In vivo dosimetry of some alkylating agents as a basis for risk estimation

Sammanfattning: The present study concerns in vivo dosimetry of ultimate electrophilic reagents as a step in risk estimation of mutagenic and carcinogenic chemicals. The level of reaction products with nucleophilic groups in macromolecules could be used for dose determination. Hemoglobin adducts were studied in mice and rats with regard to suitability for dose monitoring using radiolabelled chemicals (methyl methanesulfonate, dimethylnitrosamine, ethylene oxide, ethene, methyl bromide, 2,2-dichlorovinyl dimethyl phosphate, N-methyl-N-nitrosourea and N-(2-hydroxyethyl)-N-nitrosourea). The adducts formed were shown to be eliminated with a rate corresponding to the life-span of the erythrocytes. This stability makes it possible to use the accumulated degree of alkylation of hemoglobin as a measure of dose at chronic exposure. The predominant reactive nucleophilic groups in hemoglobin were found to be cysteine, N-terminal valine, histidine and carboxylic groups. Each alkylating agent gave a characteristic pattern of products. This pattern may in principle be used for identification of exposure to unknown chemicals. The dose in the erythrocytes, calculated from the degree of hemoglobin alkylation, was compared with the dose in different organs, calculated from the degree of alkylation of guanine-N^-7 in DNA. For small, uncharged compounds, soluble in both water and lipids, the dose was approximately the same in the erythrocytes as in other organs. Hemoglobin dosimetry could therefore be used for estimation of doses to DNA in other organs for such compounds. Other compounds give, for different reasons, an uneven dose distribution that has to be determined in experimental animals when using hemoglobin dosimetry in man for risk estimation. Risk coefficients for alkylating agents expressed in relation to the effect of gamma radiation have been determined (by others) in several test systems. On the basis of these coefficients and of dose determinations in mice attempts at risk estimation were performed for ethene and dichlorvos.