Immunotoxicological investigations on rats treated subacutely with dimethoate,As3+and Hg2+ in combination

Abstract

Effects of combined exposure with dimethoate (DM), HgCl₂(Hg),andNaAsO₂ (As)wereinvestigatedfollowinga28-day oral exposure in male Wistar rats. In preliminary experiments, the LOEL (Lowest Observed Effect Level) and NOEL (Non Observed Effect Level) doses of the substances were determined using the same experimental system [determination of body weight gain, organ weights of brain, thymus, heart, lung, kidneys, adrenals, spleen, testicles, popliteal lymph node, white blood cell (WBC) and red blood cell (RBC) count, haematocrit (Ht), mean cell volume (MCV) of RBCs, cell content of the femoral bone marrow, IgM-plaque forming cell (PFC) content of the spleen, delayed type hypersensitivity (DTH) reaction] and animal strain. In the combination studies, LOEL dose of DM (28.2 mg/kg) was combinedwithNOELdosesoftheheavymetals(HgCl₂ =0.40 mg/kg, NaAsO₂ =3.33 mg/kg), and vice versa (DM=7.04 mg/kg, HgCl₂ =3.20 mg/kg, NaAsO₂ =13.3 mg/kg). In the DM–Hg combinations, significant alterations were found versus the corresponding high-dose internal control in the body weight gain, relative liver and kidney weights, and in the PFC response. When DM was combined with As, interactions were indicated by changes of relative liver weight, MCV value, and the PFC content of the spleen.

These results support the theory that the interactions between pesticides and heavy metals may modify the toxic effects of the single substances, and may also change the functional detection limits of the exposure. The changes in the functional detection limits, if they occur, can lead to false-positive and false-negative results in human epidemiological studies.

Keywords

immunotoxicity dimethoate arsenic mercury rat

References

Groten JP , et al. Subacute toxicity of a mixture of nine chemicals in rats: detecting interactive effects with a fractionated two-level factorial design . Fundam Appl Toxicol 1997; 36: 15–29 .

Hejia JJ , et al. Effects of lead–arsenic combined exposure on central monoaminergic systems . Neurotoxicol Teratol 1997; 19: 489–497 .

Smialowitz RJ , et al. Opposite effects of 2,20,4,405,50 hexachlorobiphenyl and 2,3,7,8-tetrachlorodibenzo p-dioxin on the antibody response to sheep erythrocytes in mice . Fundam Appl Toxicol 1997; 37: 141–149 .

Thuvander A , Wikman C , Gadhasson J . In vitro exposure of human lymphocytes to trichotecenes: individual variation in sensitivity and effects of combined exposure on lymphocyte function . Food Chem Toxicol 1999; 37: 639–648 .

Institóris L , Siroki O , Dési I , ü ndeger Ü . Immunotoxicological examination of repeated dose combined exposure by dimethoate and two heavy metals in rats . Hum Exp Toxicol 1999; 18: 88–94 .

Institóris L , et al. Immunotoxicological effects of repeated combined exposure by cypermethrin and the heavy metals lead and cadmium in rats . Int J Immunopharmacol 1999; 21: 735–743 .

Institóris L, et al. Detection of the effects of repeated dose combined propoxur and heavy metal exposure by measurement of certain toxicological, haematological and immune function parameters in rats. Toxicology (in press).

Institóris L , Siroki O , Dési I . Immunotoxicological investigation of subacute combined exposure by permethrin and the heavy metals arsenic(III) and mercury(II) in rats . Int Immunopharmacol 2001; 1 (5): 925–933 .

Institóris L , et al. Detection of the effects of repeated dose combined propoxur and heavy metal exposure by measurement of certain toxicological, haematological and immune function parameters in rats . Cent Eur J Occup Environ Med 2000; 6(2–3): 194–201 .

10.

WHO/IPCS . Principles and Methods for Assessing Direct Immunotoxicity Associated with Exposure to Chemicals. Environmental Health Criteria 180. WHO, Geneva , 1996. pp. 110–112.

11.

WHO/IPCS . Inorganic Mercury. Environmental Health Criteria 118. WHO, Geneva , 1991. pp. 68–80.

12.

Fowler BA , Ishinishi N , Tsuchiya K , Vather M . Arsenic. In: Handbook on the Toxicology of Metals. Friberg L , Nordberg GF , Vouk VB (Eds). Elsevier/North-Holland Biomed. Press, Amsterdam, New York, Oxford , 1979. pp. 293–319.

13.

Institóris L , et al. Extension of the protocol of OECD guideline 407 (28-day repeated dose oral toxicity test in the rat) to detect potential immunotoxicity of chemicals . Hum Exp Toxicol 1998; 17: 206–211 .

14.

Ü ndeger Ü , et al. Simultaneous geno and immunotoxicological investigations for early detection of organo phosphate toxicity in rats . Ecotoxicol Environ Saf 2000; 45: 43–48 .

15.

Siroki O, et al. A study on geno and immunotoxicological effects of subacute propoxur and pirimicarb exposure in rats. Ecotoxicol Environ Saf (in press).

16.

Institóris L , et al. Comparison of detection sensitivity of immuno and genotoxicological effects of subacute cypermethrin and permethrin exposure in rats . Toxicology 1999; 137: 47–55 .

17.

Nagymajtényi L , Dési I , Lorencz R . Neurophysiological markers as early signs of organophosphate neurotoxicity . Neurotoxicol Teratol 1988; 10: 429–434 .

18.

Institóris L , Siroki O , Dési I . Immunotoxicity study of repeated small doses of dimethoate and methylparathion administered to rats over three generations . Hum Exp Toxicol 1995; 14: 879–883 .

19.

Reena K , Ajay K , Sharma CB . Haematological changes induced by dimethoate in rat . Arc Hig Rada Toksikol 1989; 40: 23–27 .

20.

Dési I , Nagymajtényi L , Schulz H . Effect of subchronic mercury exposure on electrocorticogram of rats . Neurotoxicology 1996; 17: 719–724 .

21.

Schulz H , Nagymajtényi L , Papp A , Dési I . Behavioural and neurophysiological consequences of subchronic mercury exposure in rats . Cent Eur J Occup Environ Med 1997; 3: 210–223 .

22.

Dieter MP , Luster MI , Boorman GA , Jameson CV , Dean JH , Cox JW . Immunological and biochemical responses in mice treated with mercuric chloride . Toxicol Appl Pharmacol 1983; 68: 218–228 .

23.

Lawrence D . Heavy metal modulation of lymphocyte activity: I. In vitro effects of heavy metals on primary immune responses . Toxicol Appl Pharmacol 1981; 57: 439–451 .

24.

Gaworski CL , Sharma RP . The effects of heavy metals on [3H]thymidine uptake in lymphocytes . Toxicol Appl Pharmacol 1978; 46: 305–313 .

25.

Descotes J . Immunotoxicology of Drugs and Chemicals. Elsevier, Amsterdam , 1986. pp. 280-280, 297–298.

26.

Blakley BR , Sisoda CS , Mukkur KT . The effect of methylmercury, tetraethyl lead and sodium arsenite on the humoral immune response in mice . Toxicol Appl Pharmacol 1980; 52: 245–254 .