MARKERS AND BIOMARKERS OF EXPOSURE AND RISK TO ENVIRONMENTAL POLLUTANTS AND LUNG

Air pollution is one of the main public health problems that affects more than 5 million inhabitants in Santiago, Chile. It is one of the factors that must be taken into account to explain the high incidence of acute and chronic respiratory diseases specially in the susceptible population. USA researchers have recently communicated a relationship between PM10 levels and daily mortality in Santiago.

In 1996, Santiago was declared a saturated zone for three regulated pollutants: ozone, carbon monoxide and respirable particulate matter PM10. The government has approved a "Plan to Prevent Air Pollution in Santiago", This plan published in June 1998, pointed out that its application in the next 14 years, would avoid 10,994 premature deaths and more than 65 million hospital attentions for respiratory and cardiovascular diseases. Furthermore, it would prevent the occurrence of 292 critical episodes.

Polycyclic Aromatic Hydrocarbons (PAHs) and their nitrated derivatives are among the pollutants that present greater risk for human health since some of them are highly mutagenic and carcinogenic. These compounds are found widely distributed in the environment and are metabolized by phase I enzymes (mainly cytochrome P-450 monooxygenases) and by phase II enzymes (conjugation enzymes, including the family of glutathione transferases). The PAH metabolites that present higher mutagenic and carcinogen activities are the bay region diol epoxides which are generated by CYP1A1 PAH activation. These final carcinogens may bind very tightly to macromolecules forming for example DNA adducts which could modify the genetic information.

Glutatione transferase GSTM1, can conjugate diol epoxides with glutathione increasing their water solubility and facilitating their elimination through the excretion systems. Therefore, conjugation reduces the risk of diol epoxides to bind DNA. It has been suggested that individual variations in the metabolic activities of each phase or in the coordination of the two phases could explain in part the individual susceptibility to cancers related to PAHs exposure.

Publications of our group has demonstrated that organic extracts from Santiagoës airborne particles are highly mutagenic, and have high content of PAHs, including six classified as carcinogenic by IARC. Santiagoís airborne particles varies in their chemical composition and their mutagenicity and PAHs levels are higher than those reported for various European and USA cities. The extracts also induced chromosomal aberrations, in human lymphocytes in cultures. In addition investigations in human lymphocites in chilean subpopulations have shown a high frecuency of mutations in CYP1A1 gene which are 3 times higher than that found in a French subpopulation suggesting an ethnical difference in the frecuency of these mutations. Furthermore, its has also be found that genetic polymorphisms in CYP1A1 and in GSTM1 are related to lung cancer susceptibility in chilean subpopulations.

In Chile, in 1996 the lung cancer mortality rate was of 13/ 100,000 being the second type of cancer with greater incidence in the country. This rate is increasing notoriously since 1935 in which it reached 1.7/ 100,000. In the North of Chile, in the mining area (II region) this rate is 3 times higher 35/100.000 probably due to high levels of arsenic exposure in drinking water. Arsenic exposure has been related to skin, bladder and lung cancer

, but the carcinogenic mechanism is unknown.

People in Antofagasta the main city in the II region was exposed for many years to extremely high arsenic

concentrations in drinking water (up to 870 ug/l). Smith et al 1995 have suggested that mortality

related to arsenic in the II region is the highest

of a population exposed to an environmental carcinogen.

Arsenic is metabolized to methylated compounds

and GSH has been suggested to be important as

intracellular reductant for arsenic methylation

and transport. It has been demonstrated

the presence

of arsenic - gluthatione complexs which are relevant

for As detoxification and clearence.

The research on going in this laboratory has the following objectives:

To study in Santiagoís respirable particulate matter (coarse and fine fraction), the presence of carcinogenic PAHs and nitrated derivatives as well as mutagenicity to bacteria and human cells in culture.

To investigate, in human populations, biomarkers of exposure: DNA-PAHs adducts, Hemoglobin-Nitro PAH adducts and risk (mutations in biotransformation enzyme genes, oncogenes and antioncogenes) that can be associated with lung cancer by exposure to PAHs and nitrated derivatives.

To investigate interactions between different type of carcinogenic pollutants PAHs- Arsenic.

This research will provide new basic scientific information that will help to understand the effects of fine and coarse respirable particles on human health, an area that it is included among the research priorities recommended by WHO and USA-EPA. For USA this is very relevant information since recently has been stablished a new standard for PM2.5. But, it has been claimed that the actual scientific knowledge does not justify this standard and that more research is needed in the field. This knowledge will be of international relevance since, due to the high exposure levels of Santiagoís inhabitants, the capital of Chile is one of the best natural laboratories in the world to investigate the effects of air pollution on human health. Specially, to evaluate cancer risk due to environmental carcinogenic exposure.

The studies in the north of Chile will provide also new basic information regarding the mechanism of arsenic carcinogenecity as well as to the interaction between different types of carcinogenic agents (genotoxic and nongenotoxic).

Atmospheric pollution is not the only source that adversely affects public health, indoor pollution can represent also a potential risk for the human health if it is considered that, in general, the individuals spend more than 80% of their time in indoor environments and 60% of this in their homes. This percentage can reach 100% among the most vulnerable groups such as: the elderly, pregnant women, persons affected by respiratory or cardiovascular diseases and newborn. Combustion processes are the main source of air pollution indoors, these mainly generate particulate matter, polycyclic aromatic hydrocarbons (PAHs), carbon monoxide, nitrogen oxides and sulphur oxides. Emissions depend on such factors as the nature of the fuel, the type of combustion device, the ventilation system and their maintenance.

Health effects from indoor pollutants can be divided into two general categories: those associated with discomfort, allergies or acute illnesses and cancer. The pollutants related to the first group include micro-organisms, carbon monoxide, carbon dioxide, nitrogen oxides, sulphur oxides, formaldehyde, solvents and other volatile organic compounds (VOCs), while the second group include: amphibole asbestos, a large variety of organic chemical compounds including benzene, N-nitrosamines and some PAHs and possibly radon and heavy metals (Cd, Pb).

Respirable particulate matter (PM₁₀) is a major indoor pollutant, as it can be deposited deep in the respiratory tract. Although these particles do not have a defined chemical composition (a large variety of organic compounds can be adsorbed by and / or can condense on their surface), they can be very dangerous to human health, particularly if they have adsorbed or condensed on their surface irritating gases or carcinogens. PAHs, present both in the gaseous and in particulates phases, are among the most dangerous indoor pollutants to human health. Several PAHs have been classified by the WHO either as carcinogenic, pre-carcinogenic or co-carcinogenic agents. Their toxicity activity depends on factors such as: chemical structure, adsorption, cellular transport, storage, metabolism and other defence mechanisms.

In the developing countries indoor pollution is mainly due to the daily activities as cooking and heating, with fuels such as: kerosene, firewood, coal and gas, which are emitters of pollutants of high toxicity, surpassing the standards recommended by WHO. Additionally, in the large cities of developing countries, an important source of indoor pollution consists of infiltrates outdoor air (which frequently of poor quality), containing hundreds of substances hazardous to human health.

The effect of the pollutants on human health will depend mainly on factors such as concentration, exposure time, host characteristics related with the metabolism and individual susceptibility (physiological, genetic, hormonal and nutritional factors) and undefined factors as temperature, humidity, smoking, indoor or occupational pollution. It has been reported that coal, firewood and kerosene increase the risk in breathing illnesses. However, these fuels are used with high frequency in extreme poverty areas mainly for economical reason.

Santiago of Chile shows a dramatic increase in respiratory diseases (especially between April and August, winter time), probably related with outdoor and/or indoor pollution. The health situation during air pollution episodes is of particularly concern, specially in extreme poverty areas, because people live in small unventilated houses, usually in overcrowded conditions, with low temperatures, lack of hygiene and using heating and cooking systems that release toxic pollutants.

Our group has been investigating the importance of outdoor infiltration on indoor air quality in downtown Santiago and in Temuco a city 700 km from Santiago with high use of wood as a heating fuel. In addition, the contribution of different fuels (coal, wood, gas and kerosene) used for cooking and/or heating on indoors pollution has been studied in La Pintana. La Pintana is located in the southern periphery of Santiago (17 km), it has a population of about 220.000 inhabitants and it has been classified by the CASEN survey (National Socioeconomic Characterization), as an extreme poverty area, with the lowest economic income in Santiago.

 

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