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 formulaBIOLOGICAL 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.; 37°C) (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 ß-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 (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)