Chemical and radiation carcinogenesis

1. Chemical carcinogenesis

• Historically linked to soot → scrotal cancer in chimney sweeps. The Ames test (Salmonella mutagenesis) screens for carcinogenicity.

Direct vs indirect agents

Type	Activation	Examples → cancer
Direct-acting	No metabolic conversion needed	Alkylating agents (chemo drugs) → leukemia/lymphoma
Indirect (procarcinogens)	Activated by cytochrome P450	Benzopyrene (tobacco) → lung; aromatic amines (2-naphthylamine) → bladder; aflatoxin (Aspergillus) → HCC (p53 mutation); nitrosamines → stomach; alcohol → oropharynx/esophagus, liver, pancreas

Multistep mechanism

• Initiation — genotoxic, irreversible mutation in DNA (e.g. RAS, p53); dose-dependent.
• Promotion — non-mutagenic; drives clonal expansion (often hormone-like substances); reversible.
• Progression — autonomous growth; morphology: hyperplasia → dysplasia → carcinoma in situ.

2. Radiation carcinogenesis

Effect via chromosome breaks, translocations, point mutations.

Ionizing radiation (X/γ-rays, α/β particles)

• Direct: point mutations + double-strand breaks. Indirect: hydroxyl free radicals.
• Susceptibility: High — AML, CML; Intermediate — breast, lung, salivary; Low — skin, bone, GI.

Non-ionizing (UV)

• Forms pyrimidine (thymine) dimers → repaired by NER; defect → xeroderma pigmentosum.
• Cumulative exposure → non-melanoma (BCC, SCC); intense intermittent sunburns → melanoma. Fair skin = higher risk.

💡 High-yield: Chemical: direct (alkylating) vs indirect (P450-activated: benzopyrene→lung, aromatic amines→bladder, aflatoxin→HCC/p53). Steps = initiation (mutation) → promotion (clonal expansion) → progression. Radiation: ionizing → DSBs (AML/CML highest); UV → thymine dimers/NER → xeroderma pigmentosum, skin cancers.