FAO/PL:1969/M/17/1
WHO/FOOD ADD./70.38
1969 EVALUATIONS OF SOME PESTICIDE RESIDUES IN FOOD
THE MONOGRAPHS
Issued jointly by FAO and WHO
The content of this document is the result of the deliberations of the
Joint Meeting of the FAO Working Party of Experts and the WHO Expert
Group on Pesticide Residues, which met in Rome, 8 - 15 December 1969.
FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS
WORLD HEALTH ORGANIZATION
Rome, 1970
DDT
Explanation
This insecticide was evaluated by the Joint FAO/WHO Joint Meeting on
Pesticide Residues in 1966 (FAO/WHO, 1967b). Additional information,
particularly on metabolism was considered again in 1967 and resulted
in a monograph addendum (FAO/WHO, 1968b). The recent public concern
for the hazards of DDT, especially in relation to the reports of
Increased tumour incidence in experimental animals fed DDT and to the
widespread occurrence of DDT in living organisms and generally
throughout the environment, led to Its further consideration by this
Joint Meeting. This monograph addendum summarizes data available on
DDT in relation to its possible ability to induce tumours. Section 2.6
of the general report of the meeting (FAO/WHO, 1970a) contains
comments on the general environmental aspects.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
Monkey
Rhesus monkeys of mixed sex (12 males and 12 females) were divided
into groups and fed over periods up to 7.5 years or longer on diets
containing 0, 5, 50, 200 and 5000 ppm. Biopsies were performed on
several organs. The histopathology gives no report of tumour formation
in any animals (Durham et al., 1963).
Mouse
A total of 683 mice of the BALB/c strain spread over five generations,
were fed dietary levels of 2.8 - 3.00 ppm of DDT (0.4 -0.7 mg/kg
body-weight/day) for six months. The background DDT content of the
diet given to 406 controls corresponded to an intake of 0.03-0.05
mg/kg body-weight/day. Altogether leukaemia occurred in 85 test
animals (12.4 percent) but only in 10 controls (2.5 Percent). The
significance became apparent in the F3 generation. The incidence of
tumours in the DDT group attained significance one generation earlier
(in the F2 group). However, a suspected transgeneration cumulative
effect resulting in progressive increase in tumour incidence with each
generation was not substantiated when the results from all five
generations became available. A total of 196 tumour-bearing animals
(28.7 percent) was recorded in the DDT group compared to 13 in the
controls (3.2 percent). The most frequent tumour types were leukaemia,
carcinoma of the lung, haemangioendothelioma and reticulium cell
carcinoma (Kemény and Tarjan, 1966; Tarjan and Kemény, 1969).
Groups of 18 mice of each sex, from two hybrid strains of mice were
given DDT for 18 months. The dose of 46 mg/kg body weight was given by
gavage from the seventh day of age to the time of weaning at four
weeks of age and thereafter DDT was added to the diet in a
corresponding amount of 140 ppm. The incidence of hepatomas was 18 out
of 35 treated males (51 percent) and 5 out of 24 treated females (21
percent) compared with the control value of 13 out of 162 males (18
percent) and 7 out of 158 (0.6 percent) females (Innes et al., 1969).
Two strains of mice, namely BALB/cJ and C3HeB/FeJ, were divided into
groups, each of which contained 100 male and 100 female animals of
each strain. The groups were fed 0 or 100 ppm of DDT in the diet for
periods up to two years. In the BALB/cJ strain there was no
significant increase in tumours in the DDT-treated group when compared
to the controls, but, because of the high incidence of mortalities in
both groups of this strain, the results ware considered to be
questionable. In the C3HeB/FeJ strain the number of deaths was much
lower. The females of this strain displayed a 24 percent incidence of
hepatomas in the group fed DDT compared to 9 percent in the controls.
There was, however, a loiter incidence of tumours at other sites in
this group when compared to the controls, resulting in no overall
increase in the total incidence of tumours. The incidence of
hepatocarcinomas was equally low in treated and control groups of both
sexes in both strains (Fitzhugh, 1969).
Rat
Groups of 12 male rats were subjected for two years to diets
containing 0, 100, 200, 400 and 800 ppm of DDT. In another experiment,
groups each of 24 rats (12 males and 12 females) were given, during
the came period, diets containing 0, 200, 400, 600 and 800 ppm. Also
additional groups of 24 animals received 600 and 800 ppm incorporated
in their feed in a dry state. In the groups receiving 400 ppm and
above, an increase in the mortality rate was seen in relation to the
does. Apart from nervous symptoms at doses of 400 ppm and above,
typical liver lesions were found at all concentrations. Hepatic cell
tumours were seen in four out of 75 animals and 11 other rats showed
nodular adenomatoid hyperplasia. The authors concluded that a minimum
tendency for the formation of hepatic cell tumours was evident and
that this feature was apparent only after 18 months of feeding
(Fitzhugh and Nelson, 1947).
Trout
Rainbow trout were fed varying levels of DDT ranging from 0 to 9600
ppm for periods up to two years. At the 75 ppm level hepatomas were
present in 7 out of 19 fish after 15 months of feeding DDT. Mortality
was high in the 2400 and 9600 ppm groups (Halver, 1967).
Studies (sponsored by WHO) on the investigation of the potential
carcinogenicity of DDT to mice or rats are presently being conducted
at the International Agency for Research on Cancer, Lyon, France; the
National Institute for the Study and Cure of Tumours, Milan, Italy;
the Institute of Experimental and Clinical Oncology, Moscow, U.S.S.R.,
and the Research Institute of Oncology, Leningrad, U.S.S.R. The
results of these studies should be available in 1971.
OBSERVATIONS IN MAN
A study was made on 35 men with 11 to 19 years' exposure to DDT in a
plant producing the compound. Levels of DDT and its metabolites in
these workers ranged from 38 to 647 ppm. Physical examinations and
clinical laboratory tests did not reveal any incidences of cancer or
blood dyscrasias, the only abnormality being a high
lymphocyte-granulocyte ratio (>1.0) in five men (Laws et al., 1967).
Levels of organo-chlorine pesticides were determined at autopsy in the
fat of 271 patients who, prior to death, had exhibited various
pathological states of the liver, brain, and other organs. These
pesticide levels were compared with those found in the fat of random
autopsy cases. Concentrations of DDT were 2 to 3 times the normal
levels in those patients who died from carcinomas of the lungs,
stomach, rectum, pancreas, prostate and bladder. Data obtained by
interviewing next-of-kin also revealed a marked relationship between
home use of DDT and the levels of DDT and its metabolites in the fat.
Because of the emaciated condition of many of the patients, it was
considered possible that the high pesticide levels were related to
loss of fat in the adipose tissue resulting in a higher concentration
of pesticides in the remaining fat. However, when the loss of
body-weight was compared to pesticide concentration, no such
relationship was observed. It is therefore not known whether the
disease caused the elevated pesticide level or vice versa (Radomski et
al., 1968).
Other epidemiological studies have failed to demonstrate any
association between human cancer and DDT (Hayes, 1961; New York,
1969).
COMMENTS
The available experimental data do not provide sufficient information
to allow a definite evaluation of the potential carcinogenicity of
DDT, however they strongly indicate that DDT ought to be extensively
tested. In fact the 1967 Joint FAO/WHO Meeting already recognized the
need for further studies. Following this recommendation, work was
initiated by WHO and IARC. The results of these studies will not be
available until 1971. For these reasons a definite decision on the
potential hazard of DDT to man cannot be taken now. However, because
the hazard to man from DDT has not been ruled out, it is recommended
that uses of DDT should be limited to those situations where there are
no satisfactory substitutes.
In the light of this consideration it was decided to lower the adi and
change it to a conditional adi in order to limit the use of DDT except
where it is absolutely necessary.
TOXICOLOGICAL EVALUATION
Level causing no significant toxicological effect
Rat: 1 ppm in the diet, equivalent to 0.05 mg/kg body-weight/day
ESTIMATE OF CONDITIONAL ACCEPTABLE DAILY INTAKE FOR MAN
0-0.005 mg/kg body-weight
RESIDUES IN FOOD AND THEIR EVALUATION
USE PATTERN
The meeting was aware that, in several countries, use patterns and
scale of use of DDT are being revised. As a consequence, the residue
levels in many food crops are likely to be reduced considerably. New
information on the amended use patterns in various countries are
required, with details of residues resulting from pertinent trials in
order to reconsider the recommendations for temporary tolerances.
In considering whether there was any need for priority in reviewing
these recommendations, it was noted that the few total diet studies
that had been carried out had revealed that the maximum intakes of DDT
and its metabolites were well below the adi as established at this
meeting.
RECOMMENDATIONS FOR TOLERANCES, TEMPORARY TOLERANCES OR PRACTICAL
RESIDUE LIMITS
With the exception of a previously recommended tolerance on fish which
has been withdrawn because adequate information on residue levels in
fish moving in trade channels wan not available, the Meeting agreed
that all other tolerances should remain in effect pending further
study.
FURTHER WORK OR INFORMATION
REQUIRED (before 30 June 1971)
1. Results of the carcinogenicity studies which are currently in
progress.
2. Information on any officially acceptable uses on agricultural
commodities, together with residues resulting from pertinent trials.
REFERENCES
Durham, W.F., Ortega, P. and Hayes, W.J. Jr. (1963) Effect of various
dietary levels of on liver function, cell morphology and DDT storage
in the Rhesus monkey. Arch. internat. Pharmacodyn., 141: 111-29
FAO/WHO (1967b) Evaluation of some pesticide residues in food. FAO,
PL: CM/115; WHO/Food Add./ 67/32
FAO/WHO (1968b) 1967 evaluations of some pesticide residues in food.
FAO/PL : 1967/M/11/1; WHO/Food Add./68.30
FAO/WHO (1970a) Pesticide residues in food; report of the 1969 Joint
Meeting of the FAO Working Party of Exports on Pesticide Residues and
the WHO Export Group on Pesticide Residues. FAO Agricultural Studies
No. 84 Wld Hlth Org Techn Rep Series No. 458
Fitzhugh, O.G. and Nelson, A.A. (1947) Chronic oral toxicity of DDT.
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Fitzhugh, O.G. (1969) A summary of a carcinogenic study of DDT in
mice. Unpub. rept. from the Bureau of Science, Food and Drug
Administration, USA
Halver, J.E. (1967) Crystalline aflatoxin and other vectors for trout
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Hayes, W.J., Jr. (1961) Diagnostic problems in toxicology
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Kemény, T. and Tarjan, R. (1966) Investigations on the effects of
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: 748-49
Laws, E.R., Jr., Curley, A. and Biros, F.J. (1967) Men with intensive
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New York. Health Research Ins. (1969) report on contract no. PH
86-65-121. Studies of cancer morbidity and mortality in New York State
as a basis for assessing potential relationships to pesticide usage,
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Radomski, J.L., Deichmann, W.B. and Clizer, E.E., (1968) Pesticide
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