Age-Related Differences in Susceptibility to Carcinogenesis: A Quantitative Analysis of Empirical Animal Bioassay Data

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).

Follow-up studies on genome damage in children after Chernobyl nuclear power plant accident

“…In vitro investigation using challenge and chromosome aberration assays shows that newborns are more sensitive to ionizing radiation than adults, which is in concordance with the findings that children are at greater risk for cancer development after exposure to ionizing radiation (Bakhmutsky et al 2014;Kleinerman 2006;Sadetzki and Mandelzweig 2009;Waugh et al 1991). Similar results have been found in an animal model (Hattis et al 2004). Currently, the Task Group 90 of the International Committee of Radiation Protection is preparing a new document "Age-dependent Dose Conversion Coefficients for External Exposures to Environmental Sources" which will for the first time use current 3D phantoms of each developmental stage of humans for the estimation of age-and gender-related radiosensitivity.…”

Approaches to Acrylamide Physiologically Based Toxicokinetic Modeling for Exploring Child–adult Dosimetry Differences

“…The estimated elevations in glycidamide AUC may lead to increased tissue macromolecular binding in children ( Figure 7B). This dosimetry factor may in theory combine with the greater sensitivity to mutagenic chemicals in early life (Ginsberg, 2003;Hattis et al, 2004;U.S. EPA, 2005) and the somewhat greater acrylamide intake rates per body weight in children (DiNovi & Howard, 2004), to affect cancer risk estimates in children as compared to adults.…”

“…Epoxide hydrolase is also capable of detoxifying glycidamide. Assessing children's risk from acrylamide toxicity is important because of (1) the dietary exposure potential; (2) toxicokinetic factors in early life that may lead to a different internal dose in children as compared to adults; and (3) toxicodynamic factors that may predispose early life stages to genetically acting carcinogens (Ginsberg, 2003;Hattis et al, 2004Hattis et al, , 2005U.S. EPA, 2005).…”

A Preliminary Operational Classification System for Nonmutagenic Modes of Action for Carcinogenesis

“…In previous work, U.S. Environmental Protection Agency (EPA) researchers (Barton et al, 2005) and our group (Hattis et al, 2004(Hattis et al, , 2005 analyzed age-related differences in sensitivity to mutagenic carcinogens (including ionizing radiation) in available rodent bioassay data. The basic finding was that mutagenic carcinogens exhibited several fold greater potency per unit dose per day when administered early in life.…”

“…1. Relative tumor risk/dose for rodents irradiated at different ages-older analysis from Hattis et al (2004) of four experiments for rats and mice, versus analysis of total mouse solid tumor data from Sasaki and Fukuda (2005).…”