FAO Meeting Report No. PL/1965/10/2
EVALUATION OF THE HAZARDS TO CONSUMERS RESULTING FROM THE USE OF
FUMIGANTS IN THE PROTECTION OF FOOD
The content of this document is the result of the deliberations of the
Joint Meeting of the FAO Committee on Pesticides in Agriculture and
the WHO Expert Committee on Pesticide Residues, which met 15-22 March
Food and Agriculture Organization of the United Nations
World Health Organization
1 Report of the second joint meeting of the FAO Committee on
Pesticides in Agriculture and the WHO Expert Committee on Pesticide
Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65.
The concept of acceptable daily intake as applied to pesticides
Biological data presented in the monographs
Note to the reader
At the present time, to feed the people of the world, recourse
must be had to pesticides to protect the crops both during growth and
during their subsequent storage and transport. While some of the
chemicals used for this purpose will not contaminate the final crop,
others, even when used in accordance with good agricultural or food
storage practice, will leave residues which will be present in the
food at the time of consumption. This meeting was concerned, as were
the previous ones, with the protection of the consumer against the
hazards that might result from the presence of these residues, and its
aim was to give guidance to authorities responsible for the health,
nutrition and welfare of people from this point of view. In carrying
out this task, the participants were mainly guided by the principles
governing consumer safety in relation to pesticide residues enunciated
at the 1961 joint meeting of the WHO Expert Committee on Pesticide
Residues and the FAO Panel of Experts on the Use of Pesticides in
The following definitions of the terms used in work on pesticide
residues are reproduced from that report.
Residue: A pesticide chemical, its derivatives and adjuvants in or
on plant or animal. Residues are expressed as parts per million (ppm)
based on the fresh weight of the sample.
Food factor: The average fraction of the total diet made up by the
food or class of foods under discussion. Details of the diet of a
country may be obtained from the FAO Food Balance Sheets or other
Acceptable daily intake: The daily dosage of a chemical which,
during an entire lifetime, appears to be without appreciable risk on
the basis of all the facts known at the time. "Without appreciable
risk" is taken to mean the practical certainty that injury will not
result even after a lifetime of exposure. The acceptable daily
intake is expressed in milligrams of the chemical, as it appears in
the food, per kilogram of body-weight (mg/kg/day).
Permissible level: The permissible concentration of a residue in or
on a food when first offered for consumption, calculated from the
acceptable daily intake, the food factor, and the average weight
of the consumer. The permissible level is expressed in ppm of the
fresh weight of the food.
1 FAO Plant Production and Protection Division Report No.
PL/1961/11; Wld Hlth Org. techn. Rep. Ser., 1962, 240.
Tolerance: The permitted concentration of a residue in or on a food,
derived by taking into account both the range of residue actually
remaining when the food is first offered for consumption (following
good agricultural practice) and the permissible level. The tolerance
is also expressed in ppm. It is never greater than the permissible
level for the food in question and is usually smaller.
The meeting was not concerned with tolerances and it wished to
re-emphasize the fundamental difference between a tolerance and an
acceptable daily intake. Only acceptable daily intakes are based
entirely on toxicological evidence.
A tolerance is then the smallest residue consistent with control
of the pest, but to be toxicologically acceptable it must not exceed
the permissible level. In the report on principles governing consumer
safety in relation to pesticide residues,1 the method outlined for
calculating a permissible level is most useful for a pesticide which
is used on a single article or class of articles of the diet, if these
form the only source of that substance for the consumer. In many
cases, a pesticide is used on a number of different types of foodstuff
and may also have non-agricultural uses, as in public health
programmes. DDT is a good example of this type of pesticide. Account
must be taken of such multiple uses of pesticides and in these cases
it may be preferable to adopt an alternative method of calculation
based on that advocated for food additives.2 The possible consumer
hazards arising from the intake of a pesticide could then be assessed
by adopting the following procedure:
(1) Determine the residue in each type of food and drink liable to
contain the pesticide in question.
(2) Calculate the daily intake level of the pesticide that might occur
if it had been used on all the foodstuffs for which it might be used,
working on the basis of the average daily diet.
(3) Knowing the average body-weight, calculate the daily intake of the
pesticide, expressed as mg per kg per day.
(4) Check this figure against the acceptable daily intake for that
1 FAO Plant Production and Protection Division Report No.
PL/1961/11; Wld Hlth Org. techn. Rep. Ser., 1962, 240.
2 See the Sixth Report of the Joint FAO/WHO Expert Committee on Food
Additives, FAO Nutrition Meetings Report Series, 1962, 31; Wld
Hlth Org. techn. Rep. Ser., 1962, 228.
(5) If the figure does not exceed the acceptable daily intake, the
proposed uses of the pesticide are acceptable. If the figure exceeds
the acceptable daily intake, one or more of the proposed uses will
have to be reconsidered with a view to reducing the residues resulting
from such use (or uses) or abandoning one or more uses entirely.
(6) When there is a margin between the figure and the acceptable daily
intake, proposals for further uses of that pesticide on foodstuffs can
THE CONCEPT OF ACCEPTABLE DAILY INTAKE AS APPLIED TO PESTICIDES
Since pesticides are, from their very nature, poisonous to some
forms of life, any intake by man in the food may be considered
undesirable. For this reason the rate of application of the pesticide
to the crop should be as low as possible, and the interval between its
last application and the consumption of the crop should be as long as
possible so that the residue is reduced to a minimum. Nevertheless, if
pesticides are to be used, as they must be, some ingestion will occur.
It would help in the assessment of any possible hazards arising from
the consumption of these tiny amounts of pesticides if it were known
how much could be consumed daily without risk.
In order to determine an acceptable daily intake the following
information should be available.
(a) The chemical nature of the residue in food as presented for
consumption. Pesticides may undergo chemical changes and are
frequently metabolized by the tissues of the plants and animals that
have been treated with them. Even when a single substance has been
applied, the residue may consist of a number of substances with
distinct properties, the exact nature of which may differ in animals
and plants and in different crops and products.
(b) The toxicities of the substances forming the residue, as judged by
acute, short-term and long-term studies in animals. In addition,
knowledge is required of the metabolism, mechanism of action, and the
possible carcinogenicity of pesticide residues when consumed.
(c) A sufficient knowledge of the effects of these residues on man.
Information on this scale is not often available at the present
time, but if it is, a daily level of intake having no observable
effect on a sensitive species of animal can be determined. In some
cases, this level has been determined for man himself. From this
starting point an acceptable daily intake for man can be proposed by
employing a suitable factor.
When an acceptable human daily intake of a residue has been
proposed, the nature of the food bearing the residue is probably
The amount of data available varies considerably for the
different pesticides. Nevertheless, even when the information about a
particular pesticide appears very complete and an acceptable intake is
proposed, it must be realized that, however carefully the data are
evaluated, the statement that x mg/kg body-weight can be eaten every
day for a lifetime without appreciable risk remains an expression of
opinion which carries no guarantee of "absolute" safety. Such a
guarantee would be impossible.1
On the other hand, the desire to use the most sensitive criteria
for the determination of the threshold effect levels, coupled with the
natural conservatism of an international body, inevitably leads to
great caution in the proposals for acceptable daily intakes. This
should be taken into account when these values are used. At the
meeting, a single set of acceptable daily intake figures was proposed.
It was recognized, however, that exceptional situations might arise
when the possibility of exceeding these figures would have to be
considered, e.g., in the event of serious food shortage. The meeting
was not in a position to offer guidance to cover all such
circumstances; each case will have to be decided on its merits by the
national authorities responsible, who should take expert advice on the
risks to health from excess intake of pesticides and the medical
consequences arising from the loss of the crop. There are obviously
conditions in which it would be unrealistic to adhere to these levels.
The only advice which can be given to those faced with making this
type of decision is to consider the nature of the criterion used to
determine the level. Obviously, when the criterion used is a minimal
change in cholinesterase activity of the blood, the level can be more
safely exceeded than when the criterion is some more serious
Only a limited number of the many pesticides now available have
been considered. The omission of a pesticide from the monographs does
not imply criticism of that pesticide, nor does it suggest that it can
be used without restraint.
The meeting strongly emphasized that new data or new knowledge
could always lead to a re-evaluation of an acceptable daily intake.
Values of this nature are always provisional. It is the duty of all
who use the material contained in the monographs to ensure that they
possess the latest information.
1 Stoner, H. B. (1964) J. Food Cosmet. Toxicol., 2, 457.
The meeting decided that a somewhat different approach was needed
in considering fumigants. To make the report as complete and as useful
as possible, it was decided to evaluate the possible consumer hazards
arising from all the uses of fumigants on food but not those arising
from other uses of these substances, e.g., as soil fumigants.
Fumigants for food form a fairly well-defined group of substances
which have remained unaltered in number and composition for many
years. These substances have been developed as fumigants and have
become accepted as suitable for that purpose for three reasons: (1)
they are effective against the pest; (2) although many of them are
highly toxic it has been possible to derive ways of using them safely;
(3) it has been considered in the past that provided the operators
adhered to good practice1 in regard to type of crop, dosage, method
of application and subsequent treatment of the crop (aeration,
milling, baking, etc.), use of these fumigants would not lead to a
consumer hazard. The meeting did not concern itself with the possible
hazards that these fumigants might offer to their users.
Fumigants could give rise to a consumer hazard in several ways:
(1) The fumigants might persist on the food chemically unchanged as a
residue which would be consumed.
(2) The fumigant might be broken down, wholly or in part, on the food
to give a residue different in composition from the fumigant itself
which would also persist and might finally be consumed.
(3) The fumigant might interact chemically with the food to form a new
substance which might also persist as a residue.
(4) The fumigant might interact chemically with the food in such a way
as to affect its nutritional value.
If a fumigant when used according to good practice had none of
these actions, it could not present a consumer hazard and its use
would be acceptable. For the assessment of the dangers that might
arise from a fumigant which did have one or nore of these actions, the
concept of "acceptable daily intakes" might be useful in the cases
when there was a residue of either the unchanged fumigant, its
decomposition products, or the chemical substances it had formed with
the food. Knowledge of the "acceptable daily intakes" of these
substances would be useful in assessing consumer hazards that might
arise from the use of the fumigant, particularly under conditions of
abnormal pest infestation when the dose might have to be increased or
the treatment repeated.
1 Monro, H. A. U. (1961) Manual of fumigation for insect control,
FAO, Agric. Studies, 56, 294.
Where the fumigant had a deleterious effect on the nutritive
value of the foodstuff, one would have to know which nutrient in the
food had been affected, what alternative sources of that nutrient were
present in the diet, and the importance of the fumigated food as a
source of that nutrient to the population at risk. The suitability of
the fumigant would be judged on the answers to these questions and the
decision might differ in different areas.
Neither the user nor the consumer hazards of a fumigant can be
assessed apart from its mode of use. This is particularly so in the
case of the consumer hazard where any residue will be determined by
the amount applied, the degree of subsequent aeration of the crop, and
its processing (milling, baking, etc.) before consumption.
The meeting took note of the fact that many formulations of
fumigants comprise two or more components, but the information on
residues and toxicology has been evaluated only for the individual
substances. Furthermore, food may sometimes be fumigated more than
once between harvest and ultimate consumption. Account should be taken
of the total effect of these treatments on the food.
The monographs for the individual fumigants have been extended to
include sections on the use of the fumigants, the nature and size of
the residues left by these uses and any effects the compound has on
the treated crops. These sections show the criteria used to assess the
fumigant. The toxicological sections of the monographs have also had
to be expanded in some cases. Where a residue of the unaltered
fumigant persists on the crop until the time of consumption, the
toxicity of the fumigant itself must be considered. Where the residue
is composed of decomposition products of the fumigant the toxicity of
these compounds must also be described. Changes in the fumigated
foodstuff have also been included.
Many of the fumigants considered have been well known to
toxicologists for many years and descriptions of their toxic effects
are to be found in most standard works on toxicology.1 Only material
appertaining to the evaluation of consumer hazards arising from the
use of these substances as fumigants has been included in the
1 See, for example: Fabre, R. & Truhaut, R. (1960) Précis de
toxicologie, Paris, Sedes, vol. 1; Patty, F. A. (1949) Industrial
hygiene and toxicology New York, Interscience, vol. 2; Oettingen, W.
F. von (1955) The halogenated aliphatic, olefinic, cyclic, aromatic
and aliphatic-aromatic hydrocarbons including the halogenated
insecticides, their toxicity and potential dangers, United States
Department of Health, Education and Welfare; Browning, E. (1953)
Toxicity of industrial organic solvents, London, HMSO, rev. ed.;
Oettingen, W. F. von (1964) The halogenated hydrocarbons of
industrial and toxicological importance, Elsevier.
It was realized that for most fumigants little information was
available on residues left in the various items of food treated;
further, that the chemical reactions that might take place between the
fumigants and components such as amino-acids or vitamins in the food
have been insufficiently investigated. In addition, the meeting did
not consider that the data presented on the biological effects of
fumigated food on experimental animals reached the standards required
in the three joint FAO/WHO reports1 dealing with the procedure for
testing food additives. In most cases the data presented were
insufficient for the estimation of acceptable daily intakes for man.
This situation is very unsatisfactory and it is urgently
recommended that governments initiate research to solve the problems
connected with the fumigation of food. In view of this unsatisfactory
situation the meeting urged that, for the safety of both user and
consumer, all fumigants should be used in accordance with good
practice as suggested in the FAO manual,2 paying particular attention
to the choice of the food to be treated, subsequent aeration of the
food, and the removal of any material used to generate the fumigant.
These difficulties are reflected in the results of the attempts
to evaluate the consumer hazards of the fumigants examined. An
acceptable daily intake value for the residue or the unchanged
fumigant was established in only one case, that of hydrogen cyanide.
The acceptable daily intake for man of cyanide resulting from the
fumigation of food was considered to be not more than 0.05 mg of HCN
per kg body-weight per day.
The residue of inorganic bromide from the use of ethylene
dibromide was thought to be unlikely to make any significant
contribution to the total bromide content of the diet. The use of
methyl bromide can lead to higher residues of inorganic bromide. It
was considered that the possible risk from these could be assessed, if
need be, on the basis that the total daily intake of this ion from
all sources should not exceed 10 mg of Br per kg body-weight per day.
Carbon tetrachloride and ethylene dibromide were not considered
to lead to a consumer hazard provided that none of the unchanged
fumigant reached the consumer (the sensitivity of the present
analytical method for carbon tetrachloride being 0.01 ppm and that for
ethylene dibromide being 1 ppm). It was also thought that ethylene
dichloride should be used as a fumigant under conditions that will
result in the lowest possible residues in the food as consumed.
1 FAO Nutrition Meetings Report Series, 1958, 17; Wld Hlth Org.
techn. Rep. Ser., 1958, 144. FAO Nutrition Meetings Report
Series, 1961, 29; Wld Hlth Org. techn. Rep. Ser., 1961, 220.
FAO Plant Production and Protection Division Report No. PL/1961/11;
Wld Hlth Org. techn. Rep. Ser., 1962, 240.
2 Monro, H. A. U. (1961) Manual of fumigation for insect control,
FAO, Agric. Studies, 56, 294.
For methyl bromide, ethylene oxide, acrylonitrile and phosphine
there was insufficient toxicological evidence available to evaluate
the significance of any residues of the unchanged fumigants. Since
phosphine is often generated in grain from aluminium phosphide it was
considered that crops treated with this substance should be freed of
residues of the powder before they reached the consumer.
Acceptable daily intake values could not be determined for carbon
disulfide or chloropicrin and a large amount of work will be necessary
on the nature and amount of the residues and the interaction of the
fumigants with the treated food, in addition to long-term
toxicological studies if the use of these fumigants is to be
continued. These remarks do not apply to the use of chloropicrin as a
What is known of the action of these fumigants on the nutritive
value of the food is included in the monographs. In so far as this has
been examined, the results, in most cases, have been reassuring, but
much more work is necessary on this topic (see above).
BIOLOGICAL DATA PRESENTED IN THE MONOGRAPHS
In using the concept of acceptable daily intakes in the control
of consumer hazard from pesticides it is not sufficient merely to
consult a list of figures. Account must also be taken of the evidence
on which the figures are based.
As much relevant information as possible has been included in the
monographs. Wherever possible this has been obtained from the
published literature but other sources of information have also been
used. The members of the meeting thanked all those who had made
information available to them and offered their apologies to any
authors whose work may not have been taken into consideration. They
emphasized the need for the early and complete publication of the
results of research in this field, particularly of that part which
could form the basis of the determination of an acceptable daily
intake for man. This is necessary so that the work reported can be the
subject of scrutiny and informed criticism by a wider group of
scientists covering disciplines not necessarily represented at the
Unpublished data, because they may include more detail than
published work, may often be required for the determination of
acceptable daily intakes. These data must be complete non-confidential
and with an indication of the authorship of the report. The
information will not be considered unless it is received by FAO/WHO at
least six months before the announced date of the Committee meeting in
sufficient copies (at least two) to be distributed to suitable
For many substances the amount of information fell short of that
required for the setting of an acceptable daily intake for man but not
all the substances for which no figure was proposed seem to offer the
same hazard. An attempt has been made to indicate the degree of hazard
in each case and an indication has also been given of further work
needed. When the additional information is forthcoming, the substances
in this category will be reconsidered. The figures already set will be
reviewed in the light of further knowledge.
The biological data are presented under various headings, as in
previous reports of this type.
These are important because they reveal the metabolism of the
pesticide in the crop during the formation of the residue and
subsequently in the animal which consumes it. It is important to know
whether a substance is absorbed, its distribution in the body after
absorption, its mechanism of action including its influence on enzyme
systems, how it is metabolized, and the routes of final elimination,
The toxicity of a pesticide may be altered at all these stages. In the
crop or - in the case of veterinary pesticides - in the animal, a
number of metabolites may be produced, some of which may be the active
forms of the pesticides, as in the formation of paraoxon from
parathion. After ingestion, these active products may be further
broken down to compounds that are excreted. Storage of these or of the
parent chemical may occur. The fact that a substance appears to be
rapidly broken down and excreted does not necessarily mean that it is
more desirable as a residue than one which is stored, say, in the
adipose tissue. Short-lived compounds formed during the breakdown
might be very poisonous, whereas persistent compounds might be stored
in an inactive form.
Broadly speaking, the more that is known of the fate and
mechanism of action of a pesticide the better should be the
understanding of its toxicity and consequently the easier it will be
to set an acceptable daily intake for man.
The value of data on acute toxicity is that they give an idea of
the inherent toxicity of the material. Where there is information of
the acute sensitivity of man to pesticides it has been included under
Investigations covering less than half the animal's life-span are
included under this heading.
In the case of some of the pesticides considered, studies have
been made in which they have been fed to man. These data are clearly
of great value and have also been taken into consideration. In a few
instances studies on workers exposed to pesticides have contributed
some information or help in arriving at figures for acceptable daily
intakes. It is desirable that further careful studies on workers be
made because of their prolonged intensive exposure.
These studies include tests covering the greater part of the
animal's lifespan and research on the possible carcinogenicity of the
residues. The requirements of the latter tests have been discussed in
Long-term studies are important for the determination of the
dietary level of the compound which produces no effect, particularly
when dealing with compounds that do not produce any measurable
biochemical changes. Obviously such tests must be carried out on a
species that has been shown by acute and/or short-term studies to be
sensitive to the compound. The sensitivity should be as similar as
possible to that of man and the metabolism of the compound in the
animal should also be similar to that in man.
The Committee again considered the significance of the inhibition
of the liver esterases by many organo-phosphorus pesticides at
concentrations below those required for the inhibition of
cholinesterase. Again, the Committee did not think that it was
possible to utilize these effects in the assessment of consumer hazard
since the functional importance of these enzymes are not known, no
symptoms appear to be attributable to their inhibition and the
symptoms of poisoning by organophosphorus pesticides can be related to
their effect on cholinesterase activity.
At the end of the introduction to the last report, the Committee
mentioned those additional factors which should be borne in mind when
using the acceptable daily intake figures, namely, addition
(summation), potentiation and the possibility of genetic differences
in the populations at risk. The Committee did not consider that it
could amplify its previous remarks on "addition" or "genetic
differences". Those remarks are now repeated.
1 Wld Hlth Org. techn. Rep. Ser., 1958, 144; FAO Nutrition
Meetings Report Series, 1958, 17.
2 Wld Hlth Org. techn. Rep. Ser., 1961, 220;FAO Nutrition
Meetings Report Series, 1961, 29.
3 Wld Hlth Org. techn. Rep. Ser., 1962, 240;FAO Plant
Production and Protection Division Report No. PL/1961/11
(a) Addition. The values given in the monographs have been
calculated on the assumption that the diet is contaminated by a single
chemical residue. In practice, foodstuffs frequently contain residues
of more than one compound, and an additive effect may then occur. The
meeting did not feel able to make any specific recommendations under
this heading, but emphasized as a general safeguard against these
additive effects the importance of always keeping the residues to a
(b) Genetic differences. The increasing appreciation that
genetically determined differences in the enzymic pattern of man can
affect his reaction to toxic agents is a further indication that
acceptable daily intakes should not be applied too rigidly.
Regarding the possibility of the potentiation of the effect of
one pesticide residue by the residue of another pesticide, the
Committee considered that the evidence which was available indicated
that potentiation was unlikely to occur at the concentrations for
pesticide residues found in food.
Since the last report more information1,2,3,4,5 has come to hand on
the results of the use of behavioural tests in the investigation of
the toxicity of pesticides. These tests offer additional ways of
investigating the actions of pesticides on mammals and the results
have been taken into account in the evaluation of the toxicity of the
pesticides considered in these monographs. At the present time it
would appear that for some substances behavioural tests are not more
sensitive than other tests (biochemical, etc.) used to detect toxicity
and the information obtained must be considered together with all the
other available information.
1 Medved, L. I., Spyn, E. I. & Kagan, I. S. (1964) Residue Reviews,
2 Goldberg, M. E. & Johnson, H. E. (1964) J. Pharm. (Lond.), 16,
3 Goldberg, M. E. & Johnson, H. E. (1964) J. Pharmacol. exp. Ther.,
4 Goldberg, M. E., Johnson, H. E. & Knaak, J. B., Psychopharma (In
5 Goldberg, M. E., Johnson, H. E. & Knaak, J. B., Biochem.
Pharmacol. (In press).
Comments on experimental studies reported
Under this heading is given a short commentary summarizing the
available evidence and leading to its evaluation from the point of
view of the determination of a maximum acceptable daily intake for
In evaluating the toxicological information, the meeting was
mainly concerned to establish the maximum dose of the compound that
could be given over a long period without producing ill effects. In
most cases this was a dose level for some animal species. For some
compounds this level had been determined in man, and such human data,
although often covering a relatively short period, naturally took
precedence. When human data of this type were not available and in the
absence of evidence to the contrary, human sensitivity in principle
was equated with that of the most sensitive animal species.
It is unfortunate that only crude criteria exist for estimating
the mammalian toxicity of many pesticides. It was felt that a cautious
attitude should be adopted towards compounds whose mechanism of action
was unknown. The meeting wished to draw the attention of research
workers to the need for more sensitive criteria for use in this type
of work. Increasing sensitivity is not valuable of itself unless it is
significant from the point of view of toxicity. The sensitivity of
those tests used to measure the toxicity of the pesticide at high
dosage levels should be increased so that proper dose-response curves
can be determined.
Extrapolation to man
Where a maximum no-effect level of dietary intake has been
established in a sensitive animal species and where there are no
comparable data for man, the animal dose rate must be taken as a basis
for calculating an acceptable daily intake for man. This can be done
in several ways.1,2 Unfortunately the more scientific methods of
making this adjustment require an amount of information that is seldom
available and was certainly lacking for the compounds studied in the
present report. Accordingly the meeting adopted the commonly used
empirical method: the maximum no-effect dietary level obtained by
animal experiment, expressed in mg/kg bodyweight per day, was divided
by a "factor", generally 100.
1 Gaddum, J. H. (1956) Brit. J. Pharmacol., 11, 156.
2 Mantel, N. & Bryan, W. R. (1961) J. nat. Cancer Inst., 27, 455
Where the maximum no-effect level for oral intake in man was
known, a smaller factor was used - in certain cases as low as 10.
The acceptable daily intake figures in the monographs that follow
are intended to be of value as a check to ensure that tolerances are
Note to the the reader
Any comments on chemical and physical information and
agricultural data should be addressed to:
Crop Protection Branch
Plant Production and Protection Division
Food and Agriculture Organization
Any comments on biological data and their evaluation should be
World Health Organization