Assessing susceptibility from early-life exposure to carcinogens

Abstract

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.

Figure 1

Schematic representation of several cancer study designs reported in the evaluated literature. The standard rodent bioassay begins after puberty, and exposures continue for about 2 years. Repeated-dosing studies typically dose during the postnatal period, with observations for tumors at approximately 2 years. Lifetime studies combine postnatal and adult exposures, sometimes beginning with in utero exposure. Acute studies (not shown) generally involve one or a few exposure during the in utero, preweaning, prepubertal, and adult periods. The adult tumors were often evaluated much earlier than 2 years *Can also include prenatal exposure.

Figure 2

Posterior geometric means and 95% confidence intervals for the ratios of juvenile to adult cancer potency for carcinogens acting primarily through a mutagenic mode of action. (A) Repeated and lifetime exposure studies (geometric mean in black). (B) Acute exposure studies mutagens (geometric mean in white). The horizontal lines to the left and right of each geometric mean correspond to 95% confidence limits. The vertical solid line represents the geometric mean; the horizontal solid line represents the 95th percentile; the vertical dotted line is the geometric mean of the 95th percentile. The geometric mean for repeat and lifetime exposures is 10.4; for acute exposures the geometric mean value is 1.5.