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 exposures of humans to the industrially important epoxide, propylene oxide (PrO). For regulatory purposes, surface-based extrapolation has been used to determine the human equivalent dose from cancer data obtained in rodents. In this context the tissue dose will more adequately reflect inter- and intraspecies differences with respect to pharmacokinetic parameters than is the case for conventional representations of exposure. The formation of adducts in nucleophilic molecular targets by directly acting electrophilic agents, like epoxides, is thought to be closely linked to the process of cancer initiation. To investigate whether 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 and the dog. Although the data base is more limited, this conclusion is also supported by measurements of DNA alkylation is selected tissues. The variations actually observed are not related to the surface area of the animal. No significant differences could be found between administration of PrO by injection or by inhalation. For this reason, the surface-based extrapolation model for estimation of the human equivalent dose is not appropriate, and the carcinogenic potency factors for PrO as previously derived by the U.S. EPA should probably be revised downward by a factor of 10 to 13.
Center for Nutrition and Toxicology, Karolinska Institute, Huddinge, Sweden.
D
D
Segerbäck
S
S
Osterman-Golkar
B
B
Molholt
R
R
Nilsson
D000477:Alkylating Agents / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001830:Body Surface Area; D001835:Body Weight / Q000502:physiology; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification; D018736:DNA Adducts / Q000032:analysis; D004285:Dogs; D004852:Epoxy Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D051381:Rats; D011916:Rats, Inbred F344; D018570:Risk Assessment; D013045:Species Specificity
D000477:Alkylating Agents; D002273:Carcinogens; D018736:DNA Adducts; D004852:Epoxy Compounds; D006454:Hemoglobins; D004247:DNA; C009068:propylene oxide