IN-VIVO TISSUE DOSIMETRY AS A BASIS FOR CROSS-SPECIES EXTRAPOLATION IN CANCER RISK ASSESSMENT OF PROPYLENE-OXIDE

The potential for causing carcinogenic and mutagenic effects has been the main concern when assessing the risks associated with low-level ex posures of humans to the industrially important epoxide, propylene oxi de (PrO). For regulatory purposes, surface-based extrapolation has bee n used to determine the human equivalent dose from cancer data obtaine d in rodents. In this context the tissue dose will more adequately ref lect inter- and intraspecies differences with respect to pharmacokinet ic parameters than is the case for conventional representations of exp osure. The formation of adducts in nucleophilic molecular targets by d irectly acting electrophilic agents, like epoxides, is thought to be c losely linked to the process of cancer initiation. To investigate whet her tissue dose is correlated to surface area of the exposed organism, the in vivo adduct levels in hemoglobin and DNA have been determined in mice, rats, and dogs after exposure to PrO by injection as well as by inhalation. The results obtained indicate that the dose in blood is virtually the same in the three investigated animal species, whereas surface-area based extrapolation predicts a difference by a factor of about seven between the mouse acid the dog. Although the data base is more limited, this conclusion is also supported by measurements of DNA alkylation in selected tissues. The variations actually observed are not related to the surface area of the animal. No significant differen ces could be found between administration of PrO by injection or by in halation. For this reason, the surface-based extrapolation model for e stimation of the human equivalent dose is not appropriate, and the car cinogenic potency factors for PrO as previously derived by the U.S. EP A should probably be revised downward by a factor of 10 to 13. (C) 199 4 Academic Press, Inc.