Environmental Diseases — Smoking, UV Exposure, Asbestos and Lifestyle Factors

The three principles that explain why environmental diseases are preventable, predictable at population level, but variable at individual level

Environmental diseases share three features that distinguish them from genetic diseases: they require an external exposure, they show a dose-response relationship (more exposure = higher risk), and they have a latency period (time between first exposure and disease manifestation). Understanding these three features makes every specific environmental disease in this lesson predictable from first principles.

Environmental diseases showing causes, mechanisms and examples

Dose-response relationship for threshold and non-threshold toxins

Principle 1 — Exposure is required

Unlike genetic diseases (which are present from conception), environmental diseases require an external agent — a carcinogen, a physical mutagen, a toxic fibre, a chemical — to initiate the disease process. Remove the exposure and the disease does not occur. This is why tobacco-related lung cancer rates fell dramatically in countries that implemented smoking bans and anti-smoking campaigns — the exposure was reduced at population level.

Principle 2 — Dose-response relationship

The probability of developing an environmental disease increases with the cumulative dose of the exposure — not just whether exposure occurred but how much and for how long. A person who smoked 20 cigarettes per day for 40 years has a much higher lung cancer risk than one who smoked 5 per day for 5 years. This is quantified by the 'pack-year' measure (packs per day × years smoked). The dose-response relationship provides the epidemiological evidence that links exposures to diseases (this will be revisited in L12–L14 on epidemiology).

Principle 3 — Latency period

Environmental diseases rarely manifest immediately after first exposure. Most have a latency period — the time between first exposure and clinical disease — ranging from years (some chemical exposures) to decades (asbestos: 20–50 years; tobacco: 20–30 years). This latency makes it difficult for individuals to perceive the harm from ongoing exposure and creates public health communication challenges. It also means that even after cessation of exposure, the risk remains elevated for years — though it does decline over time.

Over 70 carcinogens in tobacco smoke; Australia's single most preventable cause of premature death

Tobacco smoke is one of the most studied environmental carcinogens. Its effects on the body span three distinct disease pathways — mutagenic damage leading to cancer, inflammatory/toxic damage leading to COPD, and vascular damage leading to cardiovascular disease — each operating through a different molecular mechanism.

Pathway 1 — Lung cancer

Carcinogens in tobacco smoke (particularly polycyclic aromatic hydrocarbons like benzopyrene) are absorbed across the bronchial epithelium and metabolically activated in bronchial cells to reactive electrophilic forms. These electrophiles covalently bond to DNA bases, forming DNA adducts — distortions that cause errors during DNA replication. If these adducts form in critical proto-oncogenes (e.g. KRAS) or tumour suppressor genes (e.g. TP53, which encodes p53), the resulting mutations may initiate the cancer development process.

With continued smoking, additional mutations accumulate over years to decades. When enough mutations accumulate in a single bronchial cell — disabling cell cycle checkpoints (p53), activating growth signals (KRAS), and disabling apoptosis — that cell line begins to proliferate uncontrollably → lung cancer. Approximately 85% of lung cancers are attributable to smoking.

Pathway 2 — COPD (emphysema and chronic bronchitis)

Tobacco smoke irritants (not only carcinogens) trigger a chronic inflammatory response in the airways. Macrophages and neutrophils recruited to the airways release proteases (particularly elastase) that break down the elastin in the alveolar walls. Progressive destruction of alveolar walls reduces the surface area for gas exchange and eliminates the elastic recoil that drives exhalation → emphysema. Simultaneously, chronic irritation stimulates mucus-secreting cells to proliferate and produce excess mucus, obstructing small airways → chronic bronchitis. Together these produce COPD — progressive, largely irreversible airflow obstruction.

Pathway 3 — Cardiovascular disease

Tobacco smoke chemicals damage the endothelial lining of blood vessels, triggering an inflammatory response. Nicotine causes vasoconstriction and increases heart rate and blood pressure. Carbon monoxide in smoke binds haemoglobin more tightly than O₂ (forming carboxyhaemoglobin), reducing oxygen-carrying capacity. Chronic endothelial damage promotes atherosclerosis — lipid-laden plaques accumulate in artery walls, narrowing vessels and increasing the risk of thrombosis, heart attack, and stroke.

Australia has the highest rate of skin cancer in the world — a direct consequence of UV exposure combined with a fair-skinned European-descended population

UV radiation is a physical mutagen — it does not form DNA adducts like chemical carcinogens, but instead directly alters DNA structure by causing covalent bonds to form between adjacent pyrimidine bases. The result is the same: DNA damage that, if unrepaired, produces mutations during replication.

The thymine dimer mechanism

UV-B photons are absorbed by adjacent thymine bases on the same DNA strand. The absorbed energy causes a photochemical reaction — a cyclobutane ring forms between the two thymines, creating a thymine dimer (also called a cyclobutane pyrimidine dimer, CPD). This dimer distorts the DNA double helix at that point, preventing normal base pairing and blocking DNA polymerase during replication.

The body has nucleotide excision repair (NER) enzymes that normally recognise and excise thymine dimers, replacing them with correctly synthesised nucleotides. This repair is highly efficient in most cells. However, when UV exposure is intense or frequent, the rate of dimer formation exceeds the repair capacity — unrepaired dimers persist through DNA replication and cause mutations. Typical UV-induced mutations produce characteristic CC→TT transitions (a 'signature mutation' specific to UV damage) in skin cell DNA.

From mutation to melanoma

In melanocytes, UV-induced mutations accumulate over time. Mutations in the BRAF oncogene (present in ~60% of melanomas, particularly V600E mutation) activate the MAPK/ERK signalling pathway, driving uncontrolled melanocyte proliferation. Additional mutations disabling CDKN2A (encoding p16 — a tumour suppressor) remove the cell cycle brake. The combination of oncogene activation and tumour suppressor inactivation produces invasive melanoma.

Non-melanoma skin cancers (basal cell carcinoma, squamous cell carcinoma) arise from keratinocytes through the same UV-damage mechanism but in different cell types, with different mutational targets and lower metastatic potential than melanoma.

A physical carcinogen — not chemical or UV — with the longest latency period of any known occupational carcinogen

Asbestos provides a mechanistically distinct example of environmental disease — one caused not by a chemical mutagen or radiation, but by the physical properties of a durable inorganic fibre that the body cannot break down. The mechanism involves chronic inflammation, free radical generation, and mechanical DNA damage rather than direct chemical interaction with DNA.

How asbestos fibres cause mesothelioma

When asbestos fibres are inhaled, the longer fibres (>5 μm) cannot be completely engulfed by alveolar macrophages — the macrophages attempt but fail to phagocytose them, resulting in 'frustrated phagocytosis.' The macrophages release reactive oxygen species (ROS) and inflammatory cytokines in a prolonged, unsuccessful attempt to degrade the fibres.

These ROS directly damage DNA in adjacent mesothelial cells lining the pleura. The chronic inflammatory environment also promotes cell proliferation (healing response) — increasing the rate at which mutations are replicated and propagated. Over 20–50 years, cumulative DNA damage in mesothelial cells — particularly mutations in tumour suppressor genes (BAP1, NF2, CDKN2A) — leads to malignant mesothelioma.

The extreme latency (20–50 years) reflects both the slow rate of DNA damage accumulation and the fact that mesothelioma requires multiple mutations in a cell type with a very slow baseline turnover rate (mesothelial cells divide slowly, so mutations take longer to propagate into a detectable tumour mass).

Australia's asbestos problem

Australia was one of the world's largest per-capita users of asbestos — used extensively in building materials (fibro sheeting, roof tiles, insulation, pipes) from the 1940s to the 1980s. Asbestos was banned in Australia in 2003. However, because of the 20–50 year latency, Australia continues to see rising mesothelioma rates from exposures that occurred decades ago. Australia has one of the world's highest mesothelioma rates — approximately 700 deaths per year.

A molecular mechanism for gene-environment interaction that explains why identical twins can have different disease outcomes

Epigenetics describes heritable changes in gene expression that do not involve changes to the DNA sequence itself. Environmental exposures — including tobacco smoke, UV radiation, diet, stress, and pollution — can alter epigenetic marks on DNA and histones, switching genes on or off without mutating them. This provides a molecular mechanism for how the environment modifies the expression of genetic predisposition.

The two main epigenetic mechanisms

DNA methylation: The addition of a methyl group (–CH₃) to cytosine bases in CpG dinucleotides. When the promoter region of a gene is heavily methylated, transcription factors cannot bind → gene is silenced. Environmental carcinogens (tobacco smoke, air pollution) can cause abnormal methylation of tumour suppressor gene promoters — effectively silencing genes like p16 (CDKN2A) without mutating them. The result is the same as a loss-of-function mutation: the tumour suppressor is inactive, removing a brake on cell division.

Histone modification: Histones are the proteins around which DNA is wound. Adding or removing chemical groups (acetyl, methyl, phosphate) to histone tails changes how tightly DNA is wound → affects accessibility to transcription machinery → alters gene expression. Environmental exposures can alter histone modification patterns, changing the expression of many genes simultaneously.

Why epigenetics matters for understanding environmental disease

Epigenetic changes explain several phenomena that genetic mutation alone cannot:

• Why identical twins (same DNA) can have different disease outcomes from different environmental exposures over their lifetimes
• Why the same environmental exposure can have different effects on people with different genetic backgrounds
• Why some diseases respond to dietary intervention even without changing the DNA sequence (e.g. folate-rich diet can reverse some methylation changes)
• Why some environmental disease risks can be partially 'passed on' to offspring (transgenerational epigenetic inheritance — controversial but documented in some animal models)