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 µg/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 µg/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 20±5 28±5 13±1
4 32±4 29±12 21±3
6 37±7 43±6 42±5
24 68±4 66±3 73±14
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 90±11 96±16 115±18 98±10 99±4 97±5
0.03 79±15 110±23 94±12 93±11 100±4 93±6
0.10 66±17 109±17 87±11 93±8 83±12 35±8
0.30 44±9 71±16 56±13 35±6 56±7 74±6
1.00 17±3 43±10 34±5 25±9 28±5 32±5
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)