Mechanistic Exploration of Carcinogen Exposure Response Relationships

Risk Analysis, Vol. 25, No. 6, 2005

Heterogeneity of Cancer Risk Due to Stochastic Effects

Wolfgang F. Heidenreich∗

Persons with exactly the same genetic background, behavior, environment, etc. may have
differences in cancer risk due to a different number of cells on the way to malignancy. These
differences are estimated quantitatively by using the two-stage clonal expansion model. For
liver cancer the estimated relative risk for persons without intermediate cells at age 40 is less
than 10% when compared to the risk of the total population, while the top 0.1% risk group
has a more than 100-fold risk compared to the population. The risk of the 1% percentile in
risk is more than 100-fold of the risk of the more than 95% persons without intermediate cells.
The number of intermediate (premalignant) cells in the risk groups cannot be calculated from
incidence data only because they depend strongly on a nonidentifiable parameter. But under
plausible assumptions, less than about 1,000 intermediate cells are present at age 40 even in
high-risk persons.

KEYWORDS: Heterogeneity; risk; stochastic cancer model; premalignant cells

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Brooklyn Dodger Comments: The Dodger's imaginary friends at Effect Measure posted an interesting series on carcinogen risk assesment, mostly on the extrapolation of risk from laboratory bioassays, largely in rodents, to people. It's a useful, short and plain language attempt at framing the policy debate. The Dodger commends this to readers, and also to the Reveres for moving beyond the flu.

Repeating the Dodger's past posts, the key issues in public health protection from cancer causing chemical exposures are:

Does carcinogenicity in laboratory tests (mostly in mice and rats) predict carcinogenicity in people (hazard identification)

Does carcinogenicity at high doses (in laboratory or in people) predict increased carcinogenic risk at an lower dose (qualitative exposure response assessment)

Is the exposure response relationship shallow or steep (shallow meaning less reduction in risk for reduction in exposure, a lower exponent for the curve) ?

The Dodger repeats that for two chemical agents for which we have the opportunity to observe human health effects at over a wide range of exposures, the risk appears at the lower exposures. These are environmental tobacco smoke v. direct smoking, and occupational asbestos exposure v. take home house hold and community.

The shape of the exposure response relationship can't be observed directly in the lower dose range, lower meaning 1/25 of the effect level. For most lab studies there's at most two observable effect levels, giving unit risks, and a no observed effect level. For people studies, some additional rates may be observed, but the quantitative exposure is way less certain. Models estimate the risk in the unobservable range.

The linearized multi stage model, and the one hit, two hit, log probit, weibull and other models are based on an equation giving mathematical expression to a metaphorical account of cancer initiation. These may diverge by large amounts in the unobservable low dose range; the linearized multi stage model tends to give the higher lower dose estimates because of low dose linearity.

The two stage clonal expansion model attempts incorporation of parameters for some biological processes - cell replication and cell death. Two stage clonal expansion actually incorporates multiple stages but boils down to initiation and promotion. There can be only one rate determining step of a chemical process.

The issue for risk assessment is the distribution of parameters in a population - the exposure-response relationship is a population characteristic. Having observed carcinogenicity at a [relatively] high dose, is the relationship flat [higher low dose risk] or steep?

Trying to come to the point, this modeler points to a clone of a few hundred transformed cells being precurser to a full blown malignant tumor. In a handwaving way, this suggests subtantial inter individual variation in resistence to carcinogens, and thus a shallow exposure response relationship.