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Biomonitoring human exposure to environmental genotoxic chemicals

Objective


The genetic buden associated with human exposure to urban air pollution is as yet unclear, although the presence of a wide variety of carcinogens has been identified. Exposure to genotoxic carcinogens results in the formation of covalently bound adducts between carcinogen and DNA. Many non genotoxic carcinogens also damage DNA by virtue of thefact that they generate active radicals which oxidise nucleic acid bases. Exposure to genotoxic carcinogens may also be monitored by determination of adducts formed with proteins such as haemoglobin.

The research project has been concerned predominantly with the development of novel biomonitoring approaches using adduct measurement. These methods were applied to biological samples collected from populations in a representative group of European locations and from Kuwaitis exposed to high levels of oil combustion products. A questionnaire to gather relevant information on lifestyles and environmental factors was used. Other information obtained on the exposure of individuals were the analysis of their metabolic phenotype (ie capacity to metabolise carcinogens to their active species) and of their DNA repair ability.

The analytical procedures used to detect DNA adducts were P32 postlabelling and gas chromatography-mass spectrometry (GC-MS). P32 postlabelling is an exceptionally sensitive technique capable of detecting carcinogen modified bases in DNA. Several innovations were made to this method to make it more amenable for routine use. Oxidative DNA damage and adducts with haemoglobin were measured using GC-MS. Traditionally, lymphocyte DNA has been favoured for adduct measurements. Other DNA sources (eg placenta, oral tissue, buccal smears) which may be of greater relavence to carcinogen risk analysis were also investigated in detail.
A coordinated study is planned between 15 participants in 9
countries on the development, evaluation and application of
biomonitoring procedures for populations exposed to environmental genotoxic pollutants. These procedures will measure both primary events (carcinogen-adducts on DNA or protein) and secondary
effects (mutation, cytogenetic damage). Adduct detection will be by 32p-postlabelling, immunochemical, HPLC or mass spectrometric methods. Although established methods will be used, considerable method development is also planned in all assays.

Emphasis will be placed on populations exposed to urban
pollution and in particular to the genotoxicants present in such samples that result from petrochemical combustion or processing. Blood and urine samples from individuals in urban locations from 8 countries will be collected and distributed amongst the
programme's participants. Air Samples will also be collected and analysed. Populations exposed through occupational or medical sources to larger amounts of some of the genotoxic compounds present in the environmental samples will be used as positive controls for the environmentally exposed population. Samples from rural areas will be used as negative controls. The
measurement of DNA and protein adducts in these samples will be primarily devoted to those from (a) low molecular weight
alkylating agents, (b) compounds that cause oxidative DNA damage and (c) the more complex constituents of urban pollution (e.g. aromatic hydrocarbons). A more preliminary study is planned on populations exposed to pesticides/herbicides. The genotoxic
mechanism of these is not as well understood and the assessment of genetic damage will be made only by cytogenetic and mutation assays.

It is intended that the project, which is a truly multidisciplinary and multinational effort, should allow (a) a
thorough interlaboratory comparison of the application of
different biomonitoring procedures for genotoxic exposure, (b) assessment of the relationship between the internal dose of the genotoxic agent (determined from adduct levels) and the
subsequent genetic damage associated with the exposure (measured by mutation and cytogenetic effects), (c) determination of the additional genetic burden carried by the exposed populations, (d) study of interindividual variation amongst the subjects in a population, (e) development of novel, more sensitive, specific, and practical methods for biomonitoring such exposures. The
ultimate intention of our project will be the optimisation and standardisation of techniques, for general use throughout the Community, for determining genetic risk on an individual person basis. The widespread application of such techniques should have a major impact in efforts to reduce human cancer incidence.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

MEDICAL RESEARCH COUNCIL
Address
Lancaster Road University Of Leicester Hodgkin Bui
LE1 9HN Leicester
United Kingdom

Participants (12)

Centre International de Recherche sur le Cancer
France
Address
150 Cours Albert Thomas
69372 Lyon
Christie Hospital NHS Trust
United Kingdom
Address
Wilmslow Road Didsbury
M20 9BX Manchester
Istituto Nazionale per la Ricerca sul Cancro
Italy
Address
Viale Benedetto Xv 10
16132 Genova
MRC Cell Mutation Unit
United Kingdom
Address
University Of Sussex Falmer
BN1 9RR Brighton
NATIONAL HELLENIC RESEARCH FOUNDATION
Greece
Address
48,Vas. Constantinou Avenue 48
11635 Athens
National Institute of Occupational Health
Norway
Address

33 Oslo
Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek
Netherlands
Address
137-139,Lange Kleiweg
2280 HV Rijswijk
Rijksuniversiteit Leiden
Netherlands
Address
72,Wassenaarseweg
2300 RA Leiden
UNIVERSITY OF AARHUS
Denmark
Address
180,Vennelyst Boulevard, 6
8000 Aarhus C
UNIVERSITY OF WALES SWANSEA
United Kingdom
Address
Singleton Park
SA2 8PP Swansea
UNIVERSITY OF YORK
United Kingdom
Address
Heslington
YO10 5YW York
Vrije Universiteit Brussel
Belgium
Address
2,Pleinlaan
1050 Bruxelles