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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Outdoor air pollution. Lyon (FR): International Agency for Research on Cancer; 2016. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 109.)
5.4.1. Toxicokinetic considerations, including inhalation, deposition, clearance, and metabolism
The toxicokinetics of several classes of compounds that contribute to outdoor air pollution have been described in earlier IARC Monographs (see Section 4.1).
Some PM present in outdoor air is poorly soluble in water and may thus persist in the respiratory tract, producing effects associated with particle toxicity, such as inflammation and oxidative stress. The deposition of particles in the respiratory tract depends primarily on the size of the inhaled particle, the route of breathing, and the breathing pattern. Particles that deposit in the tracheobronchial region are cleared by mucociliary clearance; for particles that deposit in the alveolar region, the primary mechanism of clearance is phagocytosis by alveolar macrophages, followed by migration of the macrophages to the terminal bronchioles and subsequent mucociliary clearance. Particles that are cleared via the mucociliary escalator, whether from the tracheobronchial region or the alveolar region, can then be swallowed or expectorated. If swallowed, they will pass through the gastrointestinal tract and will subsequently be eliminated via the gut.
The deposition and clearance of particles can vary across individuals, depending on age, sex, tobacco smoking status, and pre-existing diseases such as asthma or chronic obstructive pulmonary disease.
Inhaled lipophilic organic vapours and gases readily distribute throughout the respiratory tract and are absorbed into the blood. Organic compounds in PM or adsorbed to atmospheric PM can be extracted by biological fluids.
Many studies in humans that investigated the exposure and metabolism of organic substances adsorbed to PM in outdoor air have used measurements such as urinary concentrations of hydroxylated polycyclic aromatic hydrocarbons (PAHs) as indicators of exposure and metabolism. These studies have demonstrated the ability of humans to be exposed to carcinogenic organic pollutants such as PAHs and, moreover, to adsorb, distribute, metabolize, and excrete the metabolites. Additional studies have described haemoglobin adducts of nitro-PAHs and low-molecular-weight alkenes. Collectively, the results showed that urinary 1-hydroxypyrene and haemoglobin adducts (hydroxyethyl-valine and hydroxypropyl-valine) were present in populations exposed to outdoor air pollution.
5.4.2. Genetic and related effects of outdoor air pollution
(a) In humans
Studies have investigated the ability of unaltered outdoor air to induce genetic and related effects in humans and experimental systems that are mechanistically linked to cancer. Studies of people exposed to outdoor air pollution in occupational settings (e.g. traffic police, mail carriers, and newspaper vendors) or by living in areas with elevated levels of outdoor air pollution have shown enhanced frequencies of genetic damage (chromosomal aberrations and micronuclei) in lymphocytes of exposed individuals compared with controls. In addition, studies have shown an association between selected genetic polymorphisms, such as glutathione S-transferase M1 (GSTM1) null, and an increased frequency of genotoxic damage. A single observational study of newborns in an area with elevated levels of outdoor air pollution showed an increased frequency of somatic mutations in lymphocytes. These studies, which cover several countries, collectively confirm the induction of end-points that are empirically and mechanistically linked to increased risk of cancer in humans.
Many studies have shown significant elevation in the levels of DNA adducts in lymphocytes of humans exposed to elevated levels of outdoor air pollution in occupational and urban settings. These findings are supported by a more limited number of studies detecting blood protein adducts.
Studies that examined humans exposed to elevated levels of outdoor air pollution have also documented epigenetic alterations such as changes in DNA methylation patterns and telomere shortening.
(b) In experimental systems
(i) Experimental animals
Experimental studies of rodents exposed to outdoor air in situ provided evidence that outdoor air pollution in urban/industrial areas, especially the particulate fraction, induces heritable germ-cell mutations and cytogenetic damage. Experimental studies of plants exposed to outdoor air pollution at a range of locations also showed induction of mutations and cytogenetic damage.
There is also strong evidence that outdoor air PM or samples derived from outdoor air PM can induce increases in cytogenetic damage in animals.
(ii) Human and animal cells
There is strong evidence that organic extracts, aqueous extracts, or suspensions of outdoor air PM collected from a range of locations induce mutations and cytogenetic effects (chromosomal aberrations, aneuploidy, micronuclei, and sister chromatid exchanges), bulky DNA adducts, DNA strand breaks, oxidatively generated DNA lesions, and formation of reactive oxygen species in cultured human lymphocytes, human cell lines, cultured animal primary cells, animal cell lines in vitro, and naked DNA. Evidence from source apportionment studies indicates that contributions from mobile-source emissions and residential heating combustion emissions are significant; chemical fractionation of PM extracts revealed contributions from several chemical classes, including non-polar compounds (e.g. PAHs), semipolar compounds (e.g. nitro-PAHs and quinones), and polar compounds (e.g. organic acids and hydroxy-polycyclic aromatic compounds).
(c) In bacteria
There is strong evidence that organic solvent extracts of outdoor air PM representing a wide range of locations, source emissions, seasons, and meteorological conditions induce mutations in bacteria. Published results generally show less than 10-fold variation in the mutagenic potency of PM extracts, expressed per milligram of PM or per microgram of extractable organic matter, across a wide range of locations and site conditions (i.e. source contributions, weather, season, and land use). In contrast, atmospheric mutagenic activity expressed per cubic metre varies by more than 5 orders of magnitude across locations and site conditions (i.e. season, source contributions, and land use), and increased atmospheric mutagenic activity is empirically related to increased levels of atmospheric PM. A large portion of the observed spatial and temporal variations in atmospheric mutagenic activity expressed per cubic metre can be attributed to variations in measured levels of suspended PM.
The atmospheric mutagenic activity at locations described as urban and/or industrial is generally about 2-fold higher compared with locations described as rural and/or residential. Similarly, the atmospheric mutagenic activity measured during colder months is generally about 2-fold higher compared with warmer months. High atmospheric mutagenic activity has been associated with emissions from both mobile and stationary combustion sources, and has been shown to be positively associated with higher levels of NOx, PAHs, nitro-PAHs, lead, and SO2. Chemical fractionation studies have noted that a significant portion of the mutagenic activity of organic extracts of outdoor air PM is associated with the moderately polar and polar organic fractions, and includes a wide range of substances, many of which have not been well characterized. Analyses of the non-particulate semivolatile organic compounds (SVOCs) fraction of outdoor air indicate that a significant fraction of the mutagens associated with the solvent-extractable portion of PM from polluted outdoor air may occur as organic vapours.
5.4.3. Other data relevant to carcinogenicity
Some studies have documented increased levels of DNA fragmentation in sperm in young men exposed to polluted outdoor air in an urban location. In addition, human observational studies have shown that exposure to polluted outdoor air in urban/industrial areas or outdoor occupational settings altered the expression of genes involved in DNA damage repair, cell-cycle control, inflammation, and response to oxidative stress.
One experimental exposure of human subjects to concentrated PM from outdoor air showed significant induction of inflammation, a physiological change that has been linked to tumour progression.
Several studies have demonstrated that organic solvent extracts of PM collected from urban environments cause oncogenic transformation of cultured animal cells. Moreover, cells transformed by in vitro exposures to organic solvent extracts of urban PM formed malignant tumours when injected into immunocompromised mice. There is also evidence that exposure of animal cells to PM induces inflammatory reactions, assessed mainly as secretion of cytokines and chemokines, and experimental evidence has linked the inflammation reaction in cultured cells to oxidative stress and metal-catalysed production of reactive oxygen species. This association between exposure to PM and secretion of cytokines is observed especially in lung epithelial cells and macrophages.
5.4.4. Susceptibility
The available scientific information indicates that certain groups of individuals, such as the elderly, children, and individuals with conditions such as emphysema, bronchitis, and cardiovascular illness, are especially sensitive to the health effects of toxicants in outdoor air. It is recognized that obstructive pulmonary disorders increase lung cancer risk via abnormal immune system regulation and chronic inflammation. The risk of human cancer is related to age and sex via differences in PM deposition patterns and in the capacity to metabolize organic compounds adsorbed to PM.
Polymorphisms in carcinogen-metabolizing genes have been studied as part of human biomonitoring studies investigating the frequency of cytogenetic damage in individuals exposed to polluted outdoor air, and polymorphisms such as the GSTM1 null genotype, alone or in combination with CYP1A1 polymorphisms, are associated with an increased risk of genetic and related effects linked to cancer.
5.4.5. Mechanistic considerations
In conclusion, there is strong mechanistic evidence for the ability of outdoor air pollution, as well as many of its components, to induce a myriad of genetic and related effects in humans and a wide range of experimental systems. Well-documented genotoxic effects include bulky DNA adducts, DNA strand breaks, oxidatively damaged DNA bases, genetic mutations and chromosomal damage in somatic cells, gametic mutations, and oncogenic transformation in vitro. Molecular epidemiology studies in humans have documented significant empirical associations between the frequencies of DNA damage (i.e. adducts in lymphocytes) and cytogenetic damage (e.g. chromosomal translocations and micronuclei) and exposures to PM in outdoor air and/or levels of carcinogenic PAHs in outdoor PM. In addition, several studies in humans provide evidence of an empirical association between the frequency of stable adducts in lymphocytes of individuals occupationally exposed to outdoor air and levels of outdoor PM or levels of PAHs associated with outdoor PM. Bulky adducts and cytogenetic damage have been shown to be predictive of cancer in humans. Documented changes in gene expression in response to exposures to PM or organic solvent extracts of PM include genes involved in metabolism and activation of mutagenic carcinogens, responses to DNA damage and oxidative stress, alterations of cell-cycle control, and inflammation. The multiplicity of substantiated effects documented in humans as well as in experimental systems in vivo and in vitro supports the assertion that outdoor air pollution, as well as many of its components, is capable of initiating the development of human pulmonary cancers via a genotoxic mechanism and, moreover, of promoting the progress of tumour development via oxidative stress, responses to oxidative stress, and sustained inflammation.
- Mechanistic and other relevant data - Outdoor air pollutionMechanistic and other relevant data - Outdoor air pollution
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