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    MONOCROTOPHOS (addendum)

     First draft prepared by
     A. Moretto,
     Institute of Occupational Medicine,
     University of Padua, Padua, Italy

    Explanation
    Evaluation for acceptable daily intake
         Toxicological studies
         Observations in humans
    Comments
    References

    Explanation

         An ADI of 0-0.0006 mg/kg bw was established for monocrotophos, on
    the basis of an NOAEL for erythrocyte acetylcholinesterase of
    0.006 mg/kg bw per day in a 28-day study of human volunteers (Annex I,
    reference 68). This ADI was also supported by the results of a
    long-term study in rats in which an NOAEL of 0.1 ppm (equivalent to
    0.005 mg/kg bw per day) was found for inhibition of brain and
    erythrocyte acetylcholinesterase. Monocrotophos was not found to be
    carcinogenic or teratogenic and caused no toxicity other than the
    cholinergic syndrome. The ADI was thus based on an 'acute effect'.
    Questions have been raised about the acceptability of an ADI based on
    daily exposure throughout life and occasional exposure in excess of
    the limit. It has been argued that the same dose might be acutely
    toxic if given as a single dose but have no adverse effects if given
    in several daily fractions. Hence, a different approach may be needed
    for acutely toxic compounds such as monocrotophos.

    Evaluation for acceptable daily intake

    1.  Toxicological studies

         Male and female Crl:CD rats, eight to nine weeks old, were given
    single oral doses of monocrotophos dissolved in water by gavage at
    5 ml/kg bw. Animals given 3 mg/kg bw of monocrotophos showed signs of
    cholinergic poisoning 1-2 h after treatment but recovered completely
    within 24 h (Table 1). Peak inhibition was found 2 h after treatment,
    and activity was recovered with a half-life of < 24 h. This result is
    not unexpected, since monocrotophos is a dimethylphosphate yielding
    dimethylphosphorylated erythrocyte and brain acetylcholinesterase and
    plasma cholinesterase, which undergo spontaneous reactivation. No
    significant difference in the inhibition of the three enzymes was
    seen.

         On the basis of these results, groups of five male and five
    female rats were given 0, 0.01, 0.03, 0.1, 0.3, or 1.0 mg/kg bw
    monocrotophos, and cholinesterase activities were measured 2 h later
    (Table 2). On the basis of inhibition of brain acetylcholinesterase,
    which is considered to be biologically significant when > 20%, the
    NOAEL was 0.1 mg/kg bw and the LOAEL was 0.3 mg/kg bw (Potrepka,
    1994).

    2.  Observations in humans

         Groups of six male volunteers were given daily oral doses of 3.6
    or 5.9 g/kg bw monocrotophos for 28 days. Plasma cholinesterase and
    erythrocyte acetylcholinesterase were determined twice weekly four
    times before, during, and four times after treatment. Erythrocyte
    acetylcholinesterase was not inhibited at any dose, but plasma
    cholinesterase was decreased by about 15% in animals at the low dose
    and by 24% at the high dose. Inhibition was detected after the first
    week of treatment. Recovery was slow, since activity was still
    slightly inhibited in both groups 12 days after end of treatment. A
    group of eight animals received 15 g/kg bw for seven days and then,
    after a three-day pause, for four more days. Erythrocyte
    acetylcholinesterase was not inhibited; plasma cholinesterase was
    inhibited by about 35% on day 7 and by about 51%, at the end of
    treatment. (Other details of this study can be found in FAO/WHO,
    1994). The results of field studies in which doses of monocrotophos
    were extrapolated from urinary excretion of dimethylphosphates are
    consistent with these data (FAO/WHO, 1994).

        Table 1.  Effects of a single oral dose of 3 mg/kg bw of monocrotophos
              on plasma cholinesterase and erythrocyte and brain
              acetylcholinesterase activity in five female rats
                                                                                              

    Time after        Percent of control value (mean  SD)
    treatment (h)                                                                             
                      Plasma            Erythrocyte             Brain
                      cholinesterase    acetylcholinesterase    acetylcholinesterase
                                                                                              

    2                 205              285                    131
    4                 324              2912                   213
    6                 377              436                    425
    24                684              663                    7314
                                                                                              

    Table 2.  Effects of single oral doses of monocrotophos on plasma
              cholinesterase activity in five rats 2 h after treatment
                                                                                              

    Dose            Percent of control value (mean  SD)
    (mg/kg bw)                                                                              
                    Plasma cholinesterase    Erythrocyte             Brain
                                             acetylcholinesterase    acetylcholinesterase
                                                                                              

                    Males      Females       Males      Females      Males       Females
                                                                                              

    0.01            9011      9616         11518     9810        994        975
    0.03            7915      11023        9412      9311        1004       936
    0.10            6617      10917        8711      938         8312       358
    0.30            449       7116         5613      356         567        746
    1.00            173       4310         345       259         285        325
                                                                                              
    
         Slow recovery of plasma cholinesterase and erythrocyte
    acetylcholinesterase levels was reported in a case of accidental
    poisoning with monocrotophos (Simson  et al., 1969).

    Comments

         The effects of monocrotophos differ in rats and humans. The two
    main discrepancies are: (1) in humans, erythrocyte acetylcholine-
    sterase is less sensitive than plasma cholinesterase to inhibition (no
    inhibition at a dose that inhibits plasma cholinesterase by 50%),
    while in rats these enzymes are equally sensitive; (2) the rates of
    recovery of inhibited cholinesterases are much slower in humans than
    in rats. A similar phenomenon has been described for the dimethyl
    phosphates dichlorvos and trichlorfon.

         For these reasons, data on humans are most relevant for
    establishing an ADI or an 'acute reference dose' for monocrotophos.
    The 1993 JMPR established an ADI on the basis of lack of inhibition of
    erythrocyte acetylcholinesterase in a 28-day study in humans, as
    monocrotophos was not found to be carcinogenic or teratogenic and
    caused no toxicity other than the cholinergic syndrome in animals. In
    the case of short-term exposure, the acute reference dose was derived
    from an experiment conducted with 15 mg/kg bw for seven, then four
    days after a three-day pause. In this case, too, no inhibition of
    erythrocyte acetylcholinesterase was found, but the length of
    treatment was too short to allow any conclusion about the effect after
    longer treatment. None of these experiments allowed determination of
    an LOAEL because erythrocyte acetylcholinesterase inhibition did not
    occur.

         The available toxicological data in humans allow the
    establishment of an ADI of 0-0.0006 mg/kg bw and of an acute reference
    dose of 0.002 mg/kg bw per day, on the basis of the absence of
    erythrocyte acetylcholinesterase inhibition and using, in both cases,
    a 10-fold safety factor.

         Data on inhibition of plasma cholinesterase and erythrocyte and
    brain acetyl-cholinesterase in rodent and human tissues  in vitro
    would facilitate assessment of the risk of monocrotophos. For
    instance, comparison of the sensitivity  in vitro of human plasma
    cholinesterase with that of erythrocyte and brain acetylcholinesterase
    to inhibition by monocrotophos might allow extrapolation of an NOAEL
    using the available data on humans  in vivo.

         The following considerations also relate to the acute reference
    dose: (i) Given the slow rate of reappearance of both plasma
    cholinesterase and erythrocyte acetylcholinesterase after inhibition
    by monocrotophos in humans, it is conceivable that the effect on
    erythrocyte acetylcholinesterase of a single dose equal to 7 
    0.015 mg/kg bw would not be significantly different (i.e. no

    inhibition) from that obtained with seven daily doses of 0.015 mg/kg
    bw. (ii) Given the characteristics of the dose-response curve of
    cholinesterase inhibition by organophosphorus esters and the
    relationship between acetylcholinesterase inhibition and the
    appearance of the cholinergic syndrome, it can be concluded that a
    single dose of 7  0.015 mg/kg bw is well below that which would
    induce signs of toxicity.

    References

    FAO/WHO (1994) Joint Meeting on Pesticide Residues-1993. Geneva, World
         Health Organization.

    Potrepka, R.F. (1994) Acute oral toxicity study of monocrotophos
         technical in rats. Unpublished report No. F-00189 from Ciba-Geigy
         Corp., Farmington, Connecticut, USA. Submitted to WHO by
         Ciba-Geigy Corp., Greensboro, North Carolina, USA.

    Simson, R.E., Simpson, G.R. & Penney, D.J. (1969) Poisoning with
         monocrotophos, an organophosphorus pesticide.  Med. J. Aust.,
         2, 1013-1016.
    


    See Also:
       Toxicological Abbreviations
       Monocrotophos (HSG 80, 1993)
       Monocrotophos (ICSC)
       Monocrotophos (WHO Pesticide Residues Series 2)
       Monocrotophos (WHO Pesticide Residues Series 5)
       Monocrotophos (Pesticide residues in food: 1991 evaluations Part II Toxicology)
       Monocrotophos (Pesticide residues in food: 1993 evaluations Part II Toxicology)