Carcinogenic Mechanisms and Dose-Response Relationships

The development of cancer is underpinned by a complex interplay of molecular and cellular processes whereby normal cells accumulate genetic and epigenetic alterations that drive uncontrolled proliferation. Carcinogenic mechanisms traditionally distinguish between genotoxic agents, which inflict direct DNA damage through adduct formation or strand breaks, and non-genotoxic agents, which promote tumour development indirectly via oxidative stress, inflammatory signalling or sustained cell proliferation. Multistage models of carcinogenesis describe sequential phases of initiation, promotion and progression, each characterised by distinct molecular events. Central to risk assessment is the dose-response relationship, which examines how the incidence of tumours varies with exposure level. Linear no-threshold models assume risk increases proportionately at all doses, whereas threshold models posit a safe exposure below which no adverse effect occurs. Hormetic dose-response curves exhibit biphasic behaviour, with low-dose stimulation of adaptive responses and high-dose toxicity. Advances in molecular biology, computational toxicology and high-throughput screening have elucidated mechanisms of adduct repair, receptor-mediated epigenetic modulation and the kinetics of cell-division rates, refining predictions of low-dose risk. Insights into interindividual variability and mixture effects have emphasised the need for biologically based models that link mechanistic data to human risk, guiding regulatory standards and preventive interventions worldwide.

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Carcinogenic Mechanisms and Dose-Response Relationships publication trend

The graph below shows the total number of articles in carcinogenic mechanisms and dose-response relationships across all publications each year (not limited to Nature Index journals).

Technical terms

Genotoxic carcinogen: Agent that causes direct damage to DNA through adduct formation or strand breaks, leading to mutations.

Non-genotoxic carcinogen: Agent that promotes tumour development indirectly via mechanisms such as oxidative stress, inflammation or sustained cell proliferation.

Dose-response relationship: Correlation between the level of exposure to an agent and the frequency or severity of an adverse effect.

Threshold: Exposure level below which no significant adverse effect is observed in an organism.

Linear no-threshold model: Assumption that any non-zero dose carries proportional risk, with no safe exposure level.

Hormesis: Biphasic dose-response characterised by low-dose stimulation and high-dose inhibition of biological processes.

Multistage carcinogenesis: Model of tumour development through sequential phases of initiation, promotion and progression.

DNA adduct: Covalent modification of DNA by a chemical agent that can interfere with replication and repair.

References

1. Increased Cell Proliferation as a Key Event in Chemical Carcinogenesis: Application in an Integrated Approach for the Testing and Assessment of Non-Genotoxic Carcinogenesis. International Journal of Molecular Sciences (2023).
2. After a Century of Research into Environmental Mutagens and Carcinogens, Where Do We Stand?. International Journal of Environmental Research and Public Health (2023).
3. Dose-response relationships for carcinogens: a review.. Environmental Health Perspectives (1987).
4. The distinct health risk analyses required for genotoxic carcinogens and promoting agents.. Environmental Health Perspectives (1983).
5. Multistage models of carcinogenesis.. Environmental Health Perspectives (1985).
6. Collaborative study of thresholds for mutagens: proposal of a typical protocol for detection of hormetic responses in cytotoxicity tests. Genes and Environment (2018).