Genotoxic carcinogens

Nongenotoxic carcinogens

Results of genetic toxicology tests



Multistage carcinogenesis First stage

Subsequent stages

Genetic changes Gene mutation Chromosome aberration

Genetic or epigenetic changes

Epigenetic changes Cell proliferation Regeneration Growth factor stimulation Peroxisome proliferation Intercellular communication Genomic imprinting Genetic or epigenetic changes

Dose-response at low doses (assumptions)

No carcinogenic threshold Linear dose-response curve

Carcinogenic threshold Sigmoid dose-response curve

Risk characterization (common methods)

Linearized multistage model Biologically based model

Safety factor method

a carcinogen is defined by the results of a battery of genetic toxicology tests. Genotoxic carcinogens induce direct DNA damage and nongenotoxic carcinogens induce epigenetic changes. The genotoxic mechanisms are different types of mutations, including DNA modifications and DNA adducts. The nongenotoxic mechanisms, however, are more diverse. The most common mechanisms are enhanced cell proliferation induced by cytotoxicity or chemical stimulations, peroxisome proliferation, changes in intercellular communications, and loss of imprinting.

With recent knowledge that several nongenotoxic carcinogens are indirectly responsible for inducing DNA damage, the distinction between genotoxic and nongenotoxic carcinogens is less apparent. Such a distinction is only meaningful at the first stage of carcinogenesis.

The genotoxicity of the carcinogen at the first stage of carcinogenesis has great implications for regulatory quantitative risk assessment. The dose-response of genotoxic carcinogens is considered not to have a threshold, and the dose-response curve at the low dose region is linear. The dose-response of nongeno-toxic carcinogens, however, is assumed to have a threshold and the dose-response curve is often sigmoid.

For risk characterization, the linearized multistage model is routinely used by regulatory agencies for the estimation of cancer potency of genotoxic carcinogens. For nongenotoxic carcinogens, the safety factor method is used. Recent advances in biologically based and physiologically based risk assessment modeling will undoubtedly improve the reliability of risk analysis, but the lack of experimental data for new parameters of these models limits their use at this time.

An unexpected but very important observation is that human cells in culture are extremely resistant to chemical carcinogenesis as compared with rodent cells. This difference was not observed in chemical mutagenesis of human cells. This finding raised the possibility that the mechanism of neoplastic transformation in humans, especially at stages beyond the initial mutational changes, is different from that in rodents. Further investigation should be conducted to understand this phenomenon.

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