- Email: [email protected]
Extrapolation from oral gavage doses to inhalation exposure in rodents
36 URINARY ENZYME MEASUREMENTS INDICATORS OF NEPHROTOXICITY
AS SENSITIVE IN CHRONIC TOXICOL
E.*, MARUHN, D.*, PAAR, D.+*, WEHLING, K.* INSTITUTE OF TOXICOLOGY; BAYER AG; WUPPERTAL, F.R.G. l :+DIVISION OF CLINICAL CHEMISTRY, DEPARTMENT OF MEDICINE: UNIVERSITY OF ESSEN; F.R.G.
BONHARD,
*
(LDHI, glutathione-S-transferase (GST) and total protein were determined together with plasma creatinine in male and female Wistar rats chronically treated with cadmium (as CdC12) at levels of 0 (controls), 10, 50 and 250 ppm respectively in their diet. 24 h urinary samples, collected in ice-cold containers, and blood were analysed after 1, 4. 8, 13, 18, 26, 32, 46, 57 and 67 weeks of treatment. Enzyme activities and protein concentration were measured following gel filtration of the urine. LDH and GST excretion was significantly elevated beginning from week 13 onwards in male and female rats receiving 250 ppm whfle total protein excretion as well as plasma creatinine concentration were essentially unaltered. Average increases over control animals reached up to 800 % for LDH in males, 900 % for LDH in females, 900 % for GST in males and 700 8 for GST in females. After 10 and 50 ppm no elevated enzyme excretion could be found. It is concluded that analysis of urinary enzyme excrjetionmay provide a sensitive and noninvasive tool in the evaluation of nephrotoxic substances in chronic toxicity studies. Urinary excretion OC lactate dehydrogenase
EXTRAPOLATIONFROM ORAL GAVAGE DOSES TO INRALATIONEWOSURE IN RODENTS. CAVENDER,F.L.
1820 DOLLBY HADISON BOULEVkD, UGLEAN, VIRGINIA 22102
The extrapolation of rodentdata generatedin chronicfeedingstudiesto man is especially difficult vhen humanexposureto the chemicalin questionis via inhalation. The processcan be broken$n;nLo two stepsvhererodentfeedingdata is extrapolated to a rodentinhalation exposurefollowedby extrapolation from rodentinhalation datato human inhalationexposure. For the first segment in this extrapolationprocess,pharmacokinetic data can be utilized to determinethe fractionof an administereddose that is retained in the body in both inhalationand gavage studies. In general, at lov doses a high percentageof the administereddose is retained,while at high doses, a lower percentageof
the administered &se is retained.Over a wide rangeof doses for low-mlecular-weight chlorinated hydrocarbons, the ratioof the retainedinhalation dose to the retained oral remainsrather constantfor each chemical. Using physical parameters such as molecular weight,boiling point, and solubility,a general extrapolationequationhas been developed using a stepwiseregressionanalysis techniquethat allovs the extrapolationfor rodentoral and inhalationstudies for these chlorinatedhydrocarbons.
AS SENSITIVE IN CHRONIC TOXICOL
E.*, MARUHN, D.*, PAAR, D.+*, WEHLING, K.* INSTITUTE OF TOXICOLOGY; BAYER AG; WUPPERTAL, F.R.G. l :+DIVISION OF CLINICAL CHEMISTRY, DEPARTMENT OF MEDICINE: UNIVERSITY OF ESSEN; F.R.G.
BONHARD,
*
(LDHI, glutathione-S-transferase (GST) and total protein were determined together with plasma creatinine in male and female Wistar rats chronically treated with cadmium (as CdC12) at levels of 0 (controls), 10, 50 and 250 ppm respectively in their diet. 24 h urinary samples, collected in ice-cold containers, and blood were analysed after 1, 4. 8, 13, 18, 26, 32, 46, 57 and 67 weeks of treatment. Enzyme activities and protein concentration were measured following gel filtration of the urine. LDH and GST excretion was significantly elevated beginning from week 13 onwards in male and female rats receiving 250 ppm whfle total protein excretion as well as plasma creatinine concentration were essentially unaltered. Average increases over control animals reached up to 800 % for LDH in males, 900 % for LDH in females, 900 % for GST in males and 700 8 for GST in females. After 10 and 50 ppm no elevated enzyme excretion could be found. It is concluded that analysis of urinary enzyme excrjetionmay provide a sensitive and noninvasive tool in the evaluation of nephrotoxic substances in chronic toxicity studies. Urinary excretion OC lactate dehydrogenase
EXTRAPOLATIONFROM ORAL GAVAGE DOSES TO INRALATIONEWOSURE IN RODENTS. CAVENDER,F.L.
1820 DOLLBY HADISON BOULEVkD, UGLEAN, VIRGINIA 22102
The extrapolation of rodentdata generatedin chronicfeedingstudiesto man is especially difficult vhen humanexposureto the chemicalin questionis via inhalation. The processcan be broken$n;nLo two stepsvhererodentfeedingdata is extrapolated to a rodentinhalation exposurefollowedby extrapolation from rodentinhalation datato human inhalationexposure. For the first segment in this extrapolationprocess,pharmacokinetic data can be utilized to determinethe fractionof an administereddose that is retained in the body in both inhalationand gavage studies. In general, at lov doses a high percentageof the administereddose is retained,while at high doses, a lower percentageof
the administered &se is retained.Over a wide rangeof doses for low-mlecular-weight chlorinated hydrocarbons, the ratioof the retainedinhalation dose to the retained oral remainsrather constantfor each chemical. Using physical parameters such as molecular weight,boiling point, and solubility,a general extrapolationequationhas been developed using a stepwiseregressionanalysis techniquethat allovs the extrapolationfor rodentoral and inhalationstudies for these chlorinatedhydrocarbons.