Unveiling Variability and Uncertainty for Better Science and Decisions on Cancer Risks from Environmental Chemicals

Abstract

The National Research Council 2009 "Silver Book" panel report included a recommendation that the U.S. Environmental Protection Agency (EPA) should increase all of its chemical carcinogen (CC) potency estimates by ∼7-fold to adjust for a purported median-vs.-mean bias that I recently argued does not exist (Bogen KT. "Does EPA underestimate cancer risks by ignoring susceptibility differences?," Risk Analysis, 2014; 34(10):1780-1784). In this issue of the journal, my argument is critiqued for having flaws concerning: (1) intent, bias, and conservatism of EPA estimates of CC potency; (2) bias in potency estimates derived from epidemiology; and (3) human-animal CC-potency correlation. However, my argument remains valid, for the following reasons. (1) EPA's default approach to estimating CC risks has correctly focused on bounding average (not median) individual risk under a genotoxic mode-of-action (MOA) assumption, although pragmatically the approach leaves both inter-individual variability in CC-susceptibility, and widely varying CC-specific magnitudes of fundamental MOA uncertainty, unquantified. (2) CC risk estimates based on large epidemiology studies are not systematically biased downward due to limited sampling from broad, lognormal susceptibility distributions. (3) A good, quantitative correlation is exhibited between upper-bounds on CC-specific potency estimated from human vs. animal studies (n = 24, r = 0.88, p = 2 × 10(-8)). It is concluded that protective upper-bound estimates of individual CC risk that account for heterogeneity in susceptibility, as well as risk comparisons informed by best predictions of average-individual and population risk that address CC-specific MOA uncertainty, should each be used as separate, complimentary tools to improve regulatory decisions concerning low-level, environmental CC exposures.

Low-Dose Dose–Response for In Vitro Nrf2-ARE Activation in Human HepG2 Cells

“…38,39 Under this hypothesis, the implied J-shaped DR pattern for increased tumor risk would differ fundamentally from the linear-no-threshold DR pattern implied by the multistage somatic mutation (MSM) theory of tumorigenesis. 38 -43 Consistent with this hypothesis is evidence that potently anti-inflammatory synthetic oleanane triterpenes such as the acetylenic tricyclic bis -(cyano enone) TBE-31, 1-2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl (CDDO) ethyl amide (CDDO-EA), and CDDO-imidazole (CDDO-Im) activate the Nrf2-ARE cytoprotective pathway, induce phase II enzymes, and can suppress or completely block formation of enzyme-altered proliferative hepatocellular foci and liver tumors in rodents coadministered hepatotoxic liver carcinogens such as aflatoxin B 1 (also a potent mutagen) and carbon tetrachloride. 17,36,37,44,45 Although aflatoxin B 1 exposures induce macromolecular adducts with a linear DR pattern over a wide range of doses down to 0.16 ng/kg, coadministration of CDDO-Im before and during aflatoxin B 1 exposures that otherwise efficiently increase the occurrence of liver preneoplastic foci and tumors in male rats can nearly or completely eliminate these aflatoxin B 1 -induced lesions without proportionately reducing aflatoxin B 1 –DNA adducts, 36,34,37 which appears to be at odds with MSM theory.…”

Reassessment of MTBE cancer potency considering modes of action for MTBE and its metabolites

“…However, regulatory-policy interest typically focuses not on a broad range of potency estimates for each chemical carcinogen, but rather on a conservatively defined upper confidence limit (UCL) on each such estimated potency. A recent comparison of UCLs on estimated human vs. rodent potencies for 24 chemical carcinogens showed that these UCLs exhibit a pattern consistent with the hypothesis that x = 0, and more specifically that UCL estimates of human and rodent potency for chemical carcinogens are, on average, equal to within a factor of <3 with 95% confidence (Bogen 2014).…”

Inflammation as a Cancer Co-Initiator: New Mechanistic Model Predicts Low/Negligible Risk at Noninflammatory Carcinogen Doses

“…Linear-no-threshold (LNT) risk extrapolation has long been applied to estimate risks posed by low-level environmental (particularly by default for mutagenic) carcinogen exposures, based on the 60-year-old multistage somatic mutation/clonal expansion (MSM) theory of cancer. 1 First proposed and represented mathematically by Armitage and Doll in 1957, 2 the MSM theory overlaps most other current competing theories of cancer because the critical events it posits (namely, 2 or more critical oncogene mutations in a somatic stem cell, coupled if/as applicable with intrinsic and/or exposureinduced "promotion" by net proliferation of intermediate/premalignant cells) can also be induced or augmented by events posited as critical by those theories (eg, theories focusing on: 3 oxidative stress, infection, an inflammatory microenvironment, defective wound healing, chromosome damage, genomic instability, and epigenetic dysregulation). Generalizing MSM theory and Knudsen's related 2-mutation tumor suppressor inactivation model describing inherited susceptibility to retinobalstoma, [4][5][6] Moolgavkar, Venzon, Knudson (MVK) and colleagues represented the MSM model mathematically as a 2-stage doubly stochastic Poisson process (Figure 1, left) and fit this model well to many sets of experimental cancer bioassay and human cancer incidence data.…”