PESTICIDE RESIDUES IN FOOD - 1984
Sponsored jointly by FAO and WHO
EVALUATIONS 1984
The monographs
Data and recommendations of the joint meeting
of the FAO Panel of Experts on Pesticide Residues
in Food and the Environment and the
WHO Expert Group on Pesticide Residues
Rome, 24 September - 3 October 1984
Food and Agriculture Organization of the United Nations
Rome 1985
DDT
Explanation
This pesticide was evaluated for acceptable daily intake by the
Joint Meetings in 1963, 1965, 1966, 1967, 1968, 1969, 1971, 1974,
1977, 1978, 1979, 1980 and 1983.1/ An ADI of 0-0.005 mg/kg bw was
allocated in 1963 and changed to 0-0.01 mg/kg bw in 1965. In 1967, the
ADI was extended to the metabolites DDD and DDE (or any combination of
the three). In 1969, the Joint Meeting, because of concern about the
potential carcinogenicity of DDT, lowered the ADI to 0.005 and changed
it to a conditional status. In 1983, the Joint Meeting recommended a
review of the toxicology data base for complete re-evaluation.
This monograph, considering that several reviews of DDT toxicity
have been recently published (appropriate references are given in the
text), will report only new data not reported in these recent reviews
and new and/or old data concerning some relevant chemical properties,
metabolism, special studies on carcinogenicity and observations in
humans. The meeting based the re-evaluation and the decisions on DDT
on these data.
IDENTITY
Information on chemical names, structural formula, formulations
and nomenclature of isomers is available from previous FAO/WHO reviews
(FAO/WHO and others [WHO, 1979; IARC, 1974; NIOSH, 1978]).
Other Relevant Chemical Properties
Studies on the photochemical behaviour of DDT have been recently
reported (Parlar, 1980a, b).
A comparison of the absorption spectra of DDT adsorbed on a
surface with those in solution in n-hexane demonstrate that adsorption
influences the ultraviolet behaviour. The Lb-bands responsible for
the degradation of DDT undergo a shift to higher wavelengths and, as a
result, enter the spectral region of the troposphere (above 290 nm).
Thus, shifts between 10-20 nm and up to five-fold increases in
intensity of individual bands are recorded in the adsorbed phase (Gäb
et al., 1974, 1975).
DDT, which has no chromophonic group, can be excited by
wavelengths greater than 290nm in the adsorbed state. Experiments
indicate that DDT and DDE are degraded to carbon dioxide and hydrogen
chloride even when irradiated with wavelengths greater than 290 nm.
The formation of mineralization products cannot be detected in some
chlorinated aromatic compounds. Table 1 illustrates that DDT and DDE
can be very easily degraded to CO2 and HC1 (Parlar, 1981).
1/ See Annex 2 for FAO and WHO documentation
TABLE 1. Photomineralization of DDT in Comparison to Chlorinated Alkalines
Substance Quartz (3d)1 Pyrex (6d)1
HCl and/or Cl2 CO2 formed HCl and/or Cl2 CO2 formed
(%) (%) (%) (%)
DDT 75 82 35 42
DDE 78 85 45 55
Hexachlorobutadiene 40 42 44 40
Tetrachloroethylene 35 37 25 26
1 Percentages are given by the amounts of CO2/Cl actually formed divided by the amounts of
C02/Cl expected from a total mineralization of the initial quantity adsorbed
(200 ug 14C-compounds/200 g silica gel).
DDT and DDE react under the influence of solar irradiation in the
solid phase and in the presence of oxygen and go directly to CO2 and
HC1 (Parlar, 1981). Results are summarized in Table 2.
TABLE 2. Photomineralization of DDT and Various Chlorinated
Hydrocarbons in Solid Form using a Current of Oxygen
Quartz (2 days) Pyrex (6 days)
Compound (80 mg in each case) CO2 HCl CO2 HCl
Dieldrin 51 19 8 3
Hexachlorobenzene 46 19 n.d. n.d.
Pentachlorobenzene 51 25 n.d. n.d.
2,2',4'5,5'-Hexachlorobiphenyl 47 21 n.d. n.d.
DDT 82 85 15 8
n.d.= not detected
Solar irradiation in water or organic solvents indicate that DDT
can be converted mostly to DDE and dichlorodibenzoketone. DDT is
degradable under these conditions with wavelengths that are present in
the troposphere (Plimmer et al., 1970; Wichmann et al., 1946;
Roburn et al., 1983).
DDT in the gaseous phase is transformed in small amounts to DDE.
The process can be accelerated in the presence of proton donors, such
as paraffins (Parlar, 1983).
The results of these experiments, particularly those where DDT is
adsorbed on surfaces, indicate that DDT is readily biodegradable under
natural conditions occurring worldwide.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, Distribution and Excretion
Absorption, distribution and excretion of DDT were reviewed by
FAO/WHO in 1963, 1965, 1966 and 1967 and by others (Hayes, 1965; IARC,
1974; EPA, 1975; NIOSH, 1978; WHO, 1979).
Metabolism
The metabolism of DDT was reviewed by the JMPR in 1963, 1965,
1966 and 1967 and by other authors (Hayes, 1965; IARC, 1974; NIOSH,
1978; WHO, 1979).
Syrian golden hamsters of both sexes were given orally
1 000 mg/kg 14C-DDT, and urine and faeces collected for three days.
About 60 percent of the total dose was recovered, with higher
radioactivity in faeces than in urine (about 50 percent versus
10 percent). After administration of an oral lethal dose (up to
5 × 1 000 mg/kg) DDT in brain was about 25 ppm 12 h after dosing and
50-70 ppm at the time of death.
DDT and its metabolites DDA, DDD and DDE given orally at the dose
of 25 mg/kg were excreted in the urine as total DDA as follows: 10,
60, 50 and 0 percent respectively (Gingell & Wallcave, 1974).
14C-DDT, 25 mg/kg orally, was given to Syrian golden hamsters and the
urine collected for five days. Major urinary metabolites were
conjugates of DDA. Autoradiochromatographic profiles of hexane
extracts of urine did not demonstrate the presence of DDE (Gingell,
1976).
Swiss mice of both sexes were given orally 250 mg/kg 14C-DDT and
urine and faeces collected for three days. About 60 percent of the
total dose was recovered and radioactivity was higher in faeces than
in urine (about 55 percent versus 5 percent). After administration of
an oral lethal dose (500 mg/kg), DDT in brain was 39-46 ppm 12 h after
dosing and 49-58 ppm at the time of death. DDT and its metabolites
DDA, DDD and DDE, given orally at the dose of 25 mg/kg, were excreted
in urine as total DDA as follows: 5, 47, 13 and 0 percent,
respectively (Gingell & Wallcave, 1974).
CF-1 mice of both sexes were given orally 25 mg/kg 14C-DDT and
the urine collected for five days. About 15 percent of the 14C was
recovered. Major urinary metabolites were conjugates of DDA.
Autoradiochromatograms of hexane extracts showed that 0.8 percent of
the administered dose of 14C was excreted as DDE (Gingell, 1976).
Residues of DDT and metabolites were measured in tissues of
several species after continuous feeding (Hays, 1965; IARC, 1974;
NIOSH, 1978; WHO, 1979). Residues of DDT and metabolites in rodents'
livers are summarized in Table 3.
TABLE 3. Liver Residues of DDT, DDE and DDD in Rodents Maintained at Dietary DDT
Species Dietary level Feeding period Total residues in DDT/DDE References
(ppm) (days) liver (range-ppm) ratio
mouse 250 42 56-70 1.8 Gingell &
Wallcave,
1974
rat 200 140 13-35 5 IARC, 1974
hamster 250 42 8-9.3 9 Gingell &
Wallcave,
1974
Effects on Enzymes and Other Biochemical Parameters
These effects have been reviewed by FAO/WHO (1963, 1965, 1967),
and by WHO (1979) and NIOSH (1978).
TOXICOLOGICAL STUDIES
Special Studies on Reproduction
These studies have been reviewed by NIOSH (1978) and WHO (1979).
Special Studies on Mutagenicity
These studies have been reviewed by WHO (1979), NIOSH (1978) and
IARC (1982).
Special Studies on Carcinogenicity
Mouse
Over a period of six generations, BALB/C mice were given doses of
DDT in the diet of 3 mg/kg of p,p'-DDT. There were 406 mice in the
control group and the experimental groups contained 683 mice which had
an average daily intake of 0.4-0.7 mg/kg of DDT. An increase of
leukaemias, particularly in animals fed the diet containing pure DDT
that was supplemented at the F3 generation, was observed. At least
one-third of the total malignancies found in the F4 and F5
generations were myeloid leukaemias. A high incidence of pulmonary
carcinoma was found (in 116/196 mice). Many other tumours were
described from this study, but very few hepatocellular carcinomas were
found (Tarján & Kemény, 1969).
Two strains of mice, 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 were considered 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 lower incidence of tumours at other sites in this group as
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).
DDT was given to hybrid mice produced by crossing C-57 BL/6 with
either C3H/Amf or AKR strains. At the beginning, DDT was given by
gavage at the maximum tolerated dose of 46.4 mg/kg/day and after four
weeks to the end of the experiment (approximately 18 months), the
chemical was given in the diet at approximately 21 mg/kg/day.
Hepatomas were observed in a large number of males and females given
DDT, lymphomas were significantly increased above the controls and
lung and lymphatic tumours, particularly adenomas, were described
(Innes et al., 1969).
DDT was fed to two generations of CF-1 mice at doses ranging from
0.3 to 37.5 mg/kg/day for their entire lifespan. There was no
increased incidence of cancer in female mice at the dose levels of 0.3
and 3.0 mg/kg/day. However, there was a slight increase beginning at
7.5 mg/kg/day and a higher one at 37.5 mg/kg/day. By contrast, the
male mice developed hepatomas at a rate above that of the naturally
occurring cancers at all treatment levels (Tomatis et al., 1972).
CF-1 mice were given DDT for 104 weeks at 7.5 and 15 mg/kg in the
diet. A dose response in the development of liver neoplasms was found,
which ranged as high as 53 percent at the high dose of 15 mg/kg/day
and 37 percent at 7.5 mg/kg/day; 13 percent of the controls had
tumours. There seemed to be more tumours present in the females,
particularly in the high dose animals and in the controls (Walker
et al., 1973). In a similar study, both the males and females of the
control group had 23 percent tumours, whereas the incidence was
77 percent in the males and 87 percent in the females of the high dose
groups. No reduction in longevity was observed in either males or
females in all the groups (Thorpe & Walker, 1973).
Strain A mice were dosed DDT by gavage in sunflower oil for their
entire lifespan. Daily doses of 1.5 and 7.5 mg/kg/day were given to
the parents for their lifetime and 10 mg/kg/day to the F1 through F5
offspring beginning at 6-8 weeks of age. An increase in lung adenomas
was found only at the highest dose. No liver tumours were detected
(Shabad et al., 1973).
Two generations of BALB/C mice were dosed 0.3, 3.0 and
37.5 mg/kg/day of DDT for their entire lifespan. No tumour formation
or any abnormal histology was detected at doses of 0.3 and
3.0 mg/kg/day. An increased incidence of hepatomas was found at the
high level of 37.5 mg/kg/day. At the dose of 37.5 mg/kg/day there was
a decrease in malignant lymphomas from the normal 50 percent level
observed in the colony to 14 percent in one experimental colony and 36
percent in the other one (Terracini et al., 1973).
CF-1 mice were given 37.5 mg/kg/day of DDT for 15 or 30 weeks.
The mice were autopsied at 65, 95 and 120 weeks from the start of the
study. The shorter the period of exposure, the lower was the incidence
of liver tumours. The number and size of the hepatomas observed were
related to the period of time of exposure at necropsy. No evidence of
invasiveness into surrounding tissues, hyperplasia of the cells or
metastases was found (Tomatis et al., 1974a).
DDE and DDD at doses of 37.5 mg/kg/day of each compound in the
diet of CF-1 mice and a mixture of 18.75 mg/kg/day of the compounds
were given. DDE was observed to produce more liver tumours than did
DDD. In addition, lung adenomas were increased with DDD alone. When
DDE was mixed with DDD or DDE was given alone, a decrease in lung
adenomas was observed. However, when the combination of DDD and
DDE.was given, the frequency of hepatocellular neoplasms increased in
both males and females (Tomatis et al., 1974b).
Inbred Swiss mice were treated with technical DDT orally in the
diet (15 mg/kg/day) or by gavage (10 mg/kg/day) for 80 weeks. Toxic
manifestations of DDT were observed in treated mice after 40 weeks.
DDT treatment resulted in a significant increase of tumours of
lymphoid tissues, lung and liver. Males and females were equally
susceptible (Kashyap et al., 1977).
Groups of 50 male and 50 females B6C3F1 mice were exposed to DDT,
DDD or DDE in diet (3.3-26, 62-124, and 22-38 mg/kg/day, respectively)
for 78 weeks. DDT and DDD were not carcinogenic. DDE caused a
statistically significant dose-related increase in incidence of
hepatocellular carcinomas in both sexes (National Cancer Institute,
1978). Carcinogenicity studies in mice are summarized in Table 4.
Hamster
Syrian golden hamsters were fed DDT at doses of 40-80 mg/kg/day.
No tumours were observed over the normal incidence (Agthe et al.,
1970). DDT did not cause tumour formation in hamsters at doses
equivalent to 80 mg/kg/day (Graillot et al., 1975).
Syrian golden hamsters received in the diet, over their lifetime,
0, 125, 250 and 500 parts per million (ppm) of DDT. The normal
incidence of tumours in the control males was 8 percent, whereas the
number of tumours observed in the treated males ranged between 17
percent and 28 percent. In the females, the number of tumours found
was 13 percent in the controls and in the treated females they ranged
between 11 percent and 20 percent. There appeared to be a dose-related
increase of tumours in the adrenal cortex of males fed DDT. The
authors concluded that there was no significant difference between the
control animals and those fed the diets containing DDT (Cabral et
al., 1982a).
DDE was given in the diet at 500 or 1 000 ppm to male and female
Syrian golden hamsters for their lifespan. An experimental control
group of animals were given 1 000 ppm of DDT and a fourth group served
as controls. There were 40 hamsters of each sex per group. DDT caused
no tumour formation in any of the hamsters receiving 1 000 ppm of DDT.
DDE produced hepatocellular tumours late in the life of the hamsters.
Fifteen percent of the females and 47 percent of the males at the
500 ppm DDE dose level had neoplastic nodules, whereas 21 percent of
the females and 33 percent of the males had tumours at the 1 000 ppm
DDE dose level. Syrian golden hamster normally develops adrenocortical
adenomas with age and more of these tumours were found in both the DDE
and DDT groups as compared to the control group (Rossi et al.,
1983).
Carcinogenicity studies in hamsters are summarized in Table 5.
TABLE 4. Long-Term DDT Tumorigenicity Studies in Mice
Strain No. animals Max. period Dose range Results: evidence of Reference
exposed of exposure (mg/kg/day) tumourigenicity
in diet1
BALB/C 683 5 generation 0.45 increased incidence of lung Tarján & Kemény,
carcinomas, lymphomas & other 1969
tumours
BALB/CJ 200 104 wk 15 no effect (high mortality) Fitzhugh, 1969
C3HeB/FeJ 200 104 wk 15 increased incidence of hepatomas Fitzhugh, 1969
(C57BL/6x 36 78 wk 21 2 increased incidence of hepatomas Innes et al.,
C3H/Anf)F1 & lymphomas 1969
(C57BL/6x 36 78 wk 21 2 increased incidence of hepatomas Innes et al.,
AKR)F1 & lymphomas 1969
CFl 881 2 generation 0.3-37.5 increased incidence of hepatomas Tomatis et al.,
lifespan in males at any dose level, in 1972
females above 7.5 mg/kg
CFl 120 104 wk 7.5-15 increased incidence of hepatomas Walker et al.,
at both dose levels 1973
CFl 60 110 wk 15 increased incidence of hepatomas Thorpe & Walker,
1973
A 264 5 generation 1.5-7.5 increased incidence of lung Shabad et al.,
lifespan adenomas 1973
BALB/C 946 2 generation 0.3-37.5 increased incidence of hepatomas Terracini et
lifespan at the highest dose levels al., 1973
TABLE 4. (continued)
Strain No. animals Max. period Dose range Results: evidence of Reference
exposed of exposure (mg/kg/day) tumourigenicity
in diet1
CFl 960 15-30 wk 37.5 increased incidence of hepatomas - Tomatis et al.,
incidence was reduced with shorter 1974a
exposure or when animals were
killed earlier.
CFl 118 lifespan 37.5 DDD increased incidence of lung Tomatis et al.,
adenomas 1974b
108 lifespan 37.5 DDE increased incidence of hepatomas
111 lifespan 18.75 DDD increased incidence of hepatomas
& 18.75 DDE
Swiss 120 80 wk 10-15 increased incidence of lung Kashyap et al.,
adenomas, hepatomas & lymphomas 1977
B6C3Fl 200 78 wk 3.3-26 DDT no effect National Cancer
200 78 wk 62-124 DDD no effect Institute, 1978
200 78 wk 22-38 DDE increased incidence of liver
carcinomas
1 In all cases dosage administered in the diet, except Shabad et al., 1973, administered in sunflower oil by
gavage, and Kashyap et al. in olive oil by gavage in the 10 mg/kg group.
2 Day 7 to 28, DDT given by gavage at the maximum tolerated dose of 46.4 mg/kg.
TABLE 5. Long-Term DDT Tumourigenicity Studies in Syrian Golden Hamsters
No. animals Max. period Dose range Results: Reference
exposed of exposure (mg/kg/day) evidence of
in diet tumourigenicity
115 44 wk 40-80 no effect Agthe et al., 1970
180 78 wk 20-80 no effect Graillot et al., 1975
200 lifetime 10-40 no effect Cabral et al, 1982a
80 lifetime 80 no effect Rossi et al., 1983
160 lifetime 40-80 DDE increased
incidence of
hepatomas
Rat
Groups of 12 male rats were subjected for two years to diets
containing O, 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 same 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
dose. Nervous symptoms were observed at doses of 400 ppm and above and
liver lesions, consisting of hypertrophy of the central, lobular
hepatic cells and focal necrosis, 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 & Nelson, 1947).
Rats were fed purified high and low fat and normal diets with and
without DDT. Higher incidence of leukaemia was related to the diet and
not to DDT (Kimbrough et al., 1964).
Osborne-Mendel rats were given DDT at three dose levels: 7.5 and
12.0 mg/kg/day for two years; and DDT mixed with 12 mg/kg/day each of
aramite, methoxychlor and thiourea. After two years, no synergistic or
additive effect was reported nor any change in tumour formation
(Radomski et al., 1965). Similar experiments were reported of dosing
rats with 200 ppm DDT in the diet for 27 months. Less tumour formation
was detected in the DDT-exposed rats than in the controls. However,
increased liver weights and liver pathology characteristic of high
doses of DDT were observed. Some liver tumours in rats fed DDT and
aramite or a mixture of these two pesticides with methoxychlor and
thiourea were found, although the incidence of tumour formation still
was not significant (Deichmann et al., 1967).
Weanling Fisher 344 rats were fed 10-30 mg/kg/day of DDT and no
hepatocellular toxicity or liver tumours were observed. However, when
a small dose of 2-AAF was added, hepatomas increased greatly,
particularly in the males and to a lesser extent in the females
(Weisburger & Weisburger, 1968).
Wistar rats dosed with DDT 25 mg/kg/day showed higher incidence
of hepatocellular tumours (Rossi et al., 1977). Lifelong exposure of
Wistar rats to simultaneous administration of DDT (25 mg/kg/day in the
diet) and phenobarbital (same dose) caused primary liver tumours,
including hepatocellular carcinomas (79.3 percent in females and 46.4
percent in males) (Barbieri et al., 1983).
In bioassays of DDT, DDD and DDE in male and female Osborne-Mendel
rats for a period of 78 weeks, no evidence of carcinogenicity occurred
with DDT or DDE in either sex. Similarly, DDD caused no tumour
formation in the females, but the males had an increase in follicular
cell adenomas and carcinomas of the thyroid. DDE proved to be
hepatotoxic and central lobular necrosis and fatty metamorphosis were
observed, but there was no increase in the number of tumours of the
liver (NCI, 1978).
Male and female Porton Wistar rats were fed 125, 250 or 500 ppm
of DDT over their lifespan. No adverse changes were observed on body
weight gain or growth or on the survival rate with any of the groups
fed DDT in the diet. No significant increase in hepatomas was observed
in the males but was seen in the females. No metastases of any kind
were observed (Cabral et al., 1982b).
Table 6 compares carcinogenicity of DDT, DDE and DDD in rodents.
Carcinogenicity studies in rats are summarized in Table 7.
TABLE 6. Summary of the Comparative Carcinogenicity of DDT, DDE
and DDD in Rodents
Mice Rats Hamsters
DDT + ± -
DDE + - +
DDD ± ± No studies available
+ = positive, - = negative, ± = inconclusive
TABLE 7. Long-Term DDT Tumourigenicity Studies in Rats
Strain No. animals Max. period Dose range Results: evidence of Reference
exposed of exposure (mg/kg/day) tumourigenicity
(weeks) in diet 1
Osborne-Mendel 192 104 5-40 Increase in liver tumours at Fitzhugh & Nelson,
unspecified close 1947
Carworth 240 104 2.5-25 No effect Treon & Cleveland,
1955
Sherman 75 variable 1-2 No increase in leukaemia Kimbrough et al.,
(max.= 40) incidence 1964
Osborne-Mendel 60 104 7.5-12 12 mg/kg/day, no effect. Radomski et al.,
Slight increase in liver 1965
tumour incidence at 7.5
mg/kg/day
Osborne-Mendel 60 116 10 No effect Deichmann et al.,
1967
Fischer 30 52 10-30 No effect Weisburger &
Weisburger, 1968
Wistar 72 152 25 Liver tumours in 45% of animals Rossi et al., 1977
Osborne-Mendel 200 78 DDT 10-31 DDT & DDE, no significant National Cancer
200 78 DDD 43-165 tumour incidences; DDD Institute, 1978
200 78 DDE 12-42 increased thyroid tumours
MRS Porton 196 144 25 (max) Increased hepatomas, females Cabral et al.,
(Wistar (125-500 ppm) only; no metastases. Survival 1982b.
derived) rates normal. Weak carcinogenic
effect.
1 In all cases, dosages administered in diet.
Monkey
Rhesus monkeys (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 5 000 ppm of DDT. Biopsies were performed on several
organs. The histopathology gives no report of tumour formation in any
animals (Durham et al., 1963).
Twenty-four monkeys received, by gavage, 20 mg/kg five days/wk of
DDT for 134 months, a little over 11 years. During the course of this
experiment, five of the monkeys died and no tumours were found in any
of the animals. Since all of the animals that died had severe
convulsions and tremors prior to death, they assumed that the reason
was related to DDT, which caused central nervous system toxicity. Up
to the present, the 19 surviving Rhesus monkeys appear to be normal
and have no evidence of tumour formation based on biopsies and lack of
biochemical changes. No alterations were observed in the alphafeto
protein biochemical tests (Adamson & Sieber, 1983).
Special Studies on Influence on Lymphatic Tissue and Immune Response
These studies were reviewed by NIOSH (1978) and WHO (1979).
Special Studies on Endocrine Effects
These studies were reviewed by NIOSH (1978) and WHO (1979).
Special Studies on Teratogenicity
These studies were reviewed by NIOSH (1978) and WHO (1979).
Acute Toxicity
These studies were reviewed by FAO/WHO (1963, 1965, 1966, 1968),
IARC (1974), NIOSH (1978) and WHO (1979).
Short-Term Studies
These studies were reviewed by FAO/WHO (1963, 1965, 1966, 1968),
IARC (1974), NIOSH (1978) and WHO (1979).
Long-Term Studies
These studies were reviewed by FAO/WHO (1963, 1965, 1966, 1968),
IARC (1974), NIOSH (1978) and WHO (1979).
OBSERVATIONS IN HUMANS
DDT pharmacokinetics and toxicity in humans have been summarized
in several reviews (FAO/WHO, 1963, 1965, 1966, 1967; Hayes, 1965;
IARC, 1974; EPA, 1975; NIOSH, 1978; WHO, 1979; Spindler, 1983).
Comprehensive summaries of levels of DDT and its metabolites in
organs, blood, fat and milk of a general population have been recently
published (WHO, 1979).
Seventy-seven samples of human milk from rural and urban areas of
Rwanda in Central Africa have been examined. Higher levels of p,p'-DDE
and p,p'-DDT, but not p,p'-DDD, were measured in the rural as compared
to the urban areas. Comparing these data to mothers' milk obtained at
the University Hospital in Ghent, Belgium, the DDT levels from the
rural areas of Rwanda were twice as high as the Belgian sample from
1969. However, comparing the 1983 sample from Belgium with those
obtained at the same hospital in 1969 and 1979, the DDT levels had
significantly decreased, while the DDE levels were unchanged (Warnez
et al., 1983).
Fifty individual human milk samples from mothers in the city of
Helsinki were examined for DDT. These women were between the ages of
22 and 38 and ranged in weight from about 100 to 200 pounds. No data
were available regarding their diets. The total amount of DDT present
in whole human milk has decreased since 1973 from 0.058 mg/kg to 0.031
in 1982. (The use of DDT was restricted in Finland in the early 1970s,
and totally banned in 1977.) (Wickström et al., 1983).
Fifty samples of human milk taken directly from breast-feeding
Indian mothers were examined for DDT and its metabolites. In addition,
a comparison was made of milk taken from lactating buffalo and goats.
Forty-five of the 50 human mothers' milk samples contained a
measurable amount of DDT. The mean value was 0.523 ppm. As compared to
the milk of buffalos and goats, the human milk contained 12 and 13
times more, respectively, than was found in the animal milk (Saxena &
Siddiqui, 1982).
The umbilical cord blood of 100 Indian women was analysed for DDT
and its metabolites. No difference in the amounts of DDT and its
metabolites was observed in women regardless of their area of
residence (city vs. rural populations), even though there was slightly
more DDE in city dwellers. Older mothers (26-34 years) had more DDT
present in the cord blood than did younger ones (18-25 years), and
more DDE was observed in the older women as compared to the younger
group of women. There was no apparent difference between the women who
were vegetarians and non-vegetarians (Siddiqui et al., 1981).
DDT and its metabolites have been measured in blood plasma and
adipose tissue of the normal population and an occupationally exposed
group of workers. The average concentration of DDT and its metabolites
in the blood plasma of occupationally exposed males was 0.2 ppm, or
about seven times that of the normal population, which ranged from
0.023 ppm for children, 0.023 ppm for females and 0.028 ppm for
males. DDE levels in the general population were higher than in
occupationally exposed workers. Human adipose tissue samples had a
mean value of 1.754 ppm of DDT, which is lower than that described by
other authors in India (from 0.325 to 6.611 ppm of total DDT, whereas
the level of DDE was 1.05) (Kaphalia & Seth, 1983).
A cross-sectional study was recently reported on 499 residents of
a community in the United States who had been exceptionally exposed
primarily to DDD and DDE isomers by eating contaminated fish. Mean
total DDT in serum was 76.2 ng/ml (about five times the national
mean). DDE accounted for 87 percent of total DDT. Total DDT levels
increased with age. Other independent variables, including fish
consumption, were less significantly associated with DDT levels. Total
DDT levels were not associated with specific illness or ill health
(Kreiss et al., 1981).
COMMENTS
DDT had been allocated a conditional ADI of 0 - 0.005 mg/kg body
weight and a full review of all available data was recommended by the
1983 JMPR.
The following important aspects were identified concerning the
potential hazards of DDT to human health:
1. the storage of DDT and its metabolites in human body fat,
and the possible progressive accumulation of the pesticide
in the human environment owing to its chemical stability;
2. the presence of residues of DDT and its metabolites in human
milk and other milk used in infant feeding, and the
possibility of greater hazard to neonates, as they are
relatively undeveloped in their ability to detoxicate
chemicals;
3. the potential carcinogenicity of DDT to humans, indicated by
the reported tendency of the pesticide to induce hepatomas
in mice at high dosage.
Since the last full review by the JMPR in 1969, it has been shown
that DDT and its metabolites are photochemically degraded, especially
when adsorbed onto surfaces such as molecular films. Furthermore, the
DDT and its metabolites in fat depots are in dynamic equilibrium with
DDT in the circulating blood and undergo continuous metabolism and
excretion, and probably enterohepatic circulation.
DDT is selectively concentrated in milk because of its lipid
solubility, but neonates are not at increased risk since they are not
particularly susceptible to adverse effects from DDT.
DDT has often been assumed to have a potential for
carcinogenicity in humans, primarily from the evidence of its
production of an increase in liver tumours in mice, although the
causal relationship of DDT in such carcinogenicity has never been
elucidated. Of the known molecular mechanisms of genotoxic
tumourigenicity, namely the action of viruses (oncogenes), the action
of reactive oxygen species and free radicals (species generated by
ionizing radiation, quinones, etc.)on DNA, and the formation of
electrophilic reactive intermediates which alkylate and arylate DNA
(polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines),
only the latter would seem to offer any possible explanation for any
genotoxicity of DDT, and this might; possibly involve the formation of
an epoxide of DDE.
Indeed, DDE has been associated with a greater potential than DDT
for the formation of liver tumours in mice and has been considered to
be the metabolite responsible for the oncogenicity in this species.
However, DDT has been shown not to be mutagenic in a wide variety of
test systems, but may be weakly clastogenic (chromosome-breaking).
Furthermore, although DDT has produced an increase in liver tumours in
some mouse studies, no evidence of frank invasion or metastasis of the
hepatomas has been described. In the rat, DDT induces liver tumours
capriciously, and to a very minor extent, with sex differences, and
does not have any similar tumourigenic effect in hamsters or any other
animal species studied.
The susceptibility of the mouse to the formation of liver tumours
by DDT may be due to major species differences in the metabolism of
DDT and in the activation of chemical carcinogens by this species. The
mouse forms more DDE than humans and other species; humans form more
of the polar metabolite DDA.
However, DDT is a potent inducer of the cytochromes P-450 and,
like phenobarbitone, may, if administered in a appropriate
sequence, potentiate certain known genotoxic carcinogens, such as
2-acetamidofluorene. DDT might therefore act, like phenobarbitone, as
a promoting agent.
Acute toxic effects of DDT in humans are very rare. Repeated
exposure of workers for 25 years at an average dosage of
0.25 mg/kg/day is Without any adverse effect, and this may be taken as
a no-effect level for man. From epidemiological observations of
humans, and a three-generation study in dogs at doses up to
10 mg/kg/day, together with other studies on rodents and rabbits,
there is no firm evidence that DDT has any reproductive or teratogenic
effects. All epidemiological studies in humans have indicated that DDT
is not carcinogenic for humans, and no tumourigenicity has been
observed with DDT in rats, hamsters or monkeys at doses less than
50 mg/kg bw/day, by any investigator. In a detailed study in monkeys,
conducted at the National Cancer Institute, DDT was administered by
gavage at a dose of 10 mg/kg/day for 11 years without any tumourigenic
effect; a no-effect toxicological level of 10 mg/kg bw/day in monkeys
was based on a seven-year diet study conducted by the U.S. Food and
Drug Administration.
A recent lifespan carcinogenicity study in rats showed slight
increases in the incidence of hepatomas in females only at 250 and
500 ppm in the diet; the 125 ppm dose level was without effect, and
males showed no increased tumourigenicity at any of these doses;
125 ppm may therefore be taken as the no-effect level for
tumourigenicity in the rat.
It is therefore considered that the mouse is particularly
sensitive to DDT because of genetic and metabolic differences from
humans and other animals, and that there is no significant risk of DDT
producing tumours in humans. No-effect levels for tumourigenesis have
been established for rat (6.25 mg/kg/day), and an overall no-effect
level for toxicity of 0.25 mg/kg/day established for humans.
An ADI has been estimated giving full consideration to both
animal and human data.
TOXICOLOGICAL EVALUATION
Level Causing no Toxicological Effect
Rat: 125 ppm in the diet, equivalent to 6.25 mg/kg bw/day
Monkey: 10 mg/kg bw/day
Man: 0.25 mg/kg bw/day
Estimate of Acceptable Daily Intake for Man
0 - 0.02 mg/kg bw/day
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See Also:
Toxicological Abbreviations
Ddt (ICSC)
DDT (JECFA Evaluation)
DDT (PIM 127)
DDT (FAO Meeting Report PL/1965/10/1)
DDT (FAO/PL:CP/15)
DDT (FAO/PL:1967/M/11/1)
DDT (FAO/PL:1968/M/9/1)
DDT (FAO/PL:1969/M/17/1)
DDT (Pesticide residues in food: 1979 evaluations)
DDT (Pesticide residues in food: 1980 evaluations)
DDT (JMPR Evaluations 2000 Part II Toxicological)