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Dale Hattis,¹ Robert Goble,¹ Abel Russ,¹ Margaret Chu,² and Jen Ericson¹

¹George Perkins Marsh Institute, Clark University, Worcester, Massachusetts, USA; ²Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA

Abstract
In revising cancer risk assessment guidelines, the U.S. Environmental Protection Agency (EPA) analyzed animal cancer bioassay data over different periods of life. In this article, we report an improved analysis of these data (supplemented with some chemical carcinogenesis observations not included in the U.S. EPA's original analysis) and animal bioassay studies of ionizing radiation. We use likelihood methods to avoid excluding cases where no tumors were observed in specific groups. We express dosage for animals of different weights on a metabolically consistent basis (concentration in air or food, or per unit body weight to the three-quarters power) . Finally, we use a system of dummy variables to represent exposures during fetal, preweaning, and weaning-60-day postnatal periods, yielding separate estimates of relative sensitivity per day of dosing in these intervals. Central estimate results indicate a 5- to 60-fold increased carcinogenic sensitivity in the birth-weaning period per dose ÷ (body weight^0.75-day) for mutagenic carcinogens and a somewhat smaller increase--centered about 5-fold--for radiation carcinogenesis per gray. Effects were greater in males than in females. We found a similar increased sensitivity in the fetal period for direct-acting nitrosoureas, but no such increased fetal sensitivity was detected for carcinogens requiring metabolic activation. For the birth-weaning period, we found an increased sensitivity for direct administration to the pups similar to that found for indirect exposure via lactation. Radiation experiments indicated that carcinogenic sensitivity is not constant through the "adult" period, but the dosage delivered in 12- to 21-month-old animals appears a few-fold less effective than the comparable dosage delivered in young adults (90-105 days of age) . Key words: carcinogenesis, fetal, ionizing radiation, mutagenic chemicals, risk assessment, statistical analysis, susceptibility. Environ Health Perspect 112:1152-1158 (2004) . doi:10.1289/ehp.6871 available via http://dx.doi.org/ [Online 12 May 2004]

Address correspondence to D. Hattis, George Perkins Marsh Institute, Clark University, 950 Main St., Worcester, MA 01610 USA. Telephone: (508) 751-4603. Fax: (508) 751-4600. E-mail: dhattis@aol.com

We thank H. Barton (U.S. EPA) for suggesting some additions and modifications to the data originally published by the U.S. EPA (2003) . We also thank W. Setzer and P. White (U.S. EPA) for their helpful review of technical statistical issues.

This research was supported by a cooperative agreement with the U.S. EPA (CR 829746-01) .

The conclusions are those of the authors and do not necessarily reflect the views of the U.S. EPA.

The authors declare they have no competing financial interests.

Received 19 November 2003 ; accepted 12 May 2004.