Comparison of cancer slope factors using different statistical approaches.

The U.S. Environmental Protection Agency's cancer guidelines (USEPA, 2005) present the default approach for the cancer slope factor (denoted here as s*) as the slope of the linear extrapolation to the origin, generally drawn from the 95% lower confidence limit on dose at the lowest prescribed risk level supported by the data. In the past, the cancer slope factor has been calculated as the upper 95% confidence limit on the coefficient (q*1) of the linear term of the multistage model for the extra cancer risk over background. To what extent do the two approaches differ in practice? We addressed this issue by calculating s* and q*1 for 102 data sets for 60 carcinogens using the constrained multistage model to fit the dose-response data. We also examined how frequently the fitted dose-response curves departed appreciably from linearity at low dose by comparing q1, the coefficient of the linear term in the multistage polynomial, with a slope factor, sc, derived from a point of departure based on the maximum likelihood estimate of the dose-response. Another question we addressed is the extent to which s* exceeded sc for various levels of extra risk. For the vast majority of chemicals, the prescribed default EPA methodology for the cancer slope factor provides values very similar to that obtained with the traditionally estimated q*1. At 10% extra risk, q*1/s* is greater than 0.3 for all except one data set; for 82% of the data sets, q*1 is within 0.9 to 1.1 of s*. At the 10% response level, the interquartile range of the ratio, s*/sc, is 1.4 to 2.0.

Assessing susceptibility from early-life exposure to carcinogens.

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.