Hypotheses

A. J-Shaped Dose Response and Thresholds for DNA-Reactive Carcinogens?

Earlier in this chapter, it was shown that the rate of induction of mutations is proportional to both the level of DNA damage and the rate of cell division. Recent evidence now indicates that the two aspects are not independent of each other: DNA damage can result in a delay of the cell cycle (20, 21). An increase in the mutation rate by a carcinogen-induced DNA damage could be counteracted by a decrease in the rate of cell division. This effect is expected to be limited to a non-toxic dose range. At higher dose levels of a DNA-damaging carcinogen, cytotox-icity and regenerative hyperplasia might accelerate cell proliferation. Over the entire dose range, a J-shaped dose-response relationship could result for mutations. This is shown schematically in Figure 7, where a dose-linear increase in the level of DNA damage (upper part), multiplied with a J-shaped dose response for the rate of cell division (middle part), can result in a J-shaped dose response for mutation (lower part) if the decrease in the rate of cell division is larger than the increase in DNA damage.

Cell proliferation is important not only concerning the fixation of a DNA damage as a mutation but also with regard to the process of clonal expansion of premalignant cells. Using the two-mutation, clonal-expansion model of carcinogenesis, the requirements to produce a J-shaped dose-response curve from a dose-linear increase in the level of mutation and a J-shaped dose response for cell turnover were analyzed (22). The background values chosen for the model parameters resulted in a 10.5% "spontaneous" 2-year cumulative tumor incidence. Using this as a starting point, a decrease by 3%, 10%, and 30% in the rates of cell turnover resulted in a decrease in the spontaneous tumor incidence to 9.4%, 7.1%, and 3.0%. J-Shaped dose responses for the rates of cell turnover were modeled by parabolic curves, having their minimum at dose 1. Combination with linearly increasing mutation rates generated, under certain conditions, J-shaped dose-response curves for tumor incidence. One example is shown in Figure 8. The DNA-damaging potency of the carcinogen was assumed to result in a 30% increase in the spontaneous mutation rate at dose 1. The decrease in cell turnover at dose 1 was assumed to be 3%, 10%, or 30%. For the 10% and 30% decrease, the dose-linear increase in DNA damage was more than compensated for, result-

DNA damage

DNA damage

Dose

Rate of cell division

Dose

Rate of cell division

Fig. 7. Multiplicative combination of a linear dose-response relationship for DNA damage (top chart) with a J-shaped rate of cell proliferation (center chart) to result in a J-shaped dose response for mutations (bottom chart). (From Ref. 4, with permission of Elsevier Science.)

ing in a J-shaped dose response for tumor induction. "Threshold" doses of 0.8 and 1.6 dose units, respectively, could be deduced.

A decrease of the cell turnover by 10% or 30% could well be within physiological limits. For instance, treatment of rats with caffeic acid for 4 weeks resulted in a J-shaped dose response for the DNA replication in the forestomach, with an observed maximum decrease by as much as 46% (23).

B. Anticarcinogenic Effects of Carcinogens

The TCDD example shown in Table 1 is only one of a number of examples of anticarcinogenic effects of carcinogens. In an analysis of 218 bioassays for carcinogenicity performed by the National Toxicology Program, more than 90% of the tested chemicals showed at least one statistically significant decrease in site-specific tumor incidence (24). Random variability and reductions associated with

Fig. 8. Shapes of dose-response curves generated by superposition of a doselinear increase in the rates of mutation with J-shaped dose-response curves for the rates of cell birth and death, in the two-stage clonal expansion model of carcinogenesis. The J-shape was generated by parabolic, quadratic functions intersecting the dose axis at dose 0 and 2 and reaching their minimum at dose 1.

Percent decrease in the background rate of cell turnover at dose 1:----3%;---

- 10%;---30%). The full line represents the dose response obtained from the increase in the mutation rates alone (+30% at dose 1). Model parameters chosen for the background process: 1 million normal stem cells; background mutation rate of |iN = |iP = 10-7 per day for both steps; birth and death rates for the prema-lignant cells p = 0.5, 8 = 0.49 per day. On this basis, the (spontaneous) cumulative "tumor incidence" over 2 years was 10.5%. (See text for discussion and Ref. 22 for details.)

Fig. 8. Shapes of dose-response curves generated by superposition of a doselinear increase in the rates of mutation with J-shaped dose-response curves for the rates of cell birth and death, in the two-stage clonal expansion model of carcinogenesis. The J-shape was generated by parabolic, quadratic functions intersecting the dose axis at dose 0 and 2 and reaching their minimum at dose 1.

Percent decrease in the background rate of cell turnover at dose 1:----3%;---

- 10%;---30%). The full line represents the dose response obtained from the increase in the mutation rates alone (+30% at dose 1). Model parameters chosen for the background process: 1 million normal stem cells; background mutation rate of |iN = |iP = 10-7 per day for both steps; birth and death rates for the prema-lignant cells p = 0.5, 8 = 0.49 per day. On this basis, the (spontaneous) cumulative "tumor incidence" over 2 years was 10.5%. (See text for discussion and Ref. 22 for details.)

reduced body weight can account for many of these decreases. For others, the mechanism by which reduced tumor incidence is achieved is yet to be determined, and aspects such as those in the preceding Section will have to be included.

For TCDD, J-shaped dose-response relationships were not only reported for liver tumors but also for altered hepatic foci (25) and for the rate of cell proliferation (26). A causal relationship between the three endpoints appears plausible. It also means that an inclusion of the high-dose data in a linearized extrapolation model is unlikely to give the best possible estimate of a low-dose cancer risk. A threshold model appears to be more appropriate.

C. Additivity Theory to be Revised?

J-Shaped dose responses for DNA-damaging carcinogens contradict the hypothesis that even the lowest doses of DNA-reactive carcinogens produce a damage increment to the background so that the cancer risk has to increase in an additive manner (27). The limitation in this argumentation is the understanding that all types of DNA damage add up with respect to their mutational consequences. In light of observations that DNA damage can affect the cell cycle, this hypothesis will have to be revised. Each type of DNA damage is expected to have its own specific consequence so that it cannot be considered to be just an increment to what is already there. This idea is supported by the finding that a number of DNA-reactive carcinogens generated J-shapes for the level of single-strand breaks in rat liver DNA (28).

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