous or deleterious substances and to take actions to hold the human exposure to aflatoxins in the United States to the lowest level possible.” The list of commodities in which aflatoxin had been found in market samples had expanded to cottonseed, corn, sorghum, barley, rice, wheat, soy bean, copra, pecans. walnuts, almonds, cassava, and figs. The commodities, in addition to peanuts, in which major incidences were encountered were cottonseed and corn; the occurrence of ahatoxin in the remaining commodities was relatively insignificant. The occurrence of aflatoxin in peanuts, cottonseed, and corn was found to be highly influenced by production region, and most of the contamination was found to have occurred

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either preharvest or during harvest, leading the FDA to the conclude that “prevention of mold growth and aflatoxin production in peanuts appears unattainable at the present time.” Yearly data from the peanut certification program, supported by routine regulatory surveillance data accumulated by the FDA and Canadian Health and Welfare, and by a comprehensive survey of consumer peanut products manufacturers by the FDA in 1973, provided considerable information on which to base an estimate of the aflatoxin incidence and level to be expected in peanuts as consumed. Data on peanut products consumption were available from decennial surveys carried out by the USDA Agricultural Research Service of food consumption of households in the United States. But calculations from this exposure information were not made in the tolerance proposal, because there was no toxicological information for determining a safe level on which to base a tolerance. Instead the Commissioner “sought to bring four factors into balance: the need to minimize human exposure to aflatoxins; the capabilities of sampling procedures and analytical methods to detect, measure and confirm aflatoxins; the capability of agricultural and manufacturing technology to prevent and remove contaminated peanuts; and the need for continued availability of a low cost protein source (i.e., peanuts).” In the end, sampling uncertainties and analytical capabilities at the margin below the tolerance required by industry to be assured of compliance dictated a minimum practical tolerance of 15 ppb. In response to comments received on the tolerance proposal, the FDA undertook an “assessment of estimated risk resulting from aflatoxin in consumer peanut products and otherfood commodities” [emphasis added]. This assessment was presented for comment by way of a Federal Register notice (Food and Drug Administration, 1978a) of availability on request from the FDA Hearing Clerk. At this time it was abundantly clear that the major exposure of a U.S. population to aflatoxin was in the southeastern states from the coincidental factors that dry-milled corn products (meal and grits) are consumed in those states at a much higher rate than in any of the other states, that most ofthe dry-milled corn products consumed in the Southeast are made. from local corn, locally milled (Stoloff and Dahymple, 1977), and that corn from this southeastern region suffers by far the highest incidence and level of aflatoxin contamination in the United States (Stoloff, 1976a). The analysis focused on this region, and the lifetime cancer risk was calculated using aflatoxin exposure levels estimated from consumption of corn and peanut products with aflatoxin contamination at levels for each that were derived from commodity survey data. Calculations of low-dose response were made using averaged dose/response data from five published lifetime feeding studies with rats and both Mantel-Bryan (Mantel and Bryan, 196 1) and “one hit” (Hoel, 1975) models, and also from a dose/response relationship derived from African and Asian epidemiological studies (Peers and Linsell, 1977). Additional calculations of lifetime cancer risk, using the relationship derived from epidemiological studies, were made with the average contamination assumed under various possible tolerance levels for peanut products. The ultimate conclusion could have been reached without all the laborious calculations; the exposure of the Southeast population to aflatoxin from corn products was so much greater than from peanut products that even a zero tolerance in peanut products could have little effect on the calculated risk. This conclusion, together with all the uncertainties expressed in the risk assessment, supported the basic reasoning in the original regulation proposal.

AFLATOXIN

115

CONTROL

After the public comments were received, the risk assessment was revised but never released, leaving the FDA with the flexibility in the face of changing knowledge to manage risk under its interpretation of Section 402(a)(l); managers responsible for control and enforcement activities apparently prevailed. But this situation did not last long. As a sequel to this period, a consumer action group (Community Nutrition Institute) in December of 1980 contended in a legal action that for unavoidable, deleterious contaminants in foods FDA was required to set tolerances under Section 406. The case went all the way to the Supreme Court, which decided the action guideline vs tolerance issue in FDA’s favor ( 106 S. Ct. 2360 ( 1986)). An auxiliary issue remanded to the Court of Appeals was whether a published notice and request for comment were required before an action guideline could be set. The Court of Appeals, on 15 May 1987, said a published notice was required, basing its opinion on Agency actions and statements that treated the guidelines as if they were substantive rules, and the requirement under the Administrative Procedure Act for notice of and comment on substantive rules. On 15 October 1987 an FDA petition for rehearing of the case was denied. In an attempt to undo the damage to its flexibility of action, the FDA issued a notice (Food and Drug Administration, 1988) announcing that its then current action levels for added poisonous or deleterious substances in food or feed are not binding on the courts, the public, or the Agency and do not have the force of law of substantive rules, but serve only as a general guide for action, to be used in conjunction with other factors pertinent to each individual case. YEARS

OF FORCED

DECISIONS

(1977-l 983)

While consideration of the Section 406 tolerance was dragging on, the FDA mycotoxin research staff was busy collecting and digesting the considerable literature on aflatoxin that was being created by investigators all over the world. One result of that effort was a paper (Stoloff and Friedman, 1976) on “the hazard to man from aflatoxin ingestion” that was organized in a question, detailed facts, and facts summary format. These questions and the answers to them provide a succint review of the state of knowledge on this subject in 1975: Q. Does the Fischer rat strain (the one used for most of the studies) have unusual sensitivity to aflatoxin carcinogenesis? A. Compared to USC and Wistar strain rats, the Fischer rat is highly sensitive. Q. Is aflatoxin carcinogenic to resistant animals at any level? A. Liver tumors could be induced in mice (a resistant species) by i.p. administration of a large dose at an early stage of life. A tumorigenic response was induced in a subhuman primate, but the tumor was not typical of liver tumors associated with aflatoxin carcinogenesis in the rat, and administration of the toxin included the i.m. route. Q. Is the liver the only target organ for aflatoxin carcinogenesis? A. The possibility of aflatoxin-induced tumors of the rat kidney, rat colon, rat and mouse lung. and hamster lacrimal gland has been demonstrated. Dose levels were high compared to those needed to induce liver cancer in rats, confounding factors were introduced in all experiments. and liver lesions were always part of the pathology. Q. Is there an increased risk during the prepartum or preweaning periods? A. Limited information with hamsters showed a relatively high single dose caused terata. There were no dehvered terata with rats dosed with high levels over the entire vulnerable period, but

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PARK AND STOLOFF there was some evidence of oncogenesis from exposure of the foetus through the placenta or the pups through the milk. Q. Is aflatoxin per se the carcinogen? A. There is good inferential evidence that a liver metabolite(s) of aflatoxin B, , probably the 23 epoxide, is the active carcinogen in the rat. Q. Are there any differences in the metabolism of allatoxin by livers of animals resistant and susceptible to agatoxin carcinogenesis, and how do these differences relate to man? A. In vim experiments, although in some cases producing contradictory results, show major differences in rate of aflatoxin metabolism and pattern of metabolic products formed by liver preparations of the various species studied. The aflatoxin metabolism pattern of human liver is generally different from that of the rat, and most nearly resembles that of the monkey. Q. Is there any epidemiological evidence relating to the susceptibility ofman to aflatoxin carcinogenesis? A. All 5 studies of aflatoxin ingestion in areas having local populations with relatively high rates of liver cancer show a positive correlation, but provide no basis for a conclusion that aflatoxin is a causative factor. Q. Are there any other known causes of liver cancer that could affect the epidemiology findings? A. The populations included in the epidemiological studies could have been exposed to hepatocarcinogens other than aflatoxins, e.g. pyrrolizidine alkaloids, selenium compounds, alcohol. None of the studies checked for confounding factors. Q. Does the picture of liver, kidney or colon cancer in the U.S. indicate any relation to aflatoxin exposure? A. Using the U.S. Southeast as an area of probable high exposure to aflatoxin compared to the remainder of the country, cancer incidence rate data from state and county cancer registers, and cancer mortality maps by county, the data show a negative correlation between the expected exposure to allatoxin and incidence of liver, colon or kidney cancer.

Another result of the FDA information gathering effort was a conference in 1975 of international experts to discuss “mycotoxins in human and animal health.” The proceedings of this conference (Rodricks et al., 1977) added to the body of information summarized above and, with continued additions supporting these summaries, were used in the 1978 “assessment of estimated risk-from aflatoxins-in peanut products.” At the same time that estimates of human exposure to aflatoxin from direct consumption of contaminated commodities were being developed, the possibility of exposure from aflatoxin residues in tissues of animals that had consumed contaminated feed was being examined. By 1975, sufficient information had been developed on the effects of aflatoxins, and a number of other mycotoxins, on livestock to warrant the compilation of An Encyclopedic Handbook (Wyllie and Morehouse, 1977- 1978) on the subject. The development of suitable analytical methods and the interest in aflatoxin metabolism had also resulted in a reasonably good body of information on the residues that could be expected in the tissues of poultry, swine, and cattle, including milk and eggs (Rodricks and Stoloff, 1977; Stoloff, 1979). This information was presented to an FDA task force on mycotoxins in feed with the conclusion that, except for aflatoxin M in milk, subclinical levels of aflatoxin in feed should not result in detectable (>O. 1 ppb) aflatoxin in edible tissue when normal preslaughter feed withdrawal procedures were exercised. An observation was also made that based on the then known frequency distribution of aflatoxin Ievels in southeastern corn and in southwestern cottonseed meal (Stoloff, 1976a), a feed use guideline of 100 ppb for aflatoxin in corn and 300 ppb for cottonseed meal would permit the utilization of the major portion of the Southeast corn crop and the Southwest cottonseed meal production, and that these aflatoxin levels in corn and cottonseed meal as normally

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used in mixed feeds would result in exposure to aflatoxin well below that found to cause harm to mature animals. The meager information concerning immature livestock indicated that compared to mature animals they were more susceptible to allatoxin toxicosis. Though the evidence was not sufficient for a firm judgment, in light of the small quantity of feed involved the prudent recommendation was made that existing guidelines be retained for starter rations. The recommendations for revised guidelines for aflatoxin in feed lay dormant until 1977. In that year, adverse weather conditions in the Southeast resulted in an unusually poor corn crop contaminated with a high incidence and level of aflatoxin. Responding to pleas from the commissioners of agriculture of the affected states, the FDA recalled the old recommendations of its science staff and told those states “that intrastate [emphasis added] corn containing up to 100 ppb aflatoxin may safely be used for animal feed for mature poultry and swine, and mature, non-milk-producing beefcattle. . . .” The same advice was contained in a notice (Food and Drug Administration, 1978b) that provided an exemption under specified conditions from the normal blending prohibition. The FDA limited this advice to intrastate operations, because “FDA cannot monitor the flow of corn in interstate commerce to the extent necessary to ensure that corn is used in accordance with the terms of the exemption.” When, again in 1980 and in 1982, adverse weather conditions in the Southeast resulted in corn crops badly contaminated with aflatoxin, the FDA did not confine to intrastate corn its advice concerning the safe use of corn with up to 100 ppb aflatoxin for animal feed, but building on its experience with the 1977 corn crop, provided notice (Food and Drug Administration, 198 1, 1983) of specified conditions under which interstate blending and shipment of corn with up to 100 ppb aflatoxin would be allowed. But, in each notice the exemptions were confined to corn from the specified crop year. (For those unfamiliar with the FDA blending prohibition, it is based on two concepts, one legal, the other technical. The legal concept is that mixing an adulterated product with a clean product makes the mixture adulterated: the technical concept is that dilution of an adulterant by mixing with clean product does not reduce the total adulterant load on the exposed population. For aflatoxin in feed, when the human population is considered to be the one exposed, blending allows destruction of the aflatoxin by the animals’ metabolic processes when the aflatoxin level is sufficiently low to be handled by the animal.) In 1983 a draft notice was prepared to set more practical conditions for interstate blending and shipment of corn with up to 100 ppb aflatoxins, and make them more generally applicable, but final action was postponed because the suit by the Community Nutrition Institute had brought into question the legality of this action. In 198 1, adverse weather conditions again forced an FDA action. In that year cottonseed in Arizona was so badly contaminated with aflatoxin that most of the meal from oil crushing operations contained aflatoxins in excess of the 20 ppb guideline. Cottonseed meal is an important economic factor, influencing the price of fiber and oil obtained from that crop. On the urgent request from the state of Arizona, the FDA again made use of the 1975 task force recommendation, and published a notice (Food and Drug Administration, 1982) that the “agency has determined that the action level for aflatoxins in cottonseed meal as an animal feed ingredient for beef cattle, swine, and poultry should be established at 300 ppb.”

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An offshoot of the 1977 problem

with aflatoxin in corn in the Southeast was the establishment of an action level for aflatoxin Mi in milk (Food and Drug Administration, 1977). As noted in a review of this subject (Stoloff, 198Oc), aflatoxin MI is a major metabolite of aflatoxin B, . Among other routes of excretion it appears in the milk of lactating mammals as a small fraction of the aflatoxin B, ingested. Experiments with rainbow trout and rats indicate that aflatoxin M, is a much less potent carcinogen than Bi . Although there is no rational basis for concern, health authorities in a few southeastern states inquired about the possibility of aflatoxin M in milk as a result of the unusually high level of aflatoxin in corn that year. A crash survey by FDA of milk produced in four southeastern states in November of 1977 found detectable (>O. 1 ppb) aflatoxin M in 63% of 302 samples, in 80% of 75 samples from one of those states, and in one or more of the samples from 84% of the bottling plants represented by the samples. At the insistence of state health authorities that, in the light of these findings, the FDA provide guidance, the FDA concluded that “[blased on available data, it is not possible to establish with certainty the level of human exposure to aflatoxin M, that is without risk to human health. Moreover, the special role of milk in the diet of the young, who, from studies conducted in animals, are expected to be more susceptible than adults to the toxic effects of aflatoxins, would lead to the conclusion that aflatoxin M, in milk be kept as low as possible.” The FDA concluded further that, although establishing an action level at 0.1 ppb, the then lowest practical analytical limit, would achieve this goal, enforcement of this level would, according to the survey results, “cause 60 percent of the milk supply produced in the Southeast to become unlawful.” The strategy then became the practical matter of discouraging the use of aflatoxin-contaminated feed. An action level of 0.5 ppb which, according to the survey results, would cause but 6% of the milk supply to be unlawful was established with this end in mind. FDA monitoring of the milk supply subsequent to this action showed that it did have the desired effect. Milk samples from the state that before the action had an 80% incidence of detectable aflatoxin now had an 86% incidence of no detectable aflatoxin. The natural calamities, and the FDA responses to them, demonstrated beyond doubt that the Agency needed the flexibility of action under Section 402(a)(l), as originally interpreted, to regulate permissible levels of natural toxicants, but they also demonstrated that the Agency responds much faster to political pressure than to the pressure of advancing knowledge. THE

AUDIT

YEAR

(1985)

Reviews and assessments that were presented at a symposium on mycotoxins or appeared in print in 1985, and the state of the information base at that point in time, make that year a suitable one for an audit of the risks to man and his domestic animals from ingestion of aflatoxin. Nothing that has been published since 1985 to this writing alters the picture that will be presented here. At the Sixth International Symposium on Mycotoxins and Phycotoxins, sponsored by the International Union of Pure and Applied Chemistry (IUPAC), two FDA scientists presented the rationale (Park and Pohland, 1986) that had been the basis for the FDA guidelines for aflatoxin in corn and cottonseed meal for animal feed; and a retired FDA scientist presented “A Ratio-

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nale for the Control of Aflatoxin in Human Foods” (Stoloff, 1986) supporkd by a hazard evaluation and risk analysis based on the evidence that aflatoxin is not a likely human carcinogen, but is a demonstrated human hepatotoxin. In a published review of the epidemiology of liver cancer (Wagstaff, 1985), an active FDA scientist drew a similar, though convolute, conclusion that “the evidence at present does not support the claim that prevention of aflatoxin contamination is the best hope of controlling liver cancer,” but “if conclusive evidence is not forthcoming, these chemicals are still acutely toxic and should be controlled.” The subject of a guest editorial (Blumberg and London, 1985) in the Journal of the National Cancer Institute was that “[a] convincing body of evidence now exists to support the hypothesis that chronic infection with HBV [hepatitis B virus] is required for the development of most cases of primary liver cancer in humans.” This conclusion was accepted by a research group (Van Rensburg et al., 1985) that had for a considerable period of time been investigating the hypothesis that aflatoxin might be a cause ofprimary cancer ofthe liver in African populations. Their current hypothesis with regard to aflatoxin, which they attempt to support in their latest paper, is that acute aflatoxicosis, superimposed on chronic HBV infection, is the trigger that converts liver damage due to HBV into hepatocellular carcinoma. The FDA rationale for control of aflatoxin in animal feed as presented in 198.5 (Park and Pohland, 1986) had not changed appreciably since 1977. It was still based on the premise that “until demonstrated otherwise, any animal carcinogen should be considered a human carcinogen, and that, as an unavoidable carcinogenic contaminant, aflatoxin should be controlled at the lowest practical level.” This premise, applied to the regulation of aflatoxin in animal feed, requires that levels in feed result in toxicologically insignificant levels of allatoxin and/or its metabolites in edible tissues. In addition to aflatoxins B, and M, , which had been considered potential tissue residues in 1977, information on the B, metabolite aflatoxicol had been added by 1985; aflatoxicol had been shown to be almost as carcinogenic as aflatoxin B, in the rat and rainbow trout. Data on aflatoxin residues in animal livers were used as the most sensitive indicator of residues in body tissue, and a level in tissue of 0.1 ppb was considered to be the practical limit both of determination and of toxicological significance. The best estimates from published data were used to calculate the ratio of the aflatoxin level in feed to the expected level in livers of cattle, swine. and poultry, and in cows milk and chicken eggs (Table 1). When these estimates were combined with the maximum use levels in feed of corn, peanut meal. cottonseed meal, and cottonseed (Table 2), it was possible to calculate the aflatoxin level in each of these commodities that would be expected to result in a tissue residue of 0.1 ppb (Table 3). These calculations showed that, except for milk, levels of aflatoxin contamination so high as to be rarely, if ever, encountered would be needed to produce tissue residues greater than 0.1 ppb. The limiting factor would be the effect of aflatoxin on animal health. The authors cite the actions taken by the FDA in 1982 and 1983 (see preceding section) to allow corn with up to 100 ppb aflatoxins and cottonseed meal with up to 300 ppb aflatoxins to be used in feed for mature, nonlactating animals, without mentioning that these numbers were derived from frequency distribution plots of aflatoxin levels in these commodities, although frequency distribution plots of aflatoxin levels in corn, cottonseed, cottonseed meal, and peanut meal were part of the presentation. They then note that these maximum levels would be of no toxicological

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PARK AND STOLOFF TABLE 1 RELATION

OF AFLATOXIN

LEVEL IN FEED TO AFLATOXIN

RESIDUE

LEVELS IN EDIBLE

TISSUES

Animal

Tissue

Aflatoxin

Feed/tissue ratio”

Beef cattle Dairy cattle

Liver Milk

Swine Layers Broilers

Liver Eggs Liver

B, MI Aflatoxicol B, BI J%

14,000 15 195,000 800 2,200 1,200

Note. From Park and Pohland (1986). By permission of Elsevier Science Publishers. a Level of aflatoxin B, in feed divided by the level of the specified aflatoxin in the specified tissue.

significance to the ingesting animals (Table 4), although the authors expressed reservations concerning possible immunosuppressive effects of aflatoxin. A review of the literature, made since that reservation was expressed, provides no support for that concern. The review found that aflatoxin affected the immune systems of cattle, swine, and poultry only at levels that produced clinical signs of aflatoxicosis, and that the effect was rapidly reversible on removal of the contaminated feed. The rationale for control of aflatoxin in human foods (Stoloff, 1986) was an attempt to show what the FDA could do with current information, if there were no political, legal, or bureaucratic restraints. The hazard evaluation in that paper noted the marked differences between species in their susceptibility to aflatoxin carcinogenesis, that an aflatoxin metabolite was the most likely proximate carcinogen, and that the rate and route of aflatoxin metabolism varied among species. It also presented data calculated from in vitro studies of aflatoxin activation with liver tissue of species susceptible and resistant to aflatoxin carcinogenesis, and including human liver tissue (Table 5). These data showed a strong correlation between susceptibility to aflatoxin carcinogenesis and the degree of activation, whether activation was measured by

TABLE 2 MAXIMUM

USE LEVELS IN U.S. MIXED FEEDS OF COMPONENTS SUSCEPTIBLE TO AFLATOXIN CONTAMINATION

-

Maximum use levels (70 by weight) Animal

Corn

Peanut meal

Cottonseed meal

Cottonseed

Beef cattle Dairy cattle Swine Layers Broilers

15 56 7s 68 66

10 14 11 12 13

Ii 14 5 9 10

10 20 -

Note. From Park and Pohland (1986). By permission of Elsevier Science Publishers.

AFLATOXIN

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TABLE 3 REQUIRED AFLATOXIN B, LEVELS IN FEED COMPONENTS FOR 0.1 ppb LEVELS OF AFLATOXINS IN EDIBLE TISSUES Contamination

level (B, , ppb)

Ration

Corn

Peanut meal

Cottonseed meal

Cottonseed

Beef cattle Dairy cattle Swine Layer Broiler

1800

14,000 54 730 1,835

12,725 54 1,600 2,445 1.200

14,000 38 -

Note.

14 105 325 180

925

From Park and Pohland ( 1986). By permission of Elsevier Science Publishers.

DNA binding, mutagenicity to Salmondla typhimurium. or inhibition of RNA synthesis, phenomena that are related to the carcinogenic process. Activation of aflatoxin B, by human liver tissue was similar to the activation produced by liver tissue of the most resistant species in all of the four independent studies that were conducted. In lieu of controlled in uivo studies with humans, the hazard evaluation used epidemiological studies to bridge the gap between in vitro and in vivo observations. The hazard evaluation in the rationale paper also noted what has already been mentioned about the flaws in the epidemiological studies of Asian and African populations that showed a positive correlation between aflatoxin ingestion and incidence of liver cancer, but in more detail; an active FDA scientist (Wagstaff, 1985) also noted the flaws. The data from these studies were then compared with the results of a study of liver cancer in the United States (Stoloff, 1983) by tabulation (Table 6) for statistical strength and graphically (Fig. 1) for cancer-risk/aflatoxin-exposure comparisons; the graphic comparisons included all studies with rats in which liver cancer had been observed. TABLE 4 TOXKOLCKXAL Animal Dairy cattle Beef cattle Swine Chickens“ Chickensb Sheep Turkeys Ducks (1 day)

Emcrs

Oral LDSo bw/kg MY N OS-l.0 0.6 2.0 6.3 2.0 0.5-l .o 0.4-0.6

Note. From Edds (1979). a New Hampshires. ’ Rhode Island Reds.

OF AFLATOXIN B, IN LIVESTOCK AND POULTRY Estimated no-effect level (ppb feed) 200 300 200 250 -

100

-

Toxicological effects(level in feed, ppb; exposure, weeks)

I

Stunting, decreased feed efficiency, liver damage

(200+)

Reduced hatchability Fever Liver damage, death

(600: 33)

(7OOf) (200-400; 9) (200-800; IO) (140) (300-600; 1)

122

PARK AND STOLOFF TABLE 5

RELATIVE AFLATOXIN B, ACTIVATION BY LIVER PREPARATIONS !=ROM VARIOUS SPECIES COMPARED TO THE RAT, AS MEASURED BY DNA BINDING,” 5’. typhimurium MUTATION TESTS,” OR INHIBITION OF

RNA SYNTHESIST Ratio (number of livers tested) Species Duck Rat Rabbit Green monkey Rhesus monkey Hamster Mouse Human

DNA binding 1.00(8)

0.33 (4) 0.04 (4) 0.11 (6)

Inhibition of RNA synthesis

Mutation I .oo (5) 0.84 (5) 0.41 (9) 0.47 (5) 0.06 (7)

4.24 (3) 1.oo (9)

1.00 (4)

0.41 (5)

0.52 (5)

0.24 (9) 0.14 (5)

0.14 (4) O.OOd(2)

Note. From Stoloff ( 1986). By permission of Elsevier Science Publishers. a Calculated from data published by Booth et al. (198 1). b Calculated from data published by Norpoth et al. ( 1979) and Hsieh et al. ( 1977). ‘Calculated from unpublished data provided by L. Friedman, U.S. FDA. d No measurable inhibition at aflatoxin concentrations used.

The study of liver cancer in the United States, designed to avoid most of the problems with the Asian and African population studies, had much greater statistical power than those studies. It showed an almost flat response over an aflatoxin exposure range 100X that of any of the other studies, with the highest U.S. exposure similar in level to the highest exposure in the other epidemiological studies and to the lowest exposure in the rat studies. None of the epidemiological studies were able to control for confounding factors such as industrial chemical exposure, chronic alcohol consumption, or chronic infection with HBV. As noted in the introduction to this section, and in the hazard analysis of the rationale paper, a convincing body of evidence now exists to support the hypothesis that chronic infection with HBV is required for most cases of primary cancer of the liver in humans. HBV is a more likely confounding factor in Africa and Asia than in the United States, given the relative prevalence of HBV infection in these areas, while chronic alcoholism is a more likely confounding factor in the United States, particularly in the rural populations that were the target of the U.S. study. The hypotheses that ingested aflatoxin interacts with chronic HBV infection to induce liver cancer either as an acute hepatotoxin (Van Rensburg et QZ., 1985) or by affecting the immune system (Lutwick, 1979) do not stand up to scrutiny. As mentioned above, studies with livestock, the only studies of aflatoxin immunosuppression that have been published, showed effects on the immune system only at aflatoxin levels that produced other clinical signs of aflatoxicosis. Thus, both hypotheses require exposure to acutely toxic levels of aflatoxin, and the aflatoxin exposure data show no such levels; rapid metabolism of aflatoxin precludes toxicity from cumulative exposures, and complete recovery of animals, including humans, from toxic exposures has been demonstrated (see

AFLATOXIN

123

CONTROL

TABLE 6

MAGNITUDEOFTHEDATABASESFOREACHOFTHEEPIDEMIOLOGICALSTUDIESTHATRELATEDTHE RATEOFOCCURRENCEOFPRIMARYLIVER CELLCANCER(PLC) TORATEOFAFLATOXIN INGESTION Aflatoxin analyses Country and region Thailand” Songkla Ratburi Singburi KenyabHigh Middle Low Mozambique’ Swazilandd Highveld Middleveld Lowveld Lebombo United States’ Southeast North and West

Male population at risk

PLC cases (years)

Commodity

No. of analyses (years) 922(i) 1005 (I) 1021(l)

46,976 46,782 -

Historical

Meals Meals Meals

18,394 75,138 30,949 66,000

1 13 30 185

(4) (4) (4) (8)

Meals Meals Meals Meals

808 (2) 808 (2) 816 (2) 880(l)

9 (5)

Meals Meals Meals Meals

298(l) 288(l) 288(l) 192(l)

48.628 69,136 45,814 8.713 483,000 2,246,OOO

2 (1)

5 (1)

24 (5) 35 (5) 4 (5) 1286(g) 5278’(g)

Retrospective projection from current corn and peanut contamination and past consumption surveys

Note. From Stoloff (1986). By permission of Elsevier Science Publishers. a Shank et al. (1972a.b). h Peers and Linsell(1973). ’ Van Rensburg et al. ( 1974). d Peers et al. (1976). ‘Stoloff(1983). ‘Correction of original table in which aflatoxin risk rates rather than caseswere inadvertently used.

Stoloff, 1986). The attempt to link acute aflatoxicosis with HBV-associated liver cancer through epidemiological evidence (Van Rensburg et al., 1985) has to make an unlikely, but implied, assumption: the incidence of HBV infection and the frequency distribution of aflatoxin contamination levels are dependent variables. It also fails to consider all the data. For example, a small study of Greenland Eskimos was cited as evidence that chronic HBV infection with unlikely aflatoxin exposure results in no liver cancer, but omitted was a larger study (Heyward et al., 198 1, 1982) of Alaskan Eskimos in which the usual association between HBV infection and liver cancer was observed. From the comparative metabolism and epidemiological evidence, the hazard evaluation of the rationale paper concluded that “risk of liver cancer in humans from exposure to aflatoxin appears to be exceedingly small, if there is any risk at all.” Another conclusion was that since liver tumors were found in all animal studies in which tumors of other organs (kidney. colon, and lung) were observed, the doses required

PARK AND STOLDFF

124

10-l

10-4

10-l

100

lo1 Aflatoxin

102 B1 dose,

rig/kg

lo3

lo4

bw/day

FIG. 1. Relation between aflatoxin intake and crude lifetime risk rates of primary liver-cell cancer for male rats and for male humans. Transformations from human incidence rates to lifetime risk are from Carlborg (1979) and from aflatoxin levels in rat diets to body weight exposure on the basis that 1 ppb is equivalent to 92 n&kg body wt. Rat relations are calculated from data in the following: &, Wogan and Newberne (1967)-Fischer strain;m, Butler and Barnes (1968)-Porton strain; +, Newberne and Williams (1969)-Charles River strain; v, Nixon et al. (1974)--Fischer strain; A, Nixon el ai. ( 1974)-Wistar strain; 0, Wogan et al. (1974)-Charles River strain. Human relations are calculated from data in the following: X, Shank er af. ( 1972a,b)-Thailand; +, Peers and Linsell ( 1973)-Kenya; a, Van Rensburg ef at. ( I974)Mozambique; 0, Peers et al. (1976)-Swaziland; 0, Stoloff (1983)-United States. From Stoloff (1986). By permission of Elsevier Science Publishers.

for other organ involvement were high compared to doses that elicited only liver tumors, and there was no excess over the general population of tumors of any of the other organs in the Southeast U.S. population that had been exposed to high levels of aflatoxin, there was no basis for concern that atlatoxin might cause cancer in organs other than the liver. These conclusions applied equally to atlatoxin M, , a less potent rat carcinogen than B, , and which was an unmeasured burden added to aflatoxin B, in the epidemiological study of allatoxin and liver cancer in the U.S. Southeast (Stoloff, 1983). The hazard evaluation in the rationale paper went on to point out that there is ample epidemiological evidence humans are not immune to acute aflatoxicosis. In one incident there were 272 hospital admissions with clinical symptoms of aflatoxicosis, a 27% mortality among those admissions, and a daily ailatoxin Br intake (from corn) estimated to have been at least 55 &kg body w-t for an undetermined number of days. A 1O-year follow-up of this incident found the survivors fully recovered with no ill effects from the experience. In a second incident, again related to atlatoxin in corn, there were 20 hospital admissions, a 60% mortality, and an estimated daily intake of at least 38 &kg body wt for an undetermined number of days. A third report, of an attempted suicide, provides an estimate of a no-effect level, In this inci-

AFLATOXIN

CONTROL

125

dent a female laboratory technician consumed 12 pg/kg body wt per day over a 2day period, and 6 months later 11 pg/kg body wt per day over a 14-day period. The amounts she confessed using coincided with those mi&ng from laboratory stock. Outside of transient rash, nausea, and headache there were no immediate ill effects, and on a 14-year follow-up the physical examination and blood chemistry, including tests for liver function, were all normal. The rationale for control of aflatoxin in human foods then went on to point out the survey and epidemiological evidence show that the major risk of harm from aflatoxin comes from avoidable contamination of stored and prepared foodstuffs at the local and household levels, and that management of this type of risk can be achieved best through a program of instruction and education. For commodities subject to regulatory control in the United States, the major human exposure to aflatoxin comes from milled corn products and peanut products. While the marketing and consumption pattern for peanut products in the United States creates a relatively uniform exposure distribution, the potential for aflatoxin contamination of milled corn is greatest, by far, in the Southeast. Contamination of milk with aflatoxin M is also a regional problem, related to aflatoxin contamination ofdairy feedstuffs: corn in the U.S. Southeast and cottonseed in the Southwest. The rationale continued that if the evidence is accepted that aflatoxin is not a likely human carcinogen, “there is no need to argue over the debatable proposition that no amount of a carcinogen can be allowed in the food supply. The consideration then becomes whether to start with the exposure data and relate it to the health risk or vice ver.su.” It is generally more satisfying to construct an argument from the firmest data base, which in the United States is the exposure data. This was the same reasoning used in 1975 to propose the action levels for aflatoxin in animal feed components. Accordingly, updated frequency distribution curves for aflatoxin in corn (Fig. 2) and aflatoxin in peanuts (Fig. 3) were used to determine maximum tolerated levels of aflatoxin that would allow use of all but the most badly contaminated portion of each crop as judged by the slope of the distribution curves, and consumption data were obtained from the most recent ( 1977- 1978) USDA household survey estimates. Corn contamination and consumption estimates were for the U.S. Southeast (Southeast corn accounts for ca 8% of the total U.S. corn crop). In addition, all contamination data were converted from total aflatoxins (B, + Bz + G, + G2) to aflatoxin B1 for the following reasons: Since the original FDA decision to use total aflatoxins, it had become evident that aflatoxin Br was far more prevalent and pharmacologically potent than the other aflatoxins that occurred as natural contaminants of crops; most toxicological data are in terms of aflatoxin BI ; and chemical analysis is greatly simplified when B, alone is measured. Exposure calculations were presented (Table 7) for a hypothetical rural Southeast individual who consumes cooked products made from either degermed or full-fat milled corn which had been made from grain contaminated at proposed maximum tolerated levels for aflatoxin B, of 100 and 200 ppb (permitting use of 88 and 95%, respectively, of the average year crop), or contaminated at the crop average (33 and 44 ppb, respectively) under these two maxima. Consumption data were used either from the latest USDA household survey estimates (U.S. Department of Agriculture, 1983) or from a year ( 19 16) when consumption was at a recorded high.

126

PARK AND STOLOFF

Total

aflatoxins,

nglg

FIG. 2. Frequency distribution (cumulative percentage less than the indicated level) of total aflatoxins levels in shelled corn in the state of North Carolina. Data are from 8653 farmer-submitted and elevatorsurvey samples assayed by the state analysts for the 6 crop years 1977-1978, 1980- 1983 (L. Blanton, private communication, 1983). Center plot is the average of the 6 years; boundary plots are for the year (1982) with the least aflatoxin contamination and the year ( 1977) with the most contamination. From Stoloff (1986). By permission of Elsevier Science Publishers.

Exposure calculations were made similarly for a hypothetical 70-kg individual in the United States who consumed the 1977-1978 peanut products average of 8.4 g/ day. The proposed maximum tolerated aflatoxin B, level for raw shelled peanuts was 35 ppb (equivalent to 50 ppb total aflatoxins), a level that would allow use of

Total

aflatoxins,

nglg

FIG. 3. Frequency distribution (cumulative percentage less than the indicated level) of total aflatoxins levels in raw shelled peanuts produced in the United States. Data are from crop year reports of the Peanut Administrative Committee. Center plot is the average for the 12 crop years 1973- 1984; boundary plots are for the year (1981) with the least aflatoxin contamination and the year (1980) with the most aflatoxin contamination. From Stoloff (1986). By permission of Elsevier Science Publishers.

AFLATOXIN

127

CONTROL

TABLE 7 ESTIMATED EXPOSURE” TO AFIATOXIN B, FROM CONSUMPTION OF COOKED MILLED CORN IN RURAL. U.S. SOUTHEAST, ASSUMING PROPOSED MAXIMUM TOLERATED AFLATOXIN B, LEVELS IN SHELLED CORN OF 100 AND 200 ppb, AND FREQUENCY DISTRIBUTION OF AFLATOXIN IN SHELLED CORN Is THAT OFYEAR WITH MOST AFLATOXIN CONTAMINATION (FIG. 2) Aflatoxin B, exposure (rig/kg body wt) Assumed contamination: Maximum tolerated level (ppb):

Crop average

Maximum tolerated level

100

200

100

200

1.5 12

3.4 27

6.9 55

Corn meal

Consumption basis

Degermed

1977-1978 1916

1.1 9.1

Full fat

1977-1978 1916

9.4 75

13 100

29 230

57 460

Note. From Stoloff ( 1986). By permission of Elsevier Science Publishers. ’ Based on 70-kg adult consuming milled corn in an amount estimated at 25 g/day for recent years ( I977- 1978) and at 200 g/day for a period ( 19 16) when consumption was at a recorded high. Total aflatoxins in corn was converted to aflatoxin B, by assuming B, is 87% of total. Aflatoxin B, in consumed degermed corn meal was based on 88% milling and 20% cooking losses; aflatoxin B, in consumed full-fat corn meal was based on 20% cooking loss only. See Stoloff (1983) for consumption, conversion, and aflatoxin loss justifications and U.S. Department of Agriculture (1983) for recent consumption data.

approximately 98% of the crop in an average year, 96% in a bad year, and virtually all of the crop in a good year. On the assumption that the peanuts processed had been contaminated at the proposed maximum tolerated level, and the processing loss was 50% of the allatoxin, the calculated daily exposure to aflatoxin B, would be 3 rig/kg body wt. A worst case scenario was presented as a 35-kg child who consumed at one meal a half pound of peanut butter processed from peanuts contaminated at the maximum tolerated level. This situation would result in an aflatoxin B, exposure of 110 ngf kg body wt. Aflatoxin M1 in milk was also considered on the assumption that aflatoxins B, and M, have the same acute toxicity. If the level of aflatoxin M in milk were controlled only by the maximum level of aflatoxin B, tolerated by the cow before adverse effects were evident and by the cow’s metabolic processes, the level of aflatoxin M would be in most situations below 1 ppb; the maximum reported value for aflatoxin M in a commercial milk is 8 ppb. A worst case scenario of a 35-kg child who consumed each day 1 quart of milk contaminated with 8 ppb aflatoxin M would result in a daily exposure to aflatoxin M of 220 rig/kg body wt. The author’s conclusion from this data was that average consumption of milled corn products, peanut products, or milk contaminated at the proposed maximum tolerated levels would result in aflatoxin exposure levels well below those that resulted in adverse effects in the recorded aflatoxin poisoning episodes. The exposure levels in each of the worst case scenarios were still comfortably below the levels that caused adverse effects. On the remote chance that two of the worst cases should occur simul-

128

PARK AND STOLOFF

taneously, the daily exposure to allatoxin would be more than one order of magnitude below the level that had minimum observable effect on a self-dosed female. On the even more remote chance that the three worst case scenarios happened simultaneously, the exposure would still be below that incurred by the self-dosed female. The rationale concluded that “[w]ith these data a regulator can now make subjective judgements that balance the risks and the benefits from regulated maximum tolerated levels, or even, as indicated for aflatoxin M in milk, no regulation but that of mother nature. It is also possible from these data to determine where regulatory surveillance will provide the most protection for the exposed public.” Whether the FDA will pay heed to this advice without political or economic pressure to do so is problematic, based on past performance. REFERENCES BAUER, F. J., AND PARKER, W. A. (1984). The aflatoxin problem: Industry-FDA-USDA cooperation. J. Assoc. Ofl Anal. Chem. 67,3-l. BLUMBERG, B. S., AND LONDON, W. T. ( 1985). Hepatitis B virus and prevention of primary cancer of the liver (guest editorial). J. Nail. Cancer Inst. 74,267-273. BOOTH, S. C., B~SENBERG, H., GARNER, R. C., HERZOG, P. J., AND NORPOTH, K. (198 I). The activation of aflatoxin B, in liver slices and in bacterial mutagenicity assays using livers from different species including man. Carcinogenesis 2, 1063-1068. BUTLER, W. H., AND BARNES, J. M. (1968). Carcinogenic action of groundnut meal containing atlatoxin in rats. Food Cosmet. Toxicol. 6, 135- 14 1. CAMPBELL, T. C., AND STOLOFF, L. (1974). Implication of mycotoxins for human health. J. Agric. Food Chem. 22, lOO6-1015. CARLBORG, F. W. (1979). Cancer, mathematical models and aflatoxin. Food Cosmet. Toxicol. 17, 159166. EDDS, G. T. (1979). Aflatoxins. In Conference on Mycofoxins in Animal Feeds and Grains Related to Animal Health (W. Shimoda, Ed.), pp. 80-l 55. FDA Center for Veterinary Medicine, Rockville, MD. FISCHBACH, H. (1984). Coping with the aflatoxin problem in the early years. J. Assoc. Off: Anal. Chem. 67, l-3. Food and Drug Administration (1974). Poisonous or deleterious substances in peanuts, evaporated milk, fish and shellfish-Proposed rules. Fed. Regist. 39,42,738-42,752. Food and Drug Administration (1977). Aflatoxin contamination of milk: Establishment of action level. Fed. Regist. 42,6 1,630. Food and Drug Administration (1978a). Aflatoxins in shelled peanuts and peanut products used as human foods, proposed tolerance: Reopening of comment period. Fed. Regist. 43,8808. Food and Drug Administration (1978b). Aflatoxin contaminated corn-Limited exemption from blending prohibition. Fed. Regist. 43,14,122- 14,123. Food and Drug Administration (198 1). Aflatoxin contaminated corn: Limited exemption fromprohibition of interstate shipment and blending. Fed. Regist. 46,7447-7449, Food and Drug Administration (1982). Aflatoxins in cottonseed meal; revised action level. Fed. Regisf. 47,3307-3308. Food and Drug Administration (1983). Aflatoxin contaminated corn; policy regarding interstate shipment of corn harvested in 1983. Fed. Regist. 48,53,175-53,176. Food and Drug Administration (1988). Action levels for added poisonous or deleterious substances in food. Fed. Regist. 53,5043. HEYWARD, W. L., BENDER, T. R., LANIER, A. P., FRANCIS, D. P., MCMAHON, B, J., AND MAYNARD, J. E. (1982). Serological markers of hepatitis-B-virus and alpha-fetoprotein levels preceding primary hepatocellular-carcinoma in Alaskan Eskimos. Lancet 2,889-89 1. HEYWARD, W. L., LANIER, A. P., BENDER, T. R., HARDISON, H. H., DOHAN, P. H., MCMAHON, B. J., AND FRANCIS, D. P. (198 1). Primary hepatocellular carcinoma in Alaskan natives, 1969-l 979. In?. 1. Cancer 28.47-50.

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HOEL, D. G. (1975). Estimation of risks of irreversible, delayed toxicity. J. Toxicol. Environ. Health 1, 133-151. HSIEH, D. P. H., WONG, 2. A., WONG, J. J., MICAS, C., AND REUBNER, B. H. (1977). In Mycofoxins in Human and Animal Health (J. V. Rodricks, C. W. Hesseltine. and M. A. Mehlman, Eds.), pp. 37-50. Pathotox Publishers, Park Forest South, IL. LUTWICK, L. I. (1979). Relationship between aflatoxin, hepatitis-B-virus, and hepatocellular carcinoma. Lancet

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NEWBERNE, P. M., AND WILLIAMS, G. (1969). Inhibition of aflatoxin carcinogenesis by diethylstilbestrol in male rats. Arch. Environ. Health 19.489-498. NIXON, J. E., SINNHUBER, R. O., LEE, D. J., LANDERS, M. K., AND HARR, J. R. (I 974). Effect of cyclopropenoid compounds on the carcinogenic activity of diethylnitrosamine and allatoxin B, in rats. J. Natl. Cancer

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NORPOTH, K., GROSSMEIER, R., -ENBERG, H., THEMANN, H., AND FLEISCHER, M. (1979). Mutagenicity of aflatoxin B, activated by S-9 fractions of human, rat, mouse, rabbit, and monkey liver toward S typhimurium TA 98. Int. Arch. &cup. Health 42,333-339, PARK, D. L., AND POHLAND, A. E. (1986). A rationale for the control of aflatoxin in animal feeds. In Mycotoxins and Phycotoxins (P. S. Steyn and R. Vleggaar, Eds.), pp. 473-482. Elsevier. Amsterdam. PEERS,F. G. (1967). Aflatoxin-A summary of recent work. Trop. Sci. 9, 186-203. PEERS, F. G., GILMAN, G. A., AND LINSELL, C. A. (1976). Dietary aflatoxins and human liver cancer. Int. J. Cancer

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PEERS,F. G., AND LINSELL, C. W. (1973). Dietary aflatoxins and liver cancer-A population based study in Kenya. Brit. J. Cancer 27,473-484. PEERS, F. G., AND LINSELL, C. A. (1977). Dietary aflatoxins and human primary liver cancer. Ann. Nun Aliment.

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RODRICKS, J. V.. HESSELTINE, C. W., AND MEHLMAN, M. A. eds. (1977). Mycotoxins in Human and Animal Health. Pathotox Pub., Park Forest South, IL. RODRICKS, J. V.. AND STOLOFF, L. (1977). AIlatoxin residues from contaminated feed in edible tissues of food-producing animals. In Mycotoxins in Human and Animal Health (J. V. Rodricks, C. W. He&tine. and M. A. Mehlman, Eds.), pp. 67-79. Pathotox Pub., Park Forest South. IL. SHANK, R. C., BHAMARAPRAVATI, N., GORDON, J. E., AND WOGAN, G. N. (1972a). Dietary aflatoxins and human liver cancer. IV. Incidence ofprimary liver cancer in two municipal populations in Thailand. Food Cosmet. Toxicol. 10, 17 l-l 79. SHANK, R. C.. GORDON, J. E., WOCAN, G. N., NONDASUTA, A., AND SUBHAMANI, B. (1972b). Dietary aflatoxins and human liver cancer. III. Field survey of rural Thai families for ingested aflatoxins. Food Cosmet. Toxicol. IO, 7 l-84. STOLOFF, L. ( 1972). What FDA is doing about the mycotoxin problem. Agri-Fieldman/Farm Technol. 28, 60a-63a. STOLOFF, L. (1976a). Incidence. distribution and disposition ofproducts containing allatoxins. Proc. Amer. Phytopathol.

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STOLOFF, L. (1976b). Occurrence of mycotoxins in foods and feeds. In Mycotoxins and Other Fung-ol Related Food Problems (J. V. Rodricks, Ed.), pp. 23-50. Amer. Chemical Sot.. Washington, DC. STOLOFF, L. ( 1979). Mycotoxin residues in edible animal tissues. In Interactions o$‘Mycotoxins in Animal Production (Proceedings of a Symposium, July 18, 1978). pp. 157-l 66. National Academy of Sciences. Washington, DC. STOLOFF, L. (1980a). Aflatoxin control: Past and present. J. Assoc. 08 Anal. Chem. 63, 1067- 1073. STOLOFF, L. (Ed.) (1980b). Mycotoxins Methodology, Sect. 26.076-26.082 and 26.084-26.089. Assoc. Offic. Anal. Chem., Arlington, VA. STOLOFF. L. (198Oc). Aflatoxin M in perspective. J. Food Prot. 43,226-230. STOLOFF, L. (1982). Mycotoxins as potential environmental carcinogens. In Carcinogens and Mutagens in the Environment, Vol. I., Food Products(H. F. Stich, Ed,), pp. 97-120. CRC Press, Boca Raton, FL. STOLOFF, L. ( 1983). Aflatoxin as a cause of primary liver-cell cancer in the United States: A probability study. Nutr. Cancer 5, 165- 186. STOLOFF, L. ( 1986). A rationale for the control of aflatoxin in human foods. In MycotoUxins and Phycotoxin.7(P. S. Steyn, and R. Vleggaar, Eds.), pp. 457-47 1. Elsevier. Amsterdam.

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