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Urinary excretion of trans, trans-muconic acid in rats exposed to low doses of benzene vapors
228
Poster Session 4E. Solvents
quaternary BTEX mixture based on knowledge of mechanisms of binary interactions. (Supported by CNTC and FRSQ).
IP4E1021
USE OF SERUMBILE ACIDSAS A SENSITIVE BIOLOGICAL MARKERFOR EVALUATING HEPATIC EFFECTSOF ORGANIC SOLVENTS
M. Neghab *, N.H. Stacey. National Institute of Occupational Health & Safety and The University of Sydney, Australia Serum bile acids (SBA) have been suggested as a potentially sensitive and specific indicator of liver function. These parameters, due to their sensitivity and specificity, could provide an early indication of hepatobiliary dysfunction and clearly offer some advantages over more traditional parameters of liver integrity/function. Recent studies have shown that occupational exposure to low levels of halogenated aliphatic or non-halogenated aromatic solvents is associated with significant increases in SBA levels. As this has often been evident in the absence of any effect on conventional parameters of hepatobiliary integrity/function, elevated SBA levels have been regarded as a sensitive biological marker of exposure/effect of these compounds and an early indicator of solvent-induced changes in hepatobiliary function. Extensive studies with experimental animals have also provided supporting evidence for the observations that solvent-exposed individuals, in the absence of any liver injury, had elevated SBA levels. Investigations of the mechanisms by which these increases at cellular and subcellular levels occur have suggested that these effects are likely to be the result of selective, dose-related and reversible inhibition of bile acid uptake at the sinusoidal domain of the hepatocyte plasma membrane by parent compounds. Increased concentrations of SBA under low levels of exposure to different solvents have been demonstrated to be a short-lived and reversible effect which is not accompanied by any other evidence of liver damage. Therefore, it could be assumed that it is unlikely that there would be pathological sequelae to these effects, although the longer term ramifications of such effects have not been thoroughly investigated. This presentation reviews the association between exposure to organic solvents and changes in SBA concentrations and discusses the possible underlying mechanisms of these associations. Additionally, it illustrates the importance and significance of SBA as sensitive biological markers of exposure/effect and also as sensitive tools in detecting early and subtle changes in hepatobiliary function of asymptomatic workers who are exposed to low levels of organic solvents.
1
P4E1031
FORMICACID EXCRETION IN RATSDOSEDWITH TRICHLOROETHYLENE: A POSSIBLE EXPLANATION FOR LONGTERM KIDNEY DAMAGE
a metabolite of trichloroethylene, suggesting that trichloroethylene and its major metabolites interfere with endogenous formic acid metabolism resulting in the excretion ofiarge amounts of this acid. When rats were exposed to 250 or 500 ppm trichloroethylene, 6 hours/day, for 28 days, the only significant effects were increased formic acid and ammonia excretion, and a change in urinary pH. There was no morphological or biochemical evidence of either liver or kidney damage. Long-term exposure to formic acid is known to cause kidney damage suggesting that excretion of this acid may contribute to the kidney damage seen in the long-term studies with trichloroethylene.
IP4E1041
URINARY EXCRETION OF trans,trans-MUCONIC ACIDIN RATS EXPOSED TO LOWDOSESOF BENZENE VAPORS
T. Coccini *, L. Maestri, P. Giacomello 1 , L. Manzo. University of Pavia and S. Maugeri Foundation IRCCS, Medical Centre, Pavia; 1 University ofRoma "La Sapienza", Italy Trans,trans-muconic acid (MA) has been identified in both laboratory animals and humans as one of the urinary metabolites of benzene which apparently reflects benzene activation to the toxic ring-opened compound trans,trans-muconaldehyde. The use of urinary MA as a biomarker to assess exposure to low concentrations of benzene has been proposed by several studies. There are doubts, however, regarding the specificity of MA since variable amounts of this product have been found in urine of subjects with no obvious environmental exposure to benzene. In this study, specificity and sensitivity of MA were evaluated in groups of male Sprague Dawley rats exposed by inhalation to different levels of benzene (from 0.6 to 5 ppm) for 6 h. In control, non-exposed, animals the 6-h urinary excretion of MA was 7.2 ± 5 JLglkg bw. In the exposed animals, MA excretions was: 10.6 ± 5.2, 28.9 ± 10.2, 36.8 ± 5.8, 63.4 ± 42, 329 ± 82 JLglkg bw at 0.6, 0.8, 1.2, 3.2 and 4.8 ppm benzene, respectively. Significantly difference between controls and benzene-exposed rats in the 6-h urinary excretion of MA were found at concentrations of ~ I ppm benzene. Moreover, MA excretion showed very high individual variability in both controls and exposed rats. The source of urinary MA in non-exposed animals and the possible involvement of endogenous precursors other than the reactive hematotoxic trans,trans-muconaldehyde in the generation of MA are still unclear. These findings may have implications in risk assessment of environmental exposure to low levels of benzene. [Supported by MURST and the Italian Ministry of Health].
1
P4E1051
TOXIC EFFECTSOF ORGANIC SOLVENTS ON THE CRANIALNERVES
T. Green *, J. Dow, l.R. Foster, P.M. Hext. Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, UK
Ruza Antic *1 , D. Joksovic-, S. Petkovic'', M. Makevic'", D. Baljak3 . 1Health Center "Dr. Milutin Ivkovic"; 2Military Medical Academy, Belgrade; 3 Health Center, Subotica, Yugoslavia
Rats given single or multiple doses of trichloroethylene, either by gavage or by inhalation, were found to excrete large amounts of formic acid in urine which was accompanied by changes in urinary pH, increased ammonia excretion and slight increases in the excretion of calcium. The amount of formic acid excreted after a single 6 hour exposure to 500 ppm trichloroethylene was comparable to that seen after a 500 mg/kg dose of formic acid itself. Both major metabolites of trichloroethylene, trichloroethanol and trichloroacetic acid, when dosed orally also gave large increases in formic acid excretion. A minor metabolite, S-(1,2-dichlorovinyl)cysteine, did not cause this response. The excretion of formic acid following either exposure to trichloroethylene, or a single dose of the two major metabolites, reached a maximum on day 2 and had a half-life of 4-5 days. In marked contrast, a single dose of formic acid itself was completely eliminated in urine within 24 hours. Formic acid was shown not to be
The aim of this work is to test the influence of organic solvents on the cranial nerves and to estimate diagnostic value of parameters of their tissue. The group of 23 workers occupationally exposed to mixture of organic solvents was tested at the Clinic of neurophysiology. Electrophysiology tests were done on MYSTRO MS-20 instrument by method of standardized needle electromyography with bipolar coaxial needle electrode. A twinkle reflex was tested (Blink reflex on the both sides). We founded prolonged time direct conduction (X 3.4 ± 0.2 m1s) in peripheral part of n. facials among II workers. _ Prolonged time of latency I reflex answer-Blink I (X 11.6 ± 0.6 ms) we founded among 15 workers. Prolonged time of latency 11 reflex answer-Blink II (X 38 ± 2.6 ms) had 8 workers.
Poster Session 4E. Solvents
quaternary BTEX mixture based on knowledge of mechanisms of binary interactions. (Supported by CNTC and FRSQ).
IP4E1021
USE OF SERUMBILE ACIDSAS A SENSITIVE BIOLOGICAL MARKERFOR EVALUATING HEPATIC EFFECTSOF ORGANIC SOLVENTS
M. Neghab *, N.H. Stacey. National Institute of Occupational Health & Safety and The University of Sydney, Australia Serum bile acids (SBA) have been suggested as a potentially sensitive and specific indicator of liver function. These parameters, due to their sensitivity and specificity, could provide an early indication of hepatobiliary dysfunction and clearly offer some advantages over more traditional parameters of liver integrity/function. Recent studies have shown that occupational exposure to low levels of halogenated aliphatic or non-halogenated aromatic solvents is associated with significant increases in SBA levels. As this has often been evident in the absence of any effect on conventional parameters of hepatobiliary integrity/function, elevated SBA levels have been regarded as a sensitive biological marker of exposure/effect of these compounds and an early indicator of solvent-induced changes in hepatobiliary function. Extensive studies with experimental animals have also provided supporting evidence for the observations that solvent-exposed individuals, in the absence of any liver injury, had elevated SBA levels. Investigations of the mechanisms by which these increases at cellular and subcellular levels occur have suggested that these effects are likely to be the result of selective, dose-related and reversible inhibition of bile acid uptake at the sinusoidal domain of the hepatocyte plasma membrane by parent compounds. Increased concentrations of SBA under low levels of exposure to different solvents have been demonstrated to be a short-lived and reversible effect which is not accompanied by any other evidence of liver damage. Therefore, it could be assumed that it is unlikely that there would be pathological sequelae to these effects, although the longer term ramifications of such effects have not been thoroughly investigated. This presentation reviews the association between exposure to organic solvents and changes in SBA concentrations and discusses the possible underlying mechanisms of these associations. Additionally, it illustrates the importance and significance of SBA as sensitive biological markers of exposure/effect and also as sensitive tools in detecting early and subtle changes in hepatobiliary function of asymptomatic workers who are exposed to low levels of organic solvents.
1
P4E1031
FORMICACID EXCRETION IN RATSDOSEDWITH TRICHLOROETHYLENE: A POSSIBLE EXPLANATION FOR LONGTERM KIDNEY DAMAGE
a metabolite of trichloroethylene, suggesting that trichloroethylene and its major metabolites interfere with endogenous formic acid metabolism resulting in the excretion ofiarge amounts of this acid. When rats were exposed to 250 or 500 ppm trichloroethylene, 6 hours/day, for 28 days, the only significant effects were increased formic acid and ammonia excretion, and a change in urinary pH. There was no morphological or biochemical evidence of either liver or kidney damage. Long-term exposure to formic acid is known to cause kidney damage suggesting that excretion of this acid may contribute to the kidney damage seen in the long-term studies with trichloroethylene.
IP4E1041
URINARY EXCRETION OF trans,trans-MUCONIC ACIDIN RATS EXPOSED TO LOWDOSESOF BENZENE VAPORS
T. Coccini *, L. Maestri, P. Giacomello 1 , L. Manzo. University of Pavia and S. Maugeri Foundation IRCCS, Medical Centre, Pavia; 1 University ofRoma "La Sapienza", Italy Trans,trans-muconic acid (MA) has been identified in both laboratory animals and humans as one of the urinary metabolites of benzene which apparently reflects benzene activation to the toxic ring-opened compound trans,trans-muconaldehyde. The use of urinary MA as a biomarker to assess exposure to low concentrations of benzene has been proposed by several studies. There are doubts, however, regarding the specificity of MA since variable amounts of this product have been found in urine of subjects with no obvious environmental exposure to benzene. In this study, specificity and sensitivity of MA were evaluated in groups of male Sprague Dawley rats exposed by inhalation to different levels of benzene (from 0.6 to 5 ppm) for 6 h. In control, non-exposed, animals the 6-h urinary excretion of MA was 7.2 ± 5 JLglkg bw. In the exposed animals, MA excretions was: 10.6 ± 5.2, 28.9 ± 10.2, 36.8 ± 5.8, 63.4 ± 42, 329 ± 82 JLglkg bw at 0.6, 0.8, 1.2, 3.2 and 4.8 ppm benzene, respectively. Significantly difference between controls and benzene-exposed rats in the 6-h urinary excretion of MA were found at concentrations of ~ I ppm benzene. Moreover, MA excretion showed very high individual variability in both controls and exposed rats. The source of urinary MA in non-exposed animals and the possible involvement of endogenous precursors other than the reactive hematotoxic trans,trans-muconaldehyde in the generation of MA are still unclear. These findings may have implications in risk assessment of environmental exposure to low levels of benzene. [Supported by MURST and the Italian Ministry of Health].
1
P4E1051
TOXIC EFFECTSOF ORGANIC SOLVENTS ON THE CRANIALNERVES
T. Green *, J. Dow, l.R. Foster, P.M. Hext. Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, UK
Ruza Antic *1 , D. Joksovic-, S. Petkovic'', M. Makevic'", D. Baljak3 . 1Health Center "Dr. Milutin Ivkovic"; 2Military Medical Academy, Belgrade; 3 Health Center, Subotica, Yugoslavia
Rats given single or multiple doses of trichloroethylene, either by gavage or by inhalation, were found to excrete large amounts of formic acid in urine which was accompanied by changes in urinary pH, increased ammonia excretion and slight increases in the excretion of calcium. The amount of formic acid excreted after a single 6 hour exposure to 500 ppm trichloroethylene was comparable to that seen after a 500 mg/kg dose of formic acid itself. Both major metabolites of trichloroethylene, trichloroethanol and trichloroacetic acid, when dosed orally also gave large increases in formic acid excretion. A minor metabolite, S-(1,2-dichlorovinyl)cysteine, did not cause this response. The excretion of formic acid following either exposure to trichloroethylene, or a single dose of the two major metabolites, reached a maximum on day 2 and had a half-life of 4-5 days. In marked contrast, a single dose of formic acid itself was completely eliminated in urine within 24 hours. Formic acid was shown not to be
The aim of this work is to test the influence of organic solvents on the cranial nerves and to estimate diagnostic value of parameters of their tissue. The group of 23 workers occupationally exposed to mixture of organic solvents was tested at the Clinic of neurophysiology. Electrophysiology tests were done on MYSTRO MS-20 instrument by method of standardized needle electromyography with bipolar coaxial needle electrode. A twinkle reflex was tested (Blink reflex on the both sides). We founded prolonged time direct conduction (X 3.4 ± 0.2 m1s) in peripheral part of n. facials among II workers. _ Prolonged time of latency I reflex answer-Blink I (X 11.6 ± 0.6 ms) we founded among 15 workers. Prolonged time of latency 11 reflex answer-Blink II (X 38 ± 2.6 ms) had 8 workers.