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    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)