Acceptable daily intake: Inception, evolution, and application

REGULATORY

TOXICOLOGY

Acceptable

AND

PHARMACOLOGY

8,45-60

Daily Intake: Inception,

(

1988)

Evolution,

and Application

FRANK C. Lu Food Additives, Contaminants and Environmental Chemicals, Miami, Florida 33116-0916

Received September 28, I987

The acceptable daily intake (ADI) approach to toxicological evaluation was initiated by the Joint FAO/WHO Expert Committee on Food Additives in 1961. The procedure involves collecting all relevant data, ascertaining the completeness of the available data, determining the noeffect level using the most sensitive indicator of the toxicity, and applying an appropriate safety factor to arrive at the AD1 for man. This procedure was also adopted by the Joint FAO/WHO Meeting of Experts on Pesticide Residues later in 196 1. In the ensuing years, hundreds of food additives and pesticide residues have been evaluated and reevaluated by these two international expert groups. The ADIs, used nationally and internationally in the elaboration of food standards, have proved satisfactory in permitting the judicious use of these chemicals and in protecting the health of the consumer. The successof this endeavor over the years can be attributed to the dedication and hard work of the many international experts involved as well as to the cooperation of the chemical industry in submitting all relevant published and unpublished data. It is envisaged that this approach will continue to be followed in evaluating and reevaluating additives, pesticides, and contaminants, and that it will likely be extended to other situations where toxicological evaluation forms the scientific basis of control measures. 0 1988 Academic Press, Inc.

INTRODUCTION As a result of various socioeconomical and technological developments, man has been exposed to an increasing number of chemicals over the last few decades. Regulatory agencies in some countries have established standards and control measures to minimize the potential health hazards to the public. At an international level, the World Health Assembly, the governing body of WHO, expressed at its Sixth Session, the view that the increasing use of various chemical substances in the food industry had in the last few decades created a new public health problem which might usefully be investigated (WHO, 1953). As a result of this Resolution, WHO convened, in conjunction with FAO, a conference on Food Additives in 1955, which initiated the series of annual meetings of the Joint FAO/ WHO Expert Committee on Food Additives (JECFA), the first being held in 1956. At the earlier meetings, the Committee established general principles regarding the justified and unjustified conditions of use of additives, the need for adequate toxico45 0273-2300/88 $3.00 Copy&&t 0 1988 by Academic Press, Inc. All rights of reproduction in any form reserved.

46

FRANK

C. LU

logical investigation and evaluation, and guidelines for toxicological chemical, acute, short- and long-term effects and for carcinogenicity.

HISTORICAL

studies for bio-

BACKGROUND

1. Inception In 196 1, the Committee evaluated a number of antioxidants and antimicrobials. In doing so the Committee coined the term acceptable daily intake (ADI) and it was estimated for each chemical where the available data were adequate. The procedure for the determination of ADIs and their application in practice were described (WHO, 1962a). The concept and procedure for establishing ADIs in evaluating pesticide residue in food were adopted by a Joint FAO/WHO Meeting of Expert Bodies on Pesticide Residues (JMPR) later that year (WHO, 1962b). An AD1 was defined as “the daily intake of a chemical which, during an entire lifetime, appears to be without appreciable risk on the basis of all known facts at the time.” It is expressed in milligrams of the chemical per kilogram of body weight (mg/ kg) (WHO, 1962a). It is worth noting that the AD1 is qualified by the expression “appears to be” and “on the basis of all the known facts at the time.” These cautionary qualifiers are consistent with the view that it is impossible to be absolutely certain about the safety of a chemical and the AD1 may be revised in the light of new toxicologic data.

2. Evolution At the 196 1 meeting of JECFA, the Committee established a zone of “unconditional intake.” However, it considered the likelihood that many countries might have special problems and established also a zone of “conditional intakes” which were two to four times greater than the unconditional intakes. The Committee also suggested that the special circumstances that warrant the use of the conditional intakes as the upper limits should be fully discussed by a multidisciplinary group, including a toxicologist. After a few years, the Committee stopped establishing zones of conditional intakes on a routine basis, but where appropriate, “conditional ADIs” of food additives with specified conditions of use were allocated. Examples included nonnutritive sweeteners when used in dietetic foods (WHO, 1968). Conditional ADIs have also been allocated by JMPR to DDT for agricultural use in areas where no suitable alternative pesticides were available (WHO, 1970a), although the qualifier “conditional” was removed at a recent JMPR because it did not consider DDT a human carcinogen (FAO, 1985). The data reviewed were summarized by a member and have since been published (Coulston, 1985). Another example is amitrole, a herbicide, for which a conditional ADI was allocated with the proviso that its uses be restricted to those situations where residues in foods would be unlikely to occur (WHO, 1975a).

ACCEPTABLE

PROCEDURES

DAILY

47

INTAKE

FOR ESTABLISHING

ADIS

1. Relevant Data These fall into two major groups: chemical and biological. The former includes data on the identity and purity of the chemical, nature and level of impurities, stability, breakdown products, products formed between the chemical and food components, and technological uses and levels of use as well as data on the residue levels in foods and the main metabolites in the plants and food animals. These data are valuable not only in identifying the chemical to be used in the toxicological studies but also in determining the types of toxicological studies. For example, the major impurity and breakdown product of aspartame is diketopiperazine, detailed toxicological studies of which were carried out. Similarly, cyclohexylamine, a metabolite of cyclamate, was extensively studied. Urethane, a known carcinogen, was shown to be a breakdown product of diethylpyrocarbonate under certain conditions. As a result, JECFA recommended that the uses of this preservative be suspended where urethane is likely to be formed. As a general principle, JMPR requires relevant toxicological data on the major metabolites of pesticides in plants, especially if these metabolites are not found in the animals in which the toxicological data are generated. The uses and use levels are also important in determining the type of biological data needed. For example, artificial sweeteners are often used in soft drinks and are thus likely to be consumed in large quantities, especially by children. Consequently, extensive studies have been carried out on these substances. On the other hand, much less toxicological investigation was required for certain anticaking agents because of the limited use levels and their chemical nature. This principle also applies to substances occurring naturally in foods, including a large number of flavoring substances. With respect to the procedures for toxicological testing, guidelines have been provided by JECFA at its Second, Fifth, Sixth, and Tenth Reports (WHO, 1958, 1961, 1962a, 1967a), as well as several WHO Scientific Groups which dealt with specific subjects such as carcinogenicity, mutagenicity, and teratogenicity (WHO 1967c, 1969, 197 la). Summaries of the key points have been included as an Annex in the Seventeenth Report of JECFA (WHO, 1974). The data requirements of the JMPR are essentially the same as those for food additives. A few notable exceptions include the recognition that all pesticides are toxic to certain forms of life. Consequently, these chemicals require extensive toxicological testing. Certain organophosphorus insecticides have been shown to induce delayed neurotoxicity and/or potentiation of the effects of other pesticides. The possible existence of these effects is therefore also ascertained in appropriate studies. As a general rule, the biological data acquired are grouped under the headings in Table 1. The data that are listed under “observations in man” generally fall into two categories: (1) biochemical studies (absorption, distribution, metabolism, and reversible biochemical effect) and (2) clinical studies of poisoning cases and epidemiological studies. Guidelines, especially the precautions to be adhered to, have been stated repeatedly (e.g., WHO 1967b). Much less data are deemed necessary for certain groups of additives. These additives are generally components of foods or closely related chemicals. The principles

48

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C. LU

TABLE 1 CLASSIFICATION

OF BIOLOGICAL

DATA

Biochemical aspects-absorption, distribution, elimination (and storage); biotransformation; effectson biochemical parameters. Special studies-pharmacology, potentiation, neurotoxicity, reproductive function, teratogenicity, carcinogenicity (if not part of long-term studies), mutagenicity, toxicity of reaction products and impurities, etc. Acute toxicity studies-LDSO, signs of acute toxicity. Short-term toxicity studies. Long-term toxicity studies-studies covering the entire life span or over 50% of it. Observations in man-biochemical studies; clinical and epidemiological studies.

adopted by the Committee (WHO, 1982) used in evaluating these chemicals may be summarized as follows: (a) Enzymes.No toxicological data are required for enzymes obtained from edible parts of animals and plants and from microbes which are traditionally considered constituents of foods, provided that satisfactory chemical and microbiological specifications can be established. On the other hand, short-term toxicity studies are required for enzymes derived from nonpathogenic microbes commonly found as contaminants of foods, whereas long-term toxicity studies are required for enzymes derived from less well known microbes. (b) Food colors. Similarly, no toxicological data are required for the evaluation of natural food colors provided that they fall into the following categories: (1) They are to be used at levels not higher than those normally found in the foods where they are present naturally; (2) they are not to be used in other types of foods; and (3) they are not modified during their production. (c) Metals. Certain metals (e.g., copper, iron, and zinc) are nutritionally essential to humans, but they may occur as contaminants in food. Because of the relatively narrow margin of safety between the nutritionally essential amounts and the toxic doses, and because of the existence of relatively abundant human data, their evaluation is based virtually entirely on human data. Furthermore, their ADIs are expressed, not as O-x mg/kg as for food additives and pesticides in general (see Section 4, Types of ADI), but as y-x mg/kg, where y is the daily dietary requirement.

2. No-Effect Level (NEL) It is also known as “no observed effect level” (NOEL). Most toxicological studies of each chemical involve multidose exposure of the test subjects. Ideally, each study will have at least one dose that induces no adverse effect. The NEL of a particular chemical is the dose for which the most susceptible but appropriate species of animals and the most sensitive indicator of toxicity have been used. Where a study shows two or more doses inducing no toxicity, the highest among them is considered the NEL. NELs are expressed in terms of milligram of the chemical per kilogram of body weight (mg/kg). Where the chemical is mixed in the diet, it is generally expressed in

ACCEPTABLE

DAILY TABLE

APPROXIMATERELATIONOF PARTS PER KILOGRAM

Weight (kg)

Animal Mouse Chick Rat (young) Rat (old) Guinea pig Rabbit

0.02 0.40 0.10 0.40 0.75 2.0 10.0

Dog Cat Monkey Dog Man Pig or sheep Cow (maintenance) Cow (fattening) Horse a Lehman

Food consumed per day (g) (liquids omitted)

49

INTAKE

2

PER MILLION BODY WEIGHT

IN THE DIET TO MILLIGRAMS PER DAY’

Type of diet

1 ppm in food (mg/ kg body wt per day)

1 mg/kg body wt per day (ppm of diet)

3 50 10 20 30 60 250

Dry laboratory chow diets

0.150 0.125 0.100 0.050 0.040 0.030 0.025

10 20 25 33 40

2 5 10 60

100 250 750 1,500

Moist, semisolid diets

0.050 0.050 0.075 0.025

20 20 13 40

60

2,400

0.040

25

500

7,500

Relatively dry grain forage mixtures

0.015

65

500 500

15,000 10,000

0.030 0.020

33 50

8

(1954).

terms of parts of the chemical per million parts of the diet (ppm). In converting the dose in parts per million to milligrams per kilogram, Table 2 is often used. In general, the most sensitive indicator of toxicity is observed in the long-term studies. However, this is not invariably so. For example, certain chemicals induce neurotoxicity and effects in reproductive functions at lower doses in special shortterm studies. Human data from well-conducted studies can also provide the NELs. Such NELs are preferable to those derived from animal data in that they obviate the necessity of the interspecies portion of the extrapolation. Recognizing that not all biological effects are signs of toxicity, JECFA and a WHO Scientific Group (WHO, 1962a, 1967b, 1974) cited a number of examples: changes in intestinal flora, laxative effects due to bulk or osmotic load, and cecal enlargement and diminished growth rate caused by high levels of nondigestible substances. For this reason, the NEL has also been referred to as the “no observed adverse effect level” (NOAEL). However, not all effects can be readily ascertained as adverse or not. For example, experimental finding of a decrease in the rate of body weight gain may be due to toxic anorexia or unpalatability of the diet. Consequently, JECFA advised that “whenever there is doubt about the significance of a particular effect, it should be considered as an adverse one” (WHO, 1962a).

3. Safety Factor A safety factor is used in extrapolating the NEL obtained in animal studies or in human observations to an ADI. The safety factor is intended to compensate for the

50

FRANK C. LU

probably greater sensitivity of man compared to laboratory animals. Furthermore, the NEL is obtained in studies involving small numbers of animals or human subjects in sharp contrast to the large human populations that may be exposed to the chemical in question. There is also the fact that human populations show a greater variation in susceptibility. This stems from the greater differences in genetic and other host and environmental factors, compared to the selected subjects and controlled environment encountered in the experimental studies (WHO, 1974; NAS, 1970). The figure 100 was proposed in 1954 as an adequate “margin of safety” between the level of a chemical in the diet of test animals and that in the human diet (Lehman and Fitzhugh, 1954). At its Second meeting, JECFA also suggested that the use of the factor of 100 might be adequate between the maximum ineffective dose in animals and the permitted dose in man, both calculated in milligram per kilogram body weight (WHO, 1958). In general, the safety factor of 100 has been used by the JECFA and JMPR in extrapolating from the NEL of a chemical to its ADI. However, a factor of 10 has often been used in extrapolating NELs obtained from human data, because of the absence of interspecies difference. The size of the safety factor chosen depends also on the nature of the toxicity and the adequacy of the toxicological data. Examples of smaller and larger safety factors have been cited in previous reviews (Lu, 1983, 1985). 4. Types ofADI ADIs are generally expressed as o-x mg of the chemical per kilogram body weight, indicating that any intake from o to x is acceptable. Apart from regular ADIs, under certain conditions, temporary ADZs are also allocated. This type of ADI is generally allocated to chemicals that are in use but the available data are not fully adequate. In such cases, the specific data requirements and the deadline for their submission are listed to assist the interested parties to generate the required data. In addition, conditional ADZs, as noted above, are allocated to chemicals with specified conditions of use. A group ADZ is allocated to a group of chemicals of similar chemical and toxicological properties, such as ethyl, methyl, and propyl esters ofp-hydroxybenzoic acid. For a number of food additives with very low toxicity, the ADIs may be not specified. Such type of ADI means that on the basis of the available data, the total daily intake of this substance, arising from its use at the levels necessary to achieve the desired effect and from its acceptable background in food, does not, in the opinion of the Committee, represent a hazard to health. Where the available data are grossly inadequate, no ADZ will be allocated. This term also applies to chemicals for which no information is available on their use in food. Finally, where the available data are sufficient to indicate serious toxicity, a not to be used decision is recorded. There are chemicals (e.g., sulfite) which induce allergy or hypersensitivity reactions among a small proportion of the general population. JECFA has recommended that appropriate labeling be instituted. SIGNIFICANCE

AND

ACCEPTANCE

ADIs of a large number of food additives, contaminants, and pesticide residues have been allocated by the JECFA and JMPR. These toxicological evaluations are

ACCEPTABLE

DAILY

Research Scicnlislr b in cmia, Governmenl,

NATIONAL

51

INTAKE

4 Industry

AUTHORITIES

J

1 WORLOHEALTH ORGANIZATION

FOOD 6 AGRICULTURE ORGANIZATION

informalion

[ CODEX

COMMITTEE

ON PESTICIDE

RESIDUES

‘Q+jCDDEX

RELATIONSHIP BETWEEN WlTH THE EVALUATION

ALIMENTARIUS

COMYlSSlDN

THE VARIOUS ORGANIZATIONS AND CONTROL OF PESTICIDE

CONCERNED RESIDUES

FIG. 1. The relationship among research scientists, the Joint Meeting on Pesticide Residues, the Codex Alimentarius Commission and the national authorities, aswell as their impact on the consumer and others.

accepted by the Regulatory Agencies in many countries. They are also utilized by the Codex Alimentarius Commission, an intergovernmental body, for the elaboration of international food standards. These standards are intended to protect public health and facilitate international food trade and they include provisions for acceptable food additives and pesticides and their permitted levels in foods (Lu, 1968; WHO, 1975b). Figure 1 depicts the relationship among research scientists, the Joint Meeting on Pesticide Residues, the Codex Alimentarius Commission, and the national authorities as well as their impact on the consumer and others; the same relationship exists with respect to JECFA, as shown in Figure 2. The wide acceptance did not come automatically. For example, a chairman of the Codex Committee on Pesticide Residues wished to allocate ADIs to the pesticides on the agenda of that meeting rather than adopting those allocated by the JMPR. His

52

FRANK

C. LU

EVALUATION OF ~00~ ADDITIVES RELATIONSHIP BETWEEN THE VARtOUS BODIES CDNCEfU’4ED lbssrrch

in Orrlt

kiantistr

Codex Strndsrds

CODEX ALIMENTARIUS

NATIONAL

COMMISSION

AUlHOFttlIES 4

E&JG@IlMl 4 Pmtrction of health 4 INDUSTRY

4 CONSUMER

COMMERCE

FIG. 2. The relationship among research scientists, the Joint Expert Committee on Food Additives, the Codex Alimentarius Commission and the national authorities, as well as their impact on the consumer and others.

reasoning was that there were experts from more countries than those present at the JMPR. After considerable discussion, the Committee rejected his suggestion because there was insufficient preparatory work for the Committee to make decisions on such complex matters. Furthermore, the attendees at the Codex meetings were govemment delegates, often with specific instructions. This incidence also illustrates the importance of an independent international expert body making decisions based entirely on scientific judgment, devoid of any outside influence. In the past, noneconomic barriers existed in international food trade on the basis/pretense that certain additives or pesticides were too toxic to be allowed in food or their levels in food were too high to be imported. Matters of this nature are now raised at the relevant Committees of the Codex Alimentarius Commission for referral to JECFA or JMPR for independent toxicological evaluation. The significance of the ADIs allocated by the JECFA and JMPR is evidenced not only by their wide acceptance. It is further illustrated by two specific incidents. In

ACCEPTABLE

DAILY

INTAKE

53

1969, when DDT was shown to be carcinogenic in mice, government delegates attending the FAO Conference requested that the toxicity and agricultural uses of this widely used insecticide be evaluated by JMPR on an urgent basis. Later that year JMPR withdrew the AD1 of DDT, but allocated a conditional ADI. It elaborated on the significance of the term “conditional” emphasizing that “uses of DDT should be limited to those situations where there were no satisfactory substitutes” (WHO, 1970a). The other incident involved cyclamates which were shown to cause tumor formation in rats. This finding of serious adverse effects of a widely used and generally considered as safe artificial sweetener generated so much public concern that the government delegates at the WHO Executive Board in January, and those at the World Health Assembly in May, 1970, adopted Resolution WHA 23.5C requesting, among other things, that JECFA reevaluate these additives (WHO, 1970b). The success of these and other WHO Expert Committees may be attributed to the following factors:

1. Special Status of These Committees These committees are established under special authorization and their Reports are accorded an exalted status by the Executive Board, a governing body of WHO. The Reports prepared by these Committees must be submitted to the Board for review and authorization for publication. Because of this special status, the Director-General of WHO is the ex officio secretary of all the Expert Committees. In practice, however, a senior staff member is designated to act on his behalf on most matters related to the planning, convening, and finalizing of the work of each Committee.

2. Stature and Independence of the Members Members are selected from a panel of internationally known experts. Panel members are chosen according to their special expertise, international standing, and agreement of their respective governments. In attending the WHO Expert Committees, they “act as international experts serving the Organization exclusively; in that capacity, they may not request or receive instructions from any government or authority and “they shall enjoy the privileges and immunities external to the Organization,” . . . set forth in the Convention on the Privileges and Immunities of the Specialized Agencies,” as stated in the WHO Regulations for Expert Advisory Panels and Committees (Basic Documents of WHO). Furthermore, to ensure that individual members retain their scientific judgment and conviction, they have the privileges of issuing a “minority report.” Since the meetings are private, uninvited persons are not admitted. This practice allows the members to express their scientific judgment freely at the meetings. Furthermore, the Expert Committees are ad hoc in nature. In other words, at the end of the meeting, the Committee is disbanded, thus freeing the Members of any responsibility for the decisions and recommendations incorporated in the Report and any other documents prepared during the meeting.

54

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C. LU

3. Elaborate Preparation To meet the high standards of the Organization and to inspire confidence of the users of the ADIs, much work is done prior to each meeting. The major matters involve the selection of items on the agenda, solicitation of relevant data, preparation of working papers by Consultants and Members of the Committee, and circulation of all the papers for review by all Members prior to the meeting. The dedication and hard work of the experts and the full cooperation of the chemical firms in submitting relevant data are the key elements of the success of the Committee’s work.

4. Close Collaboration with Other Bodies The wide acceptance of the ADIs allocated by JECFA and JMPR is also due to close collaboration between the Secretaries of these expert bodies and the responsible officers of national regulatory agencies and the Chairmen of the Committees of Food Additives and Pesticide Residues of the Codex Alimentarius Commission. The collaboration involves the selection of substances to be evaluated. This is done on the basis of technological need and public health concerns. The Codex Committees in elaborating food standards will not include provisions for food additives or pesticides for which JECFA and JMPR have not allocated ADIs. While human exposure to a chemical that has been allocated an AD1 is acceptable, there is an upper limit to the extent of the exposure. The Codex Committees therefore also compare the “potential daily intake” (PDI) of a chemical with its ADI. The method of estimating the PDI has been outlined in several Reports of the JECFA and JMPR (WHO, 1962a, 1970a, 1971b). Briefly, the PDI of a chemical is calculated from its permitted levels in the foods in which its use or residue is permitted, and the average consumption of these particular foods. Where the PDI exceeds the corresponding ADI, the actual levels, rather than the permitted levels, are used in the calculation. The latter procedure usually yields much smaller intake figures because the chemical is often not present in all the foods in which it is permitted. Furthermore, the average actual levels are usually lower than the permitted levels, especially with pesticides.

5. Continuity of Guiding Principles Despite the ad hoc nature of the Committees, there has been no major deviation in the principles used in the toxicological evaluation at successive meetings. The continuity of guiding principles is preserved by the practice of inviting a portion of the membership back from one year to the next. In addition, the Secretary, as a “permanent participant,” also exerts a modulating influence by elaborating on the general principles adopted at previous meetings and by requesting that any deviations from past practices be scientifically sound and clearly explained in the Report. His ability to influence the deliberation is strengthened by his rarely used “veto” power. This power can be readily exercised by his departure from the meeting room. Any decisions and recommendations of the Committees made during his absence will be considered invalid.

ACCEPTABLE

DAILY

INTAKE

55

One reason for this veto power, in theory, is to prevent the Committees from making decisions and recommendations which might be contrary to the stated policies of the Organization. The principle reason for having the Secretary present during the entire meeting is to ensure that he is thoroughly familiar with all the deliberations and thus able to elaborate on and defend the evaluations and recommendations included in the Reports before the WHO Executive Board, Codex Meetings, etc. As noted above, the Committees cease to exist at the end of their meetings. 6. “Open-Door”

Policy and Periodic Review

To compensate for the private nature of the meetings, the end results of the deliberations are open to scrutiny. The Committees prepare not only a Report outlining the principles used in the evaluation, comments on individual chemicals, a list of the ADIs and other decisions and recommendations, they also prepare a comprehensive document, the “Monographs.” This document contains summaries of all data, published and unpublished, that have been reviewed by the Committees. It also includes comments on the relevance and significance of the data, the decisions regarding the toxicity of the chemical, and the basis for the evaluation. Any interested parties may contact the Organization or the Secretary for clarification of the basis of the evaluation. They may also request a reevaluation of a chemical by submitting additional data or indicating significant points of the data overlooked by the Committees. Assessment of the safety is a dynamic issue. New data are continually being generated on many chemicals. As a result, a large number of additives and pesticides have been evaluated several times on the basis of the expanded data base. In addition, a change of the interpretation of certain types of experimental data has also prompted reevaluations. One example is the growing realization of the doubtful significance of local sarcomas appearing after repeated subcutaneous injection of a chemical. Several food colors that had been considered to have carcinogenic potentials on the basis of the development of local sarcomas per se have since been allocated ADIs. Reevaluation has also been prompted by the revelation that the validity of certain data was questionable. The chemicals affected were reevaluated either using the remainder of the data base or using additional data at a later time. DISCUSSION While the concept and utility of AD1 have become generally accepted, there have been questions regarding the following specific aspects of the procedure used (Hoe1 et al., 1975; Zbinden, 1979; Van Ryzin and Rai, 1980; Munro and Krewski, 1981; Dourson and Stara, 1983). 1. NEL

There have been suggestions that NELs are based only on the results of routine long-term studies. However, many other types of studies are reviewed and used in

56

FRANK C. LU

the determination of NELs, as outlined under Procedures for Establishing ADI under Relevant Data and No-Effect Level (NEL). It has also been suggested that the NELs are not true no-effect levels because of the limited number of animals on test and the generally meager information on the slope of the dose-response relationship. As the author has pointed out (Lu, 1985), a lOOfold increase of the number of animals used would probably reduce the NEL by 2478% only, which can be considered insignificant in light of the very large inherent biological variability. Furthermore, part of the safety factor used in extrapolating from the NEL observed with a small number of animals to the AD1 for large human populations is intended to compensate for the difference in group size. Furthermore, the significance of conducting additional, relevant tests must not be overlooked. For example, the most sensitive indicator of toxic effect of organophosphorus insecticides is cholinesterase inhibition. However, the more serious effects are potentiation between certain chemicals of this group (Frawley et al., 1957) and delayed neurotoxicity, also known as peripheral axonopathy (Johnson, 1969; AbouDonia and Preissig, 1976). Tests designed to detect these effects are now routinely carried out on this category of chemicals. Following the tragic incidence of thalidomide (Lenz and Knapp, 1962) studies for teratogenic potential have become part of the testing for toxicological evaluation. The NELs of a number of chemicals are based on the no-effect levels observed in such special short-term studies instead of longterm studies. It is doubtful that any increase in the number of animals used in routine long-term studys (to increase sample size and possible determination of the slope of the dose-response curve) could compensate for the lack of these and other relevant tests.

2. Body Surface versus Body Weight It is generally recognized that smaller mammals have greater metabolic rates. This difference appears to be much smaller when the metabolic rates are expressed in terms of body surface. Consequently, suggestions have been made, from time to time, that the NEL should be expressed in terms of body surface, rather than body weight. These suggestions have been discussed but rejected by JECFA and JMPR. The NELs obtained in 2-year studies in the rat and the dog on 12 randomly selected pesticides were compiled in a previous paper (Lu, 1985). That compilation showed that the NEL in terms of body weight provided a better interspecies extrapolation than those using body surface. A recent publication lists the NELs of a number of organophosphorus insecticides (WHO, 1986). These figures, along with those cited in the previous paper, are summarized in Table 3. The figures in Table 3 show that, on a body weight basis, 16 of the 28 pesticides were about equally toxic to the rat and the dog, and half of the remainder were more toxic to the rat, whereas the other half were more toxic to the dog. When the NELs were expressed in terms of body surface, the rat appeared more susceptible to a majority of these chemicals. These data thus lend further support to the continued use of body weight instead of body surface for interspecies comparison. It may also be worth reiterating that the body weight, as a measured value, is preferable to the body surface which is not measured but derived from the body weight.

ACCEPTABLE

DAILY TABLE

57

INTAKE

3

RELATIVE SENSITIVITY OF THE DOG AND THE RAT TO 28 PESTICIDESIN TERMS OF BODY WEIGHT AND BODY SURFACE Ratio”
0.5-2 >2

Relative sensitivity Dog more sensitive Approx equally sensitive Rat more sensitive

Body weight

Body surface

6 16 6

4 9 15

Total: 28

28

’ Expressed as ratios of NEL in the dog to those in the rat.

3. Safety Factor Although a factor of 100 is often used in extrapolating from the NEL to an ADI, larger or smaller figures are used, depending on the adequacy of the data, the nature of the toxicity, and whether or not appropriate human data are available. It has been suggested at the earlier meetings of JECFA and JMPR that there was no need to use a safety factor to arrive at an ADI, but that it would suffice to determine the adequacy of the margin ofsafety (e.g., 100) between the estimated or expected human consumption and the NEL in animals. While this approach may be satisfactory at a national level, the expert bodies noted that it would not be feasible at an international level. This is because the human consumption figure (the potential daily intake) may vary from one country to another due to differences in dietary pattern and in the uses and use levels. Furthermore, the potential daily intake may change over a period of time; it would hardly be practicable to convene an international meeting whenever such changes take place. The assumption that poor toxicological investigations are rewarded because they tend to lead to a higher NEL and thus a larger ADI is unfounded. In actual evaluations, data from studies with inadequate numbers of animals and/or with inappropriate measurements of signs of toxicity often result in no ADI or a smaller AD1 by the use of a larger safety factor. The use of a safety factor to estimate AD1 has been adopted not only internationally but also nationally, including the United States (e.g., FDA, EPA). The success of this approach has been pointed out by Klaassen and Doull(l980).

4. Future Prospects Undoubtedly, the AD1 approach will continue to be used in the evaluation and reevaluation of food additives, pesticides, and contaminants. However, as toxicology and allied sciences continue to advance, the data that will be considered relevant and essential, and the yardstick used in their assessment, will continue to undergo modifications. Furthermore, some of the developments, especially those in pharmacokinetic, mechanistic, and in vitro studies, may render the testing of chemicals for safety less costly, less time consuming, and requiring fewer animals.

58

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C. LU

The U.S. Environmental Protection Agency has adopted the AD1 approach in its future regulatory measures against environmental pollution. However, the term “uncertainty factor” is used instead of safety factor, and “reference dose” (RFD) is used in place of AD1 (Anderson and Ehrlich, 1985; EPA, 1986). The use of the safety factor approach might be extended to other situations. For example, in cases where NELs cannot be ascertained, the available data might be sufficient to set priorities for cleaning up of chemical dumps and for setting priorities for further toxicological investigation. The possibility of using all dose-effect relationships, such as levels for “frank effect, ” “adverse effect,” and “no observed effect,” has been raised (Dourson, 1986). Whether this approach represents an improvement over the generally adopted procedure needs close scrutiny, including a comparison of the results obtained with these two procedures. CONCLUSIONS (1) The AD1 approach was initiated by the Joint FAO/WHO Expert Committee on Food Additives in 196 1. It was adopted by the Joint FAO/WHO Meeting of Experts on Pesticide Residues later that year. In the ensuing years these two expert bodies used this approach in the evaluation of hundreds of food additives and pesticides. The evaluations have proved satisfactory in permitting the judicious use of these chemicals as well as in protecting the health of the consumer. (2) These ADIs have been used by Regulatory Agencies in many countries. At the international level, these values have been utilized in the elaboration of international food standards through the Codex Alimentarius Commission. These food standards are designed not only to protect the health of the consumer, but also to facilitate international food trade by eliminating certain “noneconomic barriers.” (3) Looking ahead, there likely will be changes in the data that will be considered relevant and essential as well as in the interpretation and the use of the data in the process of toxicological evaluation. Furthermore, this approach, possibly with minor modifications, will be extended to other applications. Editor ‘r note. The author has been associated with the work of WHO since 196 1, in a variety of capacities. Between 1965 and 1976, he served as Chief of the Food Additives Unit. In that capacity he acted as the Secretary of the Joint FAO/WHO Expert Committee on Food Additives and the Joint FAO/WHO Meeting on Pesticide Residues. In addition, he served as Chairman of the WHO Food Safety Program, and in that capacity he was the chief liaison officer with FAO on various matters related to the Joint FAO/ WHO Food Standards Program, the Codex Alimentarius Commission being its principal organ. He was also the coordinator of the WHO Monitoring Program and a senior scientist in the Environmental Health Criteria Program.

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