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    FAO Meeting Report No. PL/1965/10/1
    WHO/Food Add./27.65

    EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN FOOD

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Committee on Pesticides in Agriculture and
    the WHO Expert Committee on Pesticide Residues, which met in Rome,
    15-22 March 19651

    Food and Agriculture Organization of the United Nations
    World Health Organization
    1965

                
    1 Report of the second joint meeting of the FAO Committee on
    Pesticides in Agriculture and the WHO Expert Committee on Pesticide
    Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65

    PARATHION

    Chemical name

           Diethyl 4-nitrophenylphosphorothionate; O,O diethyl
    O-p-nitrophenyl phosphorothioate; O,O diethyl
    O-p-nitrophenyl thionophosphate

    Synonyms

           Thiophos; Niram; SNP; Paraphos

    Empirical formula

           C10H14O5NSP

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

    Biochemical aspects

           Parathion is readily absorbed by all the routes of
    administration. It is a powerful inhibitor of cholinesterase in
    vivo. In vitro, pure parathion had little effect on the enzyme
    (Aldridge & Davison, 1952). In mammals and plants parathion is readily
    oxidized to a powerful cholinesterase inhibitor, paraoxon, which is
    the active form of parathion (Heath, 1961). In mice given
    subcutaneously 32P labelled parathion, the highest radioactivity
    appeared in the salivary glands and cervical brown fat within 4 hours
    of injection. Liver, kidney and adipose tissues showed high uptake of
    radioactivity and fairly high activity was found in gastric and
    intestinal walls, thyroid, spleen and lungs. Less activity was noted
    in the central nervous system, musculature and bone marrow
    (Frederiksson & Bigelow, 1961). Parathion is finally broken down to
    p-nitrophenol, with traces of p-aminophenol (Gardocki & Hazleton,
    1951) and these are excreted in the urine. The final product depends
    on the species (Heath, 1961).

           The molar I50 for paraoxon against sheep erythrocyte
    cholinesterase was 2.0  10-8 (30 min.; 37C) (Aldridge & Davison,
    1952).

           In vitro studies on human liver enzyme indicated that parathion
    could inhibit the non-specific esterases to a greater degree than
    acetylesterase (Ecobichon & Kalow, 1963).

    Acute toxicity
                                                                                         
    Animal               Route         LD50 mg/kg     References
                                       body-weight
                                                                                     

    Mouse                Oral           6.0-25.0*     Frawley et al., 1952
                                                      Hazleton & Holland, 1950
                                                      Klimer & Pfaff, 1955

    Mouse, male     Intraperitoneal     10.4-11.4     Engbaek & Jensen, 1951

    Rat, female          Oral           1.75-5.0*     Deichmann et al., 1952
                                                      Edson & Noakes, 1960
                                                      Frawley et al., 1952
                                                      Gaines, 1960
                                                      Hazleton & Holland, 1950

    Rat, male            Oral           5.0-30.0*     Frawley et al., 1952
                                                      Gaines, 1960
                                                      Hazleton & Holland, 1950
                                                      Klimer & Pfaff, 1955

    Rat             Intraperitoneal        5.5        DuBois & Coon, 1952

    Guinea-pig           Oral           9.3-32.0*     Frawley et al., 1952
                                                      Hazleton & Holland, 1950

    Guinea-pig      Intraperitoneal       12.0        Klimmer & Pfaff, 1955

    Rabbit               Oral             10.0        American Cyanamid Company, 1955

    Chicken         Intraperitoneal        8.7        American Cyanamid Company, 1955

    Dog                  Oral            3.0-5.0      Hazleton & Holland, 1950
                                      (lethal dose)

    Dog             Intraperitoneal     12.0-20.0     DuBois et al., 1949
                                                                                     

    * Differences caused by the use of different vehicles.
    
           Man. An oral dose of 3-5 mg/kg is usually fatal to man (Erdmann
    & Lendle, 1960).

    Short-term studies

           Rat. Groups each of 5 male rats were placed on diets containing
    1, 5 and 25 ppm of parathion for 2 weeks. The lowest level that caused
    inhibition of the erythrocyte cholinesterase activity (the most
    sensitive to parathion) was 5 ppm (Frawley et al., 1952). 1 ppm did
    not give inhibition. Groups of 10 female rats were fed for 16 weeks
    diets containing 1, 5, 25 and 125 ppm of parathion. At 125 ppm, severe
    toxic symptoms, growth suppression and death occurred. At 25 ppm
    slight muscular fibrillation was seen in the first 2 weeks. At 5 and 1
    ppm no ill-effects were observed on general behaviour and growth.
    Erythrocyte cholinesterase activity was severely inhibited at 5 ppm
    and 25 ppm and above. No inhibition was observed at 1 ppm (Edson &
    Noakes, 1960).

           Concentrations of 0.05, 0.5 and 5.0 ppm of parathion was fed 
    for a period of 12 weeks to 4 groups of 20 rats. Of the initial 20 
    rats, after 1, 4 and 8 weeks, 4 animals, and after 12 weeks 8 animals, 
    were killed to determine the cholinesterase activity in brain, 
    erythrocytes and plasm. In this experiment 0.5 ppm was the highest 
    ineffective level in respect of toxic effects or blood cholinesterase
    inhibition (Edson, 1957).

           Dog. Groups each of one male and one female dog were placed for
    24 weeks on diets containing 1, 2 and 5 ppm of parathion, so that the
    average daily intake was 0.021, 0.047 and 0.117 mg/kg body-weight
    respectively. The 2 and 5 ppm levels caused about 60% and 70%
    inhibition of plasm cholinesterase activity and the 1 ppm level caused
    a small but significant inhibition. For erythrocyte cholinesterase
    activity only the 5 ppm level produced significant depression. The
    recovery of plasma activity at all levels was complete within 4 weeks
    after return to a control diet, and was frequently followed by a
    transient elevation above the pre-treatment activity. The recovery
    rate for erythrocyte activity was slower, requiring 11 weeks (Frawley
    & Fuyat, 1957).

           Dogs were given 100 ppm of parathion in the diet for 9 weeks. 
    In addition to a very strong inhibition of plasm and erythrocyte
    cholinesterase activity, a change in the protein content of the serum
    was noticed. The albumin content decreased from 48% to 34% and the
    -globulin content increased from 13.5% to 23.3% (Williams et al.,
    1958).

           Pig. Parathion was fed to groups each of 2 pigs for periods of
    33 to 122 days. The diets contained 0.2, 1 and 5 ppm. After 33 days
    the 0.2 ppm concentration was increased to 25 ppm, and after 40 days
    the 1 ppm concentration to 100 ppm. The highest ineffective dose in
    respect of toxic effects or depression of blood cholinesterase
    activity was 1.0 mg/kg body-weight/day (Edson, 1957).

           Man. A group of 5 subjects was fed parathion 3 mg/day for 28
    days, 4.5 mg/day for 28 days and 6 mg/day for 43 days. Three and 4.5
    mg did not produce any significant depression of erythrocyte or plasm
    cholinesterase activity, but 6 mg produced a depression of 10-15% of
    both plasm and erythrocyte cholinesterase activity. Depression of
    plasm cholinesterase activity persisted two weeks after administration
    of the drug was discontinued, whereas erythrocyte cholinesterase
    activity continued to be depressed for 43 days. No side-effects were
    observed (Moeller & Rider, 1961).

           Five groups of 4 subjects were given parathion orally at 
    dosages of 0 mg/day, 0.6 mg/day for 4 weeks followed by 9 weeks at 
    4.8 mg daily, 1.2 mg/daily, 2.4 mg/daily and 7.2 mg/daily for 6 weeks.
    Only in the latter group the whole blood cholinesterase was reduced,
    declining to 67% of the controls at the end of the 6 weeks. At this
    time red cell and plasma cholinesterases were respectively 84% and 63%
    of the controls. Whole blood cholinesterase was restored to 87% of
    control activity 28 days after withdrawal of parathion (Edson, 1964).

           Four male and 4 female subjects were fed 0.003, 0.010, 0.025 
    and 0.050 mg/kg body-weight of parathion for successive periods each 
    of 3 weeks. A significant increase in the mean plasma cholinesterase
    activity without an accompanying change in the erythrocyte
    cholinesterase activity occurred early in the feeding programs, but
    the level declined to control values when doses of 0.050 mg/kg
    body-weight were reached (Rider et al., 1958).

    Long-term studies

           Rat. In a one-year toxicity test groups of 36 male and 36
    female rats were maintained on diets containing 10, 20, 50, 75 and 100
    ppm of parathion. At 50 ppm and above growth retardation, toxic
    symptom and death occurred. Histological examination of animals dying
    with toxic symptoms revealed lesions of the salivary glands, pancreas
    and thymus. No other lesions attributable to parathion were found. At
    20 ppm and less no ill-effects were observed on growth, behaviour,
    mortality rate or histology. In breeding experiments performed with
    the animals from all groups the second generation of rats fed at 10
    ppm produced normal litters but the young frequently died (Barnes &
    Denz, 1951).

           In a 2-year study, groups of 8-10 male rats were fed diets
    containing parathion at the levels of 50 and 100 ppm, corresponding to
    average daily amounts of 1 and 2 mg per rat. At 100 ppm a slight
    retardation of growth and toxic symptoms were observed for the first
    few weeks. No growth reduction was present at 50 ppm. No ill-effects
    on food consumption, mortality rate, blood picture or gross pathology
    were observed. No histological changes attributable to parathion were
    observed. On chemical analysis no parathion was found in brain, liver,
    kidney, lung, abdominal fat or whole blood. In groups of 10-16 male
    rats placed on diets containing 10 and 25 ppm parathion for 2 years no
    ill-effects were observed on general condition, food consumption,

    growth and survival. Groups of 6-9 female rats were fed with diets
    containing 10 and 50 ppm of parathion for 2 years. There was no
    evidence of toxicity. All females in the control and 10 ppm groups,
    and all except one of the 50 ppm group, produced living litters
    (Hazleton & Holland, 1950).

           In a 2-year study, groups of rats were maintained on diets
    containing 10, 25 and 100 ppm of parathion. No morbid anatomical
    effects were seen at any level (Lehman, 1952).

    Comments on experimental studies reported

           The acute and short-term studies are extensive and cover a wide
    range of animal species. Long-term studies were also carried out in
    the rat. Experiments in the dog, though limited, suggest that this
    species is more sensitive than the rat to the anticholinesterase
    activity of parathion. Man and the rat are equally sensitive to the
    anticholinesterase action of parathion. Erythrocyte cholinesterase
    activity is a most sensitive indicator of this action of parathion and
    a wide margin exists between the highest dose without action on
    cholinesterase activity and the lowest dose needed to cause clinical
    effect. The figures for rat and man thus provide a basis for
    evaluation.

    EVALUATION

    Level causing no significant toxicological effect

           Rat. The maximum level having no effect on cholinesterase
    activity in the rat was 1 ppm, equivalent to 0.05 mg/kg body-weight.

           Man. 0.05 mg/kg body-weight per day.

    Estimate of acceptable daily intake for man

           0-0.005 mg/kg body-weight

    Further studies considered desirable

           Reproduction studies in the rat.

    REFERENCES

    Aldridge, W. N. & Davison, A. N. (1952) Biochem. J., 52, 663

    American Cyanamid Company New York (1955) Report on Parathion

    Barnes, J. M. & Denz, F. A. (1951) J. Hyg. (Lond.), 49, 430

    Deichmann W. B. Pugliese, W. & Cassidy, J. (1952) A.M.A. Arch.
    industr. Hyg., 5, 44

    DuBois, K. P. Doull, J., Salerno, P. R. & Coon, J. M. (1949) J.
    Pharmacol. exp. Ther., 95, 79

    DuBois, K. P. & Coon, J. M. (1952) A.M.A. Arch. industr. Hyg., 6,
    9

    Ecobichon, D. J. & Kalow, W. (1963) Canad. J. Biochem., 41, 1537

    Edson, E. F. (1957) Proceedings of the fourth International Congress
    of Crop Protection Hamburg, 1625; (quoted by Barnes, J. M. (1957)
    Adv. Pest. Control Res., 1, 1)

    Edson, E. F. & Noakes, D. N. (1960) Toxicol. appl. Pharmacol., 2,
    523

    Edson, E. F. (1964) Fd. Cosmet. Toxicol., 2, 311

    Engbaek, L. & Jensen, O. S. (1951) Acta pharmacol. (Kbh.), 7, 189

    Erdmann, W. D. & Lendle, L. (1960) Ergebnisse inn. Med.
    Kinderheilk., 10, 104

    Frawley, J. P., Hagan, E. C. & Fitzhugh, O. G. (1952) J. Pharmacol.
    exp. Ther., 105, 156

    Frawley, J. P. & Fuyat, H. N. (1957) J. Agr. Food Chem., 5, 347

    Frederiksson, T. & Bigelow, J. K. (1961) Arch. environm. Hlth, 2,
    663

    Gaines, T. B. (1960) Toxicol. appl. Pharmacol., 2, 88

    Gardocki, J. F. & Hazleton, L. W. (1951) J. Amer. pharm. Ass., 40,
    491

    Hazleton, L. W. & Holland, E. G. (1950) Advances in Chemistry,
    Series 1, 31

    Heath, D. F. (1961) Organophosphorus Poisons, Pergamon Press

    Klimmer, O. R. & Pfaff, W. (1955) Arzneimittel-Forsch., 5, 626

    Lehman, A. J. (1952) Quart. Bull. Assoc. Food and Drug Officials
    U.S., 16, 47

    Moeller, H. C. & Rider, J. A. (1961) Fed. Proc., 20 (Pt 1) 434

    Rider, J. A., Moeller, H. C., Swader, J. & Weilerstein, R. W. (1958)
    A.M.A. Arch. industr. Hyg., 18, 442

    Williams, M. W. Fitzhugh, O. G. & Cook, J. W. (1958) J. Pharmacol.
    exp. Ther., 122(1), 83A
    


    See Also:
       Toxicological Abbreviations
       Parathion (HSG 74, 1992)
       Parathion (ICSC)
       Parathion (PDS)
       Parathion (FAO/PL:1967/M/11/1)
       Parathion (FAO/PL:1969/M/17/1)
       Parathion (AGP:1970/M/12/1)
       Parathion (Pesticide residues in food: 1984 evaluations)
       Parathion (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)
       Parathion (IARC Summary & Evaluation, Volume 30, 1983)