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Environmental temperature, a factor modifying the acute toxicity of organic solvents, heavy metals, and agricultural chemicals
Toxicology Letters, 6 (1980) 67-70 0 Elsevier/North-Holland Biomedical
67 Press.
ENVIRONMENTAL TEMPERATURE, A FACTOR MODIFYING THE ACUTE TOXICITY OF ORGANIC SOLVENTS, HEAVY METALS, AND AGRICULTURAL CHEMICALS
KAZUO
NOMIYAMA,
KANJI MATSUI
Department of Environmental Tochigi-Ken 329-04 (Japan) (Received (Accepted
February February
and HIROKO
NOMIYAMA
Health, Jichi Medical School, Minamihawachi-Machi,
20th, 1980) 29th, 1980)
SUMMARY
1500 male mice, previously acclimatized to 8, 22 or 38”C, were used to determine the median lethal doses of organic solvents, heavy metals and agricultural chemicals by the Up-and-Down method via several routes of administration. Acute toxicity of benzene, trichloroethylene, mercuric chloride, cadmium chloride, fratol, methylparathion and dieldrin increased markedly at a low temperature of 8”C, as well as at a high temperature of 38°C. Acute toxicity of toluene, copper sulfate and chromium trioxide was only enhanced at a high temperature of 38°C.
INTRODUCTION
The toxicity of environmental pollutants has been widely studied in recent years. Most animal experiments were performed at a moderate environmental temperature of approx. 22”C, but it is possible that the environmental temperature influences the toxicity. Therefore, it is necessary to study the aggravating effects of environmental temperature and prevent health hazards specifically in hot or cold industrializing countries. The authors have conducted a series of research projects on the effect of environmental temperatures on the toxicity of environmental contaminants. MATERIALS
AND METHODS
1500 male 4-week-old mice of ICR-JCL strain were acclimatized to an environmental temperature of 8, 22 or 38°C for 4 weeks. Relative humidities were 80, 50 and 27%, respectively. The current of air in the animal cages was less than 0.05 m/set. 10 mice each were maintained in one stainless steel cage of 25 X 38 X 19 cm without any mat, and given commercial pelleted
68
food (CLEA CA-l) and water ad libitum. It takes generally 2 weeks for mice to acclimatize to these environmental temperatures from the viewpoint of body temperature and growth. At 8”C, mice shivered slightly and had a strong appetite. However, they did not die of cold, when enough food and water were supplied. At 38°C mice were inactive, and had a weak appetite but never died of starvation. Median lethal doses were determined by the Up and Down method [l] . The interval of the dose level was fixed as one and a half times. Mice were given benzene, toluene, trichloroethylene, copper sulfate or chromium trioxide i.p., or mercuric chloride S.C. Fratol, methylparathion or dieldrin were given both orally and i.p. The median lethal dose of cadmium chloride, which was determined by the Litchfield and Wilcoxon method [2], was cited from our previous report [ 31. RESULTS
As shown in Table I, the acute toxicity of benzene, trichloroethylene, mercuric chloride, cadmium chloride, fratol, methylparathion and dieldrin was strongest at an environmental temperature of 8°C. These toxicities were followed by those at 38°C with the exception of fratol. Toluene, copper sulfate, and chromium trioxide showed, on the contrary, strongest toxicities TABLE 1 MEDIAN LETHAL DOSES OF ORGANIC SOLVENTS, HEAVY METALS AND AGRICULTURAL CHEMICALS IN MICE PREVIOUSLY ACCLIMATIZED TO ENVIRONMENTAL TEMPERATURES OF 8,22 OR 38°C (MG/KG) Chemicals
Route of administrationa
Environmental temperature 8oc 22°C 38°C 101 100 40
~ ~~_ _~~ Organic solvents
Benzene Toluene Trichloroethylene
ip ip ip
Heavy metals
Copper sulfate Chromium trioxide Mercuric chloride Cadmium chlorideb
ip ip SC ip PO
4.1 18 4.8 4.0 46
5.6 35 4.5 5.4 78
3.5 14 6.5 4.5 80
Agricultural chemicals
Fratol
ip PO ip PO ip PO
7.0 4.5 14 18 27 50
9.0 21.0 44 38 75 73
9.7 26.5 35 23 63 69
Methylparathion Dieldrin
%.p., intraperitoneal; s.c., subcutaneous; p.o., per OS. bCited from [6].
____
118 126 75
115 88 68
69
at 38°C which was followed by those at 8°C. Only mercuric chloride indicated the strongest acute toxicity at an environmental temperature of 22°C which was followed by that at 8°C. Methylparathion and dieldrin indicated almost the same toxicities for both i.p. and oral administration. Cadmium chloride and fratol showed higher toxicities for i.p. administration than for oral administration, except 1 case of fratol under a low environmental temperature of 8°C. DISCUSSION
The effect of environmental temperature on the action of drugs has been reviewed by Fuhrman and Fuhrman [ 41 and Weihe [ 51. However, there have been only a few studies of the effect of environmental temperatures on the toxicity of environmental pollutants using animals previously acclimatized to various temperatures for several days. Cadmium chloride, sodium fluoroberyllate, methylmercury chloride showed higher toxicities at low temperatures than at moderate or high temperatures [ 3, 6, 71. On the contrary, the higher toxicities were proved at high temperatures for lead compounds, parathion, and l,l,l-trichloroethane [8-lo]. Our systematical studies on the acute toxicities of environmental pollutants also showed some modifications caused by environmental temperature. As to the aggravation of acute toxicity of parathion by environmental temperatures, the data of Baetjer and Smith [8] differ from ours. However, Baetjer and Smith [8] compared parathion toxicity at environmental temperatures of 16,23 and 36°C. In the present study methylparathion toxicity was strongest at 8°C followed by that at 38°C and then by that at 22°C. Therefore, as to the effect of a higher temperature on toxicity, our result agrees with that of Baetjer and Smith [8]. Up to now, environmental temperature-dependent modification of toxicity has not been found to have a certain tendency. The mechanisms of the modification of toxicity should be studied further in relation to the classification of aggravation of toxicities under low or high temperatures. Methylparathion and dieldrin had almost the same median lethal dose both with i.p. and oral administrations. This suggests that intestinal absorption of methylparathion and dieldrin is almost 100%. On the contrary, the median lethal doses of cadmium chloride and fratol by the i.p. route were lower than those of oral administration. This suggests that intestinal absorption is as low as 5-9% and 37-43% for cadmium chloride and fratol, respectively. The above values were based on the ratio of the median lethal dose by i.p. to oral administration. In addition, the intestinal absorption seemed to increase with the decrease in the environmental temperature both for cadmium chloride and fratol. This assumption agreed with that of our previous report [ 111.
70 ACKNOWLEDGEMENT
This study was supported by a research grant from Japan Ministry of Education, Science and Culture - Environmental Science Project 303543 (1978). REFERENCES 1 K.A. Brownlee, J.L. Hodges and M. Rosenblatt, The up-and-down method with small samples. J. Am. Stat. Assoc., 48 (1953) 262. 2. J.T. Litchfield Jr. and F. Wilcoxon, A simplified method of evaluating dose-effect experiment, J. Pharmacol. Exp. Ther., 96 (1949) 99. 3 K. Nomiyama, H. Nomiyama and T. Taguchi, Effects of environmental temperatures on the toxicity of cadmium in mice, Proc. 8th. Asian Conf. Occup. Health, pp. 221, Jap. Ind. Safety Assoc., Tokyo, 1978. 4 G.J. Fuhrman and F.A. Fuhrman, Effects of temperature on the action of drugs, Annu. Rev. Pharmacol., 1 (1961) 65. 5 W.H. Weihe, The effects on temperature on the action of drugs, Annu. Rev. Pharmacol., 13 (1973) 409. 6 K. Nomiyama, K. Ma&i and H. Nomiyama, Acute toxicity of beryllium in mice at different environmental temperature, Jap. J. Ind. Health, 20 (1978) 384. 7 K. Nomiyama, K. Matsui, H. Nomiyama and S. Kitamura, Factors modifying toxicity of methylmercury in mice - age, sex and environmental temperature (in preparation). 8 A.M. Baetjer and R. Smith, Effect of environmental temperature on reaction of mice to parathion, an anticholinesterase agent, Am. J. Physiol., 186 (1956) 39. 9 A.M. Baetjer, S.N.D. Joardar and W.A. McQuary, Effects of environmental temperature and humidity on lead poisoning in animals, Arch. Environ. Health, 1 (1960) 463. 10 S. Horiguchi and K. Horiuchi, Effect of environmental temperature on the toxicity of l,l,l-trichloroethane in mice (Supplementary report on the toxicity of l,l,l-trichloroethane II), Jap. J. Ind. Health, 13 (1966) 290. 11 K. Nomiyama and H. Nomiyama, Effect of environmental temperatures on the acute toxicity of cadmium in mice, Kankyo Hoken Report, 38 (1973) 153.
67 Press.
ENVIRONMENTAL TEMPERATURE, A FACTOR MODIFYING THE ACUTE TOXICITY OF ORGANIC SOLVENTS, HEAVY METALS, AND AGRICULTURAL CHEMICALS
KAZUO
NOMIYAMA,
KANJI MATSUI
Department of Environmental Tochigi-Ken 329-04 (Japan) (Received (Accepted
February February
and HIROKO
NOMIYAMA
Health, Jichi Medical School, Minamihawachi-Machi,
20th, 1980) 29th, 1980)
SUMMARY
1500 male mice, previously acclimatized to 8, 22 or 38”C, were used to determine the median lethal doses of organic solvents, heavy metals and agricultural chemicals by the Up-and-Down method via several routes of administration. Acute toxicity of benzene, trichloroethylene, mercuric chloride, cadmium chloride, fratol, methylparathion and dieldrin increased markedly at a low temperature of 8”C, as well as at a high temperature of 38°C. Acute toxicity of toluene, copper sulfate and chromium trioxide was only enhanced at a high temperature of 38°C.
INTRODUCTION
The toxicity of environmental pollutants has been widely studied in recent years. Most animal experiments were performed at a moderate environmental temperature of approx. 22”C, but it is possible that the environmental temperature influences the toxicity. Therefore, it is necessary to study the aggravating effects of environmental temperature and prevent health hazards specifically in hot or cold industrializing countries. The authors have conducted a series of research projects on the effect of environmental temperatures on the toxicity of environmental contaminants. MATERIALS
AND METHODS
1500 male 4-week-old mice of ICR-JCL strain were acclimatized to an environmental temperature of 8, 22 or 38°C for 4 weeks. Relative humidities were 80, 50 and 27%, respectively. The current of air in the animal cages was less than 0.05 m/set. 10 mice each were maintained in one stainless steel cage of 25 X 38 X 19 cm without any mat, and given commercial pelleted
68
food (CLEA CA-l) and water ad libitum. It takes generally 2 weeks for mice to acclimatize to these environmental temperatures from the viewpoint of body temperature and growth. At 8”C, mice shivered slightly and had a strong appetite. However, they did not die of cold, when enough food and water were supplied. At 38°C mice were inactive, and had a weak appetite but never died of starvation. Median lethal doses were determined by the Up and Down method [l] . The interval of the dose level was fixed as one and a half times. Mice were given benzene, toluene, trichloroethylene, copper sulfate or chromium trioxide i.p., or mercuric chloride S.C. Fratol, methylparathion or dieldrin were given both orally and i.p. The median lethal dose of cadmium chloride, which was determined by the Litchfield and Wilcoxon method [2], was cited from our previous report [ 31. RESULTS
As shown in Table I, the acute toxicity of benzene, trichloroethylene, mercuric chloride, cadmium chloride, fratol, methylparathion and dieldrin was strongest at an environmental temperature of 8°C. These toxicities were followed by those at 38°C with the exception of fratol. Toluene, copper sulfate, and chromium trioxide showed, on the contrary, strongest toxicities TABLE 1 MEDIAN LETHAL DOSES OF ORGANIC SOLVENTS, HEAVY METALS AND AGRICULTURAL CHEMICALS IN MICE PREVIOUSLY ACCLIMATIZED TO ENVIRONMENTAL TEMPERATURES OF 8,22 OR 38°C (MG/KG) Chemicals
Route of administrationa
Environmental temperature 8oc 22°C 38°C 101 100 40
~ ~~_ _~~ Organic solvents
Benzene Toluene Trichloroethylene
ip ip ip
Heavy metals
Copper sulfate Chromium trioxide Mercuric chloride Cadmium chlorideb
ip ip SC ip PO
4.1 18 4.8 4.0 46
5.6 35 4.5 5.4 78
3.5 14 6.5 4.5 80
Agricultural chemicals
Fratol
ip PO ip PO ip PO
7.0 4.5 14 18 27 50
9.0 21.0 44 38 75 73
9.7 26.5 35 23 63 69
Methylparathion Dieldrin
%.p., intraperitoneal; s.c., subcutaneous; p.o., per OS. bCited from [6].
____
118 126 75
115 88 68
69
at 38°C which was followed by those at 8°C. Only mercuric chloride indicated the strongest acute toxicity at an environmental temperature of 22°C which was followed by that at 8°C. Methylparathion and dieldrin indicated almost the same toxicities for both i.p. and oral administration. Cadmium chloride and fratol showed higher toxicities for i.p. administration than for oral administration, except 1 case of fratol under a low environmental temperature of 8°C. DISCUSSION
The effect of environmental temperature on the action of drugs has been reviewed by Fuhrman and Fuhrman [ 41 and Weihe [ 51. However, there have been only a few studies of the effect of environmental temperatures on the toxicity of environmental pollutants using animals previously acclimatized to various temperatures for several days. Cadmium chloride, sodium fluoroberyllate, methylmercury chloride showed higher toxicities at low temperatures than at moderate or high temperatures [ 3, 6, 71. On the contrary, the higher toxicities were proved at high temperatures for lead compounds, parathion, and l,l,l-trichloroethane [8-lo]. Our systematical studies on the acute toxicities of environmental pollutants also showed some modifications caused by environmental temperature. As to the aggravation of acute toxicity of parathion by environmental temperatures, the data of Baetjer and Smith [8] differ from ours. However, Baetjer and Smith [8] compared parathion toxicity at environmental temperatures of 16,23 and 36°C. In the present study methylparathion toxicity was strongest at 8°C followed by that at 38°C and then by that at 22°C. Therefore, as to the effect of a higher temperature on toxicity, our result agrees with that of Baetjer and Smith [8]. Up to now, environmental temperature-dependent modification of toxicity has not been found to have a certain tendency. The mechanisms of the modification of toxicity should be studied further in relation to the classification of aggravation of toxicities under low or high temperatures. Methylparathion and dieldrin had almost the same median lethal dose both with i.p. and oral administrations. This suggests that intestinal absorption of methylparathion and dieldrin is almost 100%. On the contrary, the median lethal doses of cadmium chloride and fratol by the i.p. route were lower than those of oral administration. This suggests that intestinal absorption is as low as 5-9% and 37-43% for cadmium chloride and fratol, respectively. The above values were based on the ratio of the median lethal dose by i.p. to oral administration. In addition, the intestinal absorption seemed to increase with the decrease in the environmental temperature both for cadmium chloride and fratol. This assumption agreed with that of our previous report [ 111.
70 ACKNOWLEDGEMENT
This study was supported by a research grant from Japan Ministry of Education, Science and Culture - Environmental Science Project 303543 (1978). REFERENCES 1 K.A. Brownlee, J.L. Hodges and M. Rosenblatt, The up-and-down method with small samples. J. Am. Stat. Assoc., 48 (1953) 262. 2. J.T. Litchfield Jr. and F. Wilcoxon, A simplified method of evaluating dose-effect experiment, J. Pharmacol. Exp. Ther., 96 (1949) 99. 3 K. Nomiyama, H. Nomiyama and T. Taguchi, Effects of environmental temperatures on the toxicity of cadmium in mice, Proc. 8th. Asian Conf. Occup. Health, pp. 221, Jap. Ind. Safety Assoc., Tokyo, 1978. 4 G.J. Fuhrman and F.A. Fuhrman, Effects of temperature on the action of drugs, Annu. Rev. Pharmacol., 1 (1961) 65. 5 W.H. Weihe, The effects on temperature on the action of drugs, Annu. Rev. Pharmacol., 13 (1973) 409. 6 K. Nomiyama, K. Ma&i and H. Nomiyama, Acute toxicity of beryllium in mice at different environmental temperature, Jap. J. Ind. Health, 20 (1978) 384. 7 K. Nomiyama, K. Matsui, H. Nomiyama and S. Kitamura, Factors modifying toxicity of methylmercury in mice - age, sex and environmental temperature (in preparation). 8 A.M. Baetjer and R. Smith, Effect of environmental temperature on reaction of mice to parathion, an anticholinesterase agent, Am. J. Physiol., 186 (1956) 39. 9 A.M. Baetjer, S.N.D. Joardar and W.A. McQuary, Effects of environmental temperature and humidity on lead poisoning in animals, Arch. Environ. Health, 1 (1960) 463. 10 S. Horiguchi and K. Horiuchi, Effect of environmental temperature on the toxicity of l,l,l-trichloroethane in mice (Supplementary report on the toxicity of l,l,l-trichloroethane II), Jap. J. Ind. Health, 13 (1966) 290. 11 K. Nomiyama and H. Nomiyama, Effect of environmental temperatures on the acute toxicity of cadmium in mice, Kankyo Hoken Report, 38 (1973) 153.