Assessing Susceptibility from Early-Life Exposure to Carcinogens
Barton, Hugh A., Cogliano, V. James, Flowers, Lynn, Valcovic, Larry, Setzer, R. Woodrow, Woodruff, Tracey J., Environmental Health Perspectives
Cancer risk assessment methods currently assume that children and adults are equally susceptible to exposure to chemicals. We reviewed available scientific literature to determine whether this was scientifically supported. We identified more than 50 chemicals causing cancer after perinatal exposure. Human data are extremely limited, with radiation exposures showing increased early susceptibility at some tumor sites. Twenty-seven rodent studies for 18 chemicals had sufficient data after postnatal and adult exposures to quantitatively estimate potential increased susceptibility from early-life exposure, calculated as the ratio of juvenile to adult cancer potencies for three study types: acute dosing, repeated dosing, and lifetime dosing. Twelve of the chemicals act through a mutagenic mode of action. For these, the geometric mean ratio was 11 for lifetime exposures and 8.7 for repeat exposures, with a ratio of 10 for these studies combined. The geometric mean ratio for acute studies is 1.5, which was influenced by tissue-specific results [geometric mean ratios for kidney, leukemia, liver, lymph, mammary, nerve, reticular tissue, thymic lymphoma, and uterus/vagina > 1 (range, 1.6-8.1); forestomach, harderian gland, ovaries, and thyroid < 1 (range, 0.033-0.45)]. Chemicals causing cancer through other modes of action indicate some increased susceptibility from postnatal exposure (geometric mean ratio is 3.4 for lifetime exposure, 2.2 for repeat exposure). Early exposures to compounds with endocrine activity sometimes produce different tumors after exposures at different ages. These analyses suggest increased susceptibility to cancer from early-life exposure, particularly for chemicals acting through a mutagenic mode of action. Key words: cancer, children, early-life exposure, exposure, mode of action, risk assessment, susceptible populations. doi:10.1289/ehp.7667 available via http://dx.doi.org/[Online 7 April 2005]
The cancer database used by the U.S. Environmental Protection Agency (EPA) and other agencies for risk assessment for exposure to carcinogens focuses on adults and adult exposures. Much cancer epidemiology comes from occupational studies and rodent cancer studies, which were designed to last approximately a lifetime (2 years) beginning after sexual maturity. Cancer risks from childhood exposures to chemicals are generally analyzed using methods based on exposure to adults, which assumes chemicals are equally potent for inducing risks of exposures in both early life and later life. Animal and human data suggest that further analysis is warranted to determine whether early-life exposure results in increased susceptibility to cancer compared with adult exposures (Anderson et al. 2000; National Research Council 1993). There is extensive literature demonstrating that exposures early in life (i.e., transplacental or in utero, early postnatal, and lactational) in animals can result in the development of cancer (reviewed in Anderson et al. 2000; Della Porta and Terracini 1969; Druckrey 1973; Rice 1979; Rice and Ward 1982; Toth 1968; Vesselinovitch 1983; Vesselinovitch et al. 1979a). However, except for data on radiation and prenatal exposure to diethylstilbesterol (DES), there are virtually no human data adequate for quantitative analysis.
Standard animal bioassays generally begin dosing after the animals are 6-8 weeks of age, when many organs and systems are relatively mature, although substantial growth in body size continues thereafter. Reviews comparing perinatal carcinogenesis bioassays with standard bioassays for a limited number of chemicals (McConnell 1992; U.S. EPA 1996) have concluded that the same tumor sites usually are observed after either perinatal or adult exposure, and that perinatal exposure in conjunction with adult exposure usually increases the incidence of tumors or reduces the latent period before tumors are observed.
There is limited evidence to inform the mode(s) of action leading to differences in tumor type and tumor incidence after early-life exposure compared with exposure later in life. …