LEPTOPHOS JMPR 1978
Explanation
Leptophos was reviewed by Meetings in 1974 and 1975 (FAO/WHO,
1975b, 1976b) and discussed briefly in 1976 (FAO/WHO, 1977a). Some
guideline levels for residues in food were recorded in 1974 as no
ADI was allocated. In 1975 a temporary ADI was allocated together
with an expanded list of temporary MRLs. A number of further
requirements, by 1978, were recorded. They included expressions of
need for further information on biochemistry and toxicology, also
relating to the current usage and the occurrence of residues of the
compound.
The new information received is evaluated in the present
monograph amendment.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Biotransformation
Results of studies on the metabolic fate of leptophos in the
rat have confirmed those previously reported. Urinary metabolites
were identified as demethylation reaction products of leptophos and
the oxygen analog. There was no mention of the occurrence of the
desbrominated leptophos metabolite although unidentified
metabolites, which may include this compound, accounted for a small
quantity of the excreted product. Leptophos, a lipophilic molecule,
was observed to concentrate and be released slowly from adipose
tissue. While the major quantity of leptophos was eliminated in 48
hours, trace residues in omental and subcutaneous tissues were
evident for as long as 12 weeks after a single acute oral dose of
15 mg/kg (Hassan, et al., 1977a). Dietary administration of
leptophos again resulted in cholinesterase depression pointing to
the adequacy or the use of this enzyme as an indicator of exposure
(Hassan, et al., 1977b).
Effects on enzymes and other biochemical parameters
El-Sebae, et al., (1978) again confirmed the weak
anticholinesterase activity of leptophos reporting in vivo PI50
values of < 4.5 for brain and plasma cholinesterase in mice. In
vitro bioassays were somewhat more sensitive with PI50 values
exceeding 5 for brain cholinesterase.
Acute Toxicity
Species Sex1 Route Formulation LD50 References
(mg/kg)
Mice N.S. Oral Technical 162 El Sebae, et al., 1978
N.S. Oral 30%, E.C. 83 El Sebae et al., 1978
1 N.S. - not specified
2 Corn oil solution
Special studies on neurotoxicity
Chickens
Several studies reviewed in draft form by the 1975 Meeting
have been published in detail attesting to the neurotoxic effects
of leptophos both chemically and histologically in the hen (Abou
Donia, 1976b; Abou Donia and Preissig, 1976; Preissig and Abou Donia,
1976). A conference was held in 1976 to review all known information
on the subject. The positive neurotoxic results obtained in a variety of
programs evaluating the effects of leptophos were confirmed (Baron,
1976). It was reported that a "threshold" effective dose of 1 mg/kg
was observed over a prolonged period of oral administration of
leptophos to hens. Clinical signs of ataxia were reported after 62
days of administration of 1 mg/kg. These signs were not accompanied by
histological evidence of pathological change (Abou Donia, 1976a).
In a one year dietary study, groups of hens (35 hens/group were
fed leptophos in the diet for one year at dosage levels of 0, 0.1,
0.3, 1.0, 3.0, 10.0, 30.0 and 100.0 ppm. Mortality was observed in all
groups although there was no relationship of the leptophos dose fed to
the mortality observed. Growth and food consumption were normal over
the first 13 weeks of the experiment. Egg production was also normal
over this period. Clinical signs of ataxia were initially noted at 58
days in the 100 ppm dose group. All birds in this high dose group
ultimately showed varying degrees of clinical ataxia. This was not
observed in any hens of the 30 ppm group. Histological studies were
incomplete (Fletcher, 1978). (100 ppm in the diet appears to
correspond to a daily intake of 5.8 mg/kg body weight).
Ducklings
The neurotoxic effects of prolonged exposure of immature (1 week
old) mallard ducklings to leptophos was reported by Herin et al.,
(1978). Within 17 to 23 days after exposure to 260 ppm, ducklings
showed clinical signs of ataxia that progressed to paralysis.
Observations in man
A group of eight of nine occupationally-exposed workers were
found to have developed a severe neuropathy, which was probably
associated with their exposure to leptophos in a manufacturing plant
(Xintaras et al., 1978). In addition to leptophos exposure, these
workers were also exposed to high levels of n-hexane and toluene,
both of which have been known to be associated with neuropathies in
humans. Leptophos exposure was excessive in the occupational setting
with the workers on occasion reporting general symptoms of
organophosphorus poisoning. Paraesthesia of the extremities was
observed in eight workers. Altered pain, vibration and position sense,
decreased motor function and decreased muscle tone were found in six
workers. Only one afflicted worker showed a decreased cholinesterase
value. One of three workers tested displayed a decreased nerve
conduction. Two of five EEG examinations and one of two EKG
examinations were abnormal. It was established that the workers were
occupationally exposed to excessive levels of leptophos in its
manufacture and this exposure (alone with or complicated by their
exposure to certain solvents) directly contributed to a neurotoxic
response similar to that noted in the hen bioassay.
A group of 32 individuals exposed to leptophos used in an
agricultural spray program were examined for clinical and his chemical
indices to evaluate the effect of occupational exposure (Hassan et
al., 1978). Some of the highly exposed individuals reported typical
symptoms of cholinesterase depression (which when assayed was
depressed, suggesting exposure). No other clinical parameter was
affected. A follow-up examination on 14 weeks did not show signs of
muscle weakness or paralysis. Recovery of the cholinesterase activity
was generally slow. In a similar study of 18 occupationally exposed
agricultural workers, signs and symptoms of cholinesterase depression
were reported (Hassan, 1978). Recovery or the subjects was noted
within two weeks and follow-up examinations in 6 to 18 months again
showed no sign of muscle weakness or paralysis. Two males and one
female were administered 14c-leptophos to examine the fate in man.
Cholinesterase was unaffected by the 10 mg oral dose. Elimination was
slow with 12 to 65% eliminated within 12 days. Hydrolic products were
the metabolites observed (Hassan, 1978). The metabolic details were
insufficient to evaluate metabolism in man.
COMMENTS
The toxicological aspects of leptophos have been considered in
previous Meetings (FAO/WHO, 1976a, 1977a) and based on no-effect
levels observed in two-year studies in rats and dogs, a temporary ADI
was allocated. An exceptionally high safety factor was used in this
evaluation reflecting concerns over the delayed neurotoxicological
events noted in short term bioassays in hens, a species reflective of
a similar neurological syndrome observed in man.
Current studies available to the Meeting confirmed the
susceptibility of humans to delayed neurotoxicity resulting from
exposure to high levels of leptophos in an industrial setting. The
extensive animal toxicological data base available for review and new
prolonged bioassay neurotoxicity tests in hens further supported the
existence of a dose-response relationship and a no-effect level.
Information had come to the attention of the Meeting that leptophos
was no longer being manufactured and therefore the following
conclusion was reached.
TOXICOLOGICAL EVALUATION
The previously allocated temporary ADI should be withdrawn.
RESIDUES IN FOOD AND THEIR EVALUATION
APPRAISAL AND RECOMMENDATION
The Meeting was informed that leptophos is not now manufactured,
although small stocks are being used in various countries until they
are depleted. In the light of the latter situation and the low
probability of additional responses to recorded requirements for
further information becoming available., also in the absence of an
ADI, it was decided that the recommendations for temporary MRLs should
be withdrawn.
Interested parties are referred to FAO/WHO 1978c and to previous
monographs for guidance on the levels that may follow the use of the
pesticide on food crops.
REFERENCES
Abou Donia, M.B. Discussion of Research Reported in "Proceedings of
(1976a) a Conference Pesticide Induced Delayed
Neurotoxicity". Washington, D.C., February 19-20,
1976. Environmental Protection Agency,
Environmental Health Effects Research Series, EPA-
600/1-76-025, July 1976.
Abou Donia, M.B. Pharmacokinetics of a Neurotoxic Oral Dose of
(1976b) Leptophos in Hens. Arch. Toxicol. 36: 103-110.
Abou Donia, M.B. and S.H. Preissig Delayed Neurotoxicity of
(1976) Continuous Low Dose Oral Administration of
Leptophos to Hens. Tox. Appl. Pharmacol. 38:
595-608.
Baron, R.L. Ed. Pesticide Induced Delayed Neurotoxicity,
(1976) Proceedings of a Conference Washington, D.C.,
February 19-20, 1976. Environmental Protection
Agency, Environmental Health Effects Research
Series, EPA-600/1-76-025, July 1976.
El-Sebae, A.H., N.S. Ahmed and S.A. Soleman Effect of Pre-exposure
(1978) on Acute Toxicity of Organophosphorus Insecticides
to White Mice. J. Environ. Sci. Health B13 (1):
11-24.
Fletcher, D.W. One Year Chronic Oral Neurotoxicity Test with
(1978) Technical Reference Standard Phosvel. Unpublished
Draft Report from Industrial Biotest Laboratories,
Inc. submitted by Velsicol Chemical Co. to the
WHO.
Hassan, A., Abdel-Hamid, F.M., Abou-Zeid, A., Mokhtar, O.A.,
(1978b) Abdel Razek, A.A. and Ibrahim, M.S. Clinical
Observations and Biochemical Studies on Humans
exposed to leptophos. Chemosphere 3 283-90.
Hassan, A., F.M. Abdel-Hamid and S.I. Mohammed Metabolism of
(1977a) 14C leptophos in the rat. Arch. Env. Contam.
Toxicol. 6: 447-454.
Hassan A. Personal Communication
(1978)
Herin, R.A., A.A. Komeil, D.C. Graham, A. Curley and M.B. Abou
(1978) Donia Delayed Neurotoxicity Induced by
Organophosphorus Compounds in the Wild Mallard
Duckling. Env. Path. Tox. 1: 233-240.
Preissig, S.H. and M.B. Abou Donia The Chronological Effects of
(1976) Leptophos on the Spinal Cord and Sciatic Nerve of
Hens. J. Neuropathol. Exp. Neurol. 35: 303.
Xintaras, C., J.R. Burg, S. Tanaka, S.T. Lee, B.L. Johnson, C.A.
(1978) Cottrill and J.Bender NIOSH Health Survey of
Velsicol Pesticide Workers. NIOSH Technical
Report-Publication No. 78-136. U.S. Dept. of
Health, Education and Welfare.