FAO Meeting Report No. PL/1965/10/1
WHO/Food Add./27.65
EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN 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 in Rome,
15-22 March 19651
Food and Agriculture Organization of the United Nations
World Health Organization
1965
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
CONTENTS
General considerations
The concept of acceptable daily intakes as applied to pesticides
Re-evaluation of consumer hazards of pesticides
Additional pesticides
Biological data presented in the monographs
Note to the reader
Monographs:
Aldrin
Allethrin
Azinphos-Methyl
BHC
Capan
Carbaryl
Chlorbenside
Chlordane
Chlorfenson
Chlorobenzilate
Chlorpropham
Chlorthion
DDT
Demeton
Demeton-S-Methyl Sulfoxide
Diazinon
Dichlorvos
Dieldrin
Dimethoate
Dimethrin
DNOC
Endosulfan
Endrin
Ferbam
Heptachlor
Lead arsenate
Lindane
Malathion
Maneb
Methoxychlor
Mevinphos
Nabam
Parathion
Methyl Parathion
Phenylmercuric Acetate
Piperonyl Butoxide
Phosphamidon
Propham
Pyrethrins
Thiram
Triphenyltin compounds
Zineb
Ziram
GENERAL CONSIDERATIONS
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
Agriculture.1
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
similar data.
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 follow 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
pesticide.
(5) If the figure does not exceed the acceptable daily intake, the
proposed was 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.
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.
(6) When there is a margin between the figure and the acceptable daily
intake, proposals for further uses of that pesticide on foodstuffs can
be considered.
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
immaterial.
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
functional change.
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.
RE-EVALUATION OF CONSUMER HAZARDS OF PESTICIDES
The 37 pesticides evaluated in 1963 were reconsidered by the
meeting, not only on the basis of the information contained in the
previous report,2 but also in the light of further data that have
since become available.
For 21 substances the monographs remain unchanged.
For 11 substances (aldrin, dieldrin, endrin, heptachlor,
dimethoate, malathion, parathion, carbaryl, captan, triphenyltin
compounds and lead arsenate) new information was added to the
monographs without affecting the evaluation of the hazard to man.
1 Stoner, H. B. (1964) J. Food Cosmet. Toxicol., 2, 457.
2 FAO Meeting Report No. PL/1963/13 (mimeographed); WHO/Food
Add./23/1964 (mimeographed).
A re-evaluation was made for chlordane, propham and chlorpropham.
For chlordane, new data have demonstrated a maximum no-effect level in
the rat, and the meeting was informed that the suggestion that propham
and chlorpropham possessed co-carcinogenic activity had not been
substantiated. Nevertheless, the information about these compounds was
still insufficient to allow an acceptable daily intake for man to be
established.
In the case of DDT, the meeting considered that in view of the
vast amount of information on the metabolism, fate and toxic effects
of this compound in man obtained from observations on large numbers of
people in many countries, a wider range could be accepted for the
"acceptable daily intake" for man. This has now been set at 0-0.01
mg/kg/day.
Finally, in the case of diazinon it was considered on
re-evaluation of new data that an "acceptable daily intake" for man
could be estimated to be 0.0002 mg/kg/day. This was based on the
threshold level for the dog which is very sensitive to this pesticide.
The meeting re-emphasized the lack of information on the toxicity of
diazinon to man.
The meeting found that there was still insufficient knowledge for
complete assessment of the possible consumer hazards from these
pesticides. An attempt has been made in the monographs to indicate in
a little more detail than in the previous monographs what information
is still missing. The heading "Further work required" indicates a
higher priority than "Further work considered desirable". In some
cases it has been possible, under the heading "Comments on
experimental studies reported", to draw attention to the absence of a
specific piece of information which would materially assist in setting
an "acceptable daily intake" value. It is hoped that such work will be
forthcoming for consideration at future meetings.
The meeting still felt concern about some results indicating that
certain organo-chlorine compounds could evoke the formation of tumours
in susceptible strains of laboratory animals. Since it was realized
that a precipitate withdrawal of these pesticides would create
difficulties in agriculture and public health in some countries, the
meeting urged that serious attempts should be made to remove the
doubts concerning the significance of these findings.
ADDITIONAL PESTICIDES
The meeting also considered five additional pesticides
- dichlorvos, pyrethrins, allethrin, dimethrin and piperonyl butoxide
- using the same criteria for their evaluation as were used in the
previous report.1
1 FAO Meeting Report No. PL/1963/13 (mimeographed); WHO/Food
Add./23/1964 (mimeographed).
No acceptable daily intake was determined for any of these
pesticides. It would have been possible to set a figure for dichlorvos
based on inhalation experiments in man. The value would have been an
extremely low one. However, it is known, from animal experiments, that
dichlorvos is more toxic when inhaled than when taken by mouth, and no
data are available on the effects of oral administration in man.
Although the available data for the pyrethrins and the related
allethrin and dimethrin were insufficient to establish acceptable
daily intakes for those substances, there was no reason to question
the customary uses of pyrethrins. Piperonyl butoxide was considered
because it is often present, as a synergist, in pyrethrin
formulations. Although there is no evidence that the uses of piperonyl
butoxide as at present approved involve any danger, there is not
enough information on the compound to allow the setting of an
acceptable daily intake figure for man.
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
Committee meeting.
Unpublished data, because they may include more detail than
published work, may often be required for the determination of
acceptable daily intakes. These data most 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
experts.
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.
Biochemical studies
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.
Acute toxicity
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
this heading.
Short-term studies
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.
Long-term studies
These studies include tests covering the greater part of the
animal's life-span and research on the possible carcinogenicity of the
residues. The requirements of the latter tests have been discussed in
previous reports.1,2,3
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.
Special studies
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 organo-phosphorus 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.
(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
minimum.
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
(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.
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
man.
Evaluation
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.
1 Medved, L. I., Spyn, E. I. & Kagan, I. S. (1964) Residue Reviews,
6, 42.
2 Goldberg, M. E. & Johnson, H. E. (1964) J. Pharm. (Lond.), 16,
60.
3 Goldberg, M. E. & Johnson, H. E. (1964) J. Pharmacol. exp. Ther.,
145, 367.
4 Goldberg, M. E., Johnson, H. E. & Knaak, J. B., Psychopharma (In
press).
5 Goldberg, M. E., Johnson, H. E. & Knaak, J. B., Biochem.
Phamacol. (In press).
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.
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
toxicologically acceptable.
Note to 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
Rome, Italy
Any comments on biological data and their evaluation should be
addressed to:
Nutrition Unit
World Health Organization
Geneva, Switzerland
1 Gaddum, J. H. (1956) Brit. J. Pharmacol., 11, 156.
2 Mantel, N. & Bryan, W. R. (1961) J. nat. Cancer Inst., 27, 455