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.
See Also: Toxicological Abbreviations Leptophos (WHO Pesticide Residues Series 4) Leptophos (WHO Pesticide Residues Series 5)