Comparison of contact site cancer potency across dose routes: case study with epichlorohydrin.
Risk assessment for airborne carcinogens is often limited by a lack of inhalation bioassay data. While extrapolation from oral-based cancer potency factors may be possible for some agents, this is not considered feasible for contact site carcinogens. The change in contact sites (oral: g.i. tract; inhalation: respiratory tract) when switching dose routes leads to possible differences in tissue sensitivity as well as chemical delivery. This research evaluates the feasibility to extrapolate across dose routes for a contact site carcinogen through a case study with epichlorohydrin (EPI). EPI cancer potency at contact sites is compared across three bioassays involving different dose routes (gavage, drinking water, inhalation) through the use of dosimetry models to adjust for EPI delivery to contact sites. Results indicate a large disparity (two orders of magnitude) in potency across the three routes of administration when expressed as the externally applied dose. However, when expressed as peak delivered dose, inhalation and oral potency estimates are similar and overall, the three potency estimates are within a factor of seven. The results suggest that contact site response to EPI is more dependent upon the rate than the route of delivery, with peak concentration the best way to extrapolate across dose routes. These results cannot be projected to other carcinogens without further study.
Ginsberg
G L
GL
State of Connecticut, Department of Public Health, Hartford 06134-0308, USA.
Pepelko
W E
WE
Goble
R L
RL
Hattis
D B
DB
D000280:Administration, Inhalation; D000284:Administration, Oral; D000393:Air Pollutants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001681:Biological Assay; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004811:Epichlorohydrin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D009928:Organ Specificity; D051381:Rats; D018570:Risk Assessment
D000393:Air Pollutants; D002273:Carcinogens; D004811:Epichlorohydrin