Modeling Lower Dose Cancer Risk After Effects are Found at Directly Observable Levels

BrooklynDodger argues that the shape of the exposure response relationship for carcinogens in the region where that relationship can't be directly observed decides the high dose-low dose extrapolation which is critical to public health interventions. Does the curve go through zero dose [therefore every reduction has a benefit], or is there a practical threshold [a region where there is no dose response relationship]?

It's generally accepted that genotoxic - somatic mutagenic - carcinogens don't show a threshold. Houdini risk assessments can still make the low dose risk go away through other means, but extra mathematical means.

The two natural experiments, environmental tobacco smoke and lung cancer, and take home asbestos and mesothelioma, demonstrate no threshold, or at least risk persisting to low fractions of the previously known hazard level. Asbestos is not conventionally genotoxic [ames test positive.] Tobacco smoke is ames test positive, but is also a promoter.

David Gaylor is a Jedi among modelers. While at NCTR, he seemed often intuned to the bright side of the public health force. A few key quotes ripped from the abstract:

"However, a threshold dose is questionable if a nongenotoxic carcinogen acts via a cell receptor. Also, a nongenotoxic carcinogen that increases the cell proliferation rate, via the cell division rate and/or cell removal rate by apoptosis, by augmenting an existing endogenous mechanism is not likely to have a threshold dose."

"small changes in the cell proliferation rate, that may be obscured by the background noise in rates, can produce large changes in the lifetime tumor incidence as calculated from the Moolgavkar-Venzon-Knudson model. That is, dose response curves for cell proliferation and tumor incidence do not necessarily mimic each other. This makes the use of no observed effect levels (NOELs) for cell proliferation rates often inadmissible for establishing acceptable daily intakes (ADIs) of nongenotoxic carcinogens."

Application of EPA-IRIS style safety factors to most carcinogenicity bioassay data, and all human epidemiology data, projects to drastrically reduced PEL's compared to what prevail now.

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Risk Anal. 1996 Apr;16(2):221-5.

Risk assessment of nongenotoxic carcinogens based upon cell proliferation/death rates in rodents.

Gaylor DW, Zheng Q.

Division of Biometry and Risk Assessment, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079, USA.

Increased cell proliferation increases the opportunity for transformations of normal cells to malignant cells via intermediate cells. Nongenotoxic cytotoxic carcinogens that increase cell proliferation rates to replace necrotic cells are likely to have a threshold dose for cytotoxicity below which necrosis and hence, carcinogenesis do not occur. Thus, low dose cancer risk estimates based upon nonthreshold, linear extrapolation are inappropriate for this situation. However, a threshold dose is questionable if a nongenotoxic carcinogen acts via a cell receptor. Also, a nongenotoxic carcinogen that increases the cell proliferation rate, via the cell division rate and/or cell removal rate by apoptosis, by augmenting an existing endogenous mechanism is not likely to have a threshold dose. Whether or not a threshold dose exists for nongenotoxic carcinogens, it is of interest to study the relationship between lifetime tumor incidence and the cell proliferation rate. The Moolgavkar-Venzon-Knudson biologically based stochastic two-stage clonal expansion model is used to describe a carcinogenic process. Because the variability in cell proliferation rates among animals often makes it impossible to detect changes of less than 20% in the rate, it is shown that small changes in the cell proliferation rate, that may be obscured by the background noise in rates, can produce large changes in the lifetime tumor incidence as calculated from the Moolgavkar-Venzon-Knudson model. That is, dose response curves for cell proliferation and tumor incidence do not necessarily mimic each other. This makes the use of no observed effect levels (NOELs) for cell proliferation rates often inadmissible for establishing acceptable daily intakes (ADIs) of nongenotoxic carcinogens. In those cases where low dose linearity is not likely, a potential alternative to a NOEL is a benchmark dose corresponding to a small increase in the cell proliferation rate, e.g., 1%, to which appropriate safety (uncertainty) factors can be applied to arrive at an ADI.