GENE-ENVIRONMENT INTERACTIONS 
(A CHALLENGE FOR THE FUTURE)1

ROSIVAL, L., TRNOVEC, T.

Institute of Preventive and Clinical Medicine, Bratislava, Slovak Republic

Corresponding author: Prof. L. Rosival, M. D., D. Sc.
Institute of Preventive and Clinical Medicine
Limbová ul. 14, 83101 Bratislava, Slovak Republic
Tel: 59369226

Fax: 54773906

CEJOEM 1999, Vol.5. No.1.:3-16

Abstract: Human health is determined by the interplay between genetic factors and the environment. Scientists collaborate on studies to understand the molecular and genetic problems of environmentally caused diseases. The Environmental Genome project in the U.S.A. seeks to determine genetic sequence diversity data for the U.S. population on more than 200 genes known to control susceptibility to environmentally linked diseases. Studies at the molecular level in humans suggest that there is an individual variability in genetic parameters, consistent with the differing susceptibility to disease. More work is needed to assess genetic polymorphisms of key enzymes, for the activation and detoxication of xenobiotics is a determining factor for the susceptibility to environmental agents. Much can be learned from the mechanisms, genetics, and epidemiology of environmental carcinogens. The incorporation of biochemical, molecular, and cytogenetic probes (biologic markers of exposure, effect and susceptibility) in epidemiologic studies is of utmost importance. To assess the potential risk to individuals or the population, more extensive knowledge is needed about the genetic background and the interaction between genes and the environment. The complex interplay between genes and the environment represents a great challenge to scientists, and also an important opportunity to reduce the burden of disease and dysfunctions to humans.

Key words: Genes, environment, genetic polymorphism, public health

INTRODUCTION
The changing world is experiencing changing patterns of health. Influences include: rapid modernisation; an everyday life dependent on technological progress; changing behaviour: sedentary living, excessive or ill-balanced diets and smoking; and a deteriorating environment: air pollution, exposure to chemicals and radiations, contamination of soil and water, and hazards to food safety.

Human health is determined by the interplay between genetic factors and the environment. Genes are only one part of the disease picture. Many common diseases such cancer, asthma, osteoporosis are known to have important environmental elements.

Many of the genes in the genome of humans (human genome encodes for 50,000 to 100,000) influence the impact of environmental agents on the organism. The exact number of genes involved in the organism’s response to environmental factors is unknown but could be very large (Barrett et al., 1997).

Genes control cellular differentiation, division and death. When critical genetic material is altered, the functions over which it exerts control can go away, leading to birth defects, cancer, neurobehavioral abnormalities, and other diseases and dysfunctions. A better understanding of these genes, the ability of environmental agents to interact and damage them, the relationships between a xenobiotic’s chemical structure and its binding affinity to critical cellular targets, and the consequences of genetic malfunction (Olden, 1994) is needed.

Understanding the role of genes in human disease will improve our understanding of genetic disease etiology as well as our ability to predict. Insight into the genetic basis of chronic disease etiology will have an immediate impact by suggesting novel therapeutic approaches and aiding new drug discovery (Ellsworth et al., 1997).

The most important basis for these studies is the Human Genom Project, which began in 1990 and is a co-operative multinational initiative in the U.S.A. and has gained support with the biomedical science community. The ultimate goal is
to determine the complete DNA sequence of human genome as well as genomes of several model organisms: bacteria (Escherichia coli), yeast (Saccharomyces cerevisiae), nematode (Caenorhabditis elegans), fruit fly (Drosophila melanogaster), and mouse (Mus musculus). Important similarities in chromosomal structure and gene function between study organisms and humans will prove invaluable in the process of determining gene functions and mechanisms of genetic disease etiology.

The contributions of genetic toxicology to an integrated information system on genetics will facilitate the translation of Human Genom Project into the practice of medicine and public health in the 21st century (Khoury, 1997).

Progress on the Human Genome project has led to an explosion of genetic information. Of the estimated 100,000 human genes, more than 5,000 have been mapped to specific chromosomes (Khoury and Dorman, 1998).

The keen interest in this project has several reasons (Guengerich, 1998):

Studies on human drug metabolism over the past 20 years have provided convincing evidence of the wide variability in function of the enzymes of xenobiotic metabolism (e.g. cytochromes P450, N-acetyltransferases, and glutathione S- transferases) and in vivo significance of these variations in the disposition of these drugs in humans.

A large part of environmental health research is focusing on identifying the environmental causes of disease (e.g. endocrine disruptions and lead). Future research can help in understanding the molecular and genetic basis of environmentally caused diseases. Polymorphisms in Environmental Response Genes are depicted in Fig. 1. (Albers, 1997).


Fig. 1. Polymorphisms in environmental response genes can modify an individuals risk for disease (Albers, 1997)

GENETIC POLYMORPHISM

Genetic polymorphism is a term used to describe variants occurring at an incidence of > 1%. Polymorphisms are common among humans. Some have no functional significance, and the identification of which do and which do not have any functional significance will be necessary in order to be able to interpret the information obtained in the Environment Genome Project (Guengerich, 1998).

Polymorphisms often affect the functions of genes but some may change the level of expression of a gene or change the activity of a gene product, for example, an enzyme (Barrett et al., 1997).

Most of the approximately 50 known inherited traits that could potentially enhance an individual’s susceptibility are often difficult to detect. Many genetic conditions associated with enhanced susceptibility to environmental chemicals remain to be discovered. As human population is biologically diverse and genetically heterogeneous, it is not surprising that differences in susceptibility to disease among individuals with or without exposure to environmental chemicals exist.

Studies at the molecular level in humans suggest that there is a wide interindividual variability in genetic parameters, consistent with this differing susceptibility to disease.

Genetic variations among individuals represent a basic attribute of living matter (e.g. blood groups, enzyme variants, protein variants, chromosomal variants). It appears that the genetic diversity of the three major human races (Caucasian, Mongoloid and Negroid) is much smaller than the average heterozygosity (Goedde, 1986) and ethnic differences in reactions to drugs and xenobiotics have also been reviewed.

Effects of genetic variation on susceptibility to occupational and environmental chemicals is drawn primarily from the differences observed in the response to drugs (Vesell, 1987).

It has long been suspected that genetic factors affect susceptibility to occupational diseases. It must be appreciated that this response is modified by many other host (e.g. nutrition, health status, gender, life-styles) and environmental factors (e.g. coexisting exposures) (Table 1).

Enhanced susceptibility to occupational and environmental chemicals has clinical implications (observation of the susceptibility of workers and the vulnerability of the foetus, the neonate, the elderly, and those who are ill) implications related to administered drugs and regulatory implications (the issue of special susceptibility in the standard-setting process for air and water pollutants). A more specific and consistent approach is needed in the formulation of environmental policy and the setting of standards for pollution control in children (especially air and water pollutants and pesticide residues in food).

The fields of human genetics and epidemiology used to be independent disciplines with very little interaction between them (Ellsworth et al., 1997). Genetic concepts were integrated with epidemiologic methods to capitalise on the advantages of their perspectives. The greatest benefit to public health from genetic epidemiology research will come from the better understanding of the genetic etiology of the common chronic diseases (e.g. coronary artery disease and diabetes) and the common forms of cancer (such as breast and colon cancer) and from gene-environment interactions.

It can be seen that epidemiology has moved away from a search for explanation of diseases at the population level to search at the individual level. This means emphasis on the inherited factors in common diseases. Placing undue emphasis on them does not comport with scientific realities (e.g. no more than 5 percent of all cancer incidences can be attributed to single inherited factors – Trichopoulos et al., 1996).

This may also impede efforts to understand the complex causes of the disease. There is a pressing need for research on the sensitivity and predictive value of genetic tests, the efficacy of efforts to prevent the occurrence of or treat the resulting disorders and the development of adequate informed consent procedures (Holtzman and Andrews, 1997).

Different visions of the future of public health are influenced by a combination of medical, technological, social-economic and political factors. New gene discoveries require that the public health community should take a leading role in translating the results of these discoveries into effective strategies to prevent epidemies and disability in the population by targeting environmental, behavioural and medical interventions to each person’s genetic susceptibility. (Khoury, 1997). Table 2 shows that genetic epidemiology will play a central role in providing data that will be useful for evaluating disease risks, developing sound health policies and providing valuable information both for professionals and the public.
 
 

TABLE 1. Genetic Factors and Susceptibility to Occupational and Environmental Chemicals (Tarcher and Calabrese, 1992)
Predisposing factor
Incidence 
Chemical(s)
Status of genetic-
environmental
interaction
Glucose-6-phosphate dehydrogenase deficiency About 12% among African-American males; very high in tropical and subtropical countries Oxidizing chemicals  Likely
Sickle-cell trait 7–13% among African–Americans; 30% of population in parts of Africa  CO, aromatic amino compounds No clear evidence
Methaemoglobin reductase deficiency About 1% of population are heterozygotes Nitrites, aniline Definite
Aryl hydrocarbon hydroxylase induction High-induction-type Caucasians about 30% Polycyclic aromatic hydrocarbons  Possible
Slow acetylator phenotype Caucasians and Negroes about 60%; Orientals about 10–20% Aromatic amine-induced cancer Possible
Paraoxonase variant  Caucasians about 50%, Orientals about 30%, Negroes about 10% Parathion Possible
Acatalasia Mainly Japan and Switzerland, reaching 1% in some areas of Japan Hydrogen peroxide Definite
Nontaster status 30% Caucasians, 10% Chinese, 3% Negroes Goitrogens (thiourea, etc.) Definite
a1-Antitrypsin deficiency Homozygotes about one in 6700 North American Caucasians Respiratory irritants Smoking Most likely definite
Immotile cilia syndrome About 1:40,000 in all major races Respiratory irritants, smoking Most likely
Immunologic hypersensitivity Unknown, 2% in some occupational populations Isocyanate  Definite
The incorporation of biochemical, molecular, and cytogenic probes (termed biomarkers) into epidemiology overcomes the limitations of classical epidemiology (the frequent lack of exposure assessment data and the long delay between toxic exposure and the appearance of symptoms).
 
TABLE 2. The impact of genetic epidemiology on the future of public health 
(Khoury, 1997)
  1. Will provide data on the public health impact of human genes and their interaction with preventable risk factors on disease morbidity, mortality and disability in various populations. 
  2. Will provide data to health policy guidelines on the appropriate use of genetic testing in disease prevention and public health programmes.
  3. Will provide data to evaluate the impact of population based prevention programmes that reduce morbidity and disability associated with disease genes.
  4. Will provide data on the laboratory quality of genetic testing.
  5. Will become increasingly needed in core training programmes in epidemiology and public health. 
  6. Will provide more qualitative disease genetic risk information in integrated and online genetic information systems used by medical and public health professionals and the public.

BIOMARKERS

Biomarkers in the context of environmental health are indicators of events in biological systems and samples. Fig. 2 shows the progression from exposure to clinical disease (Jendrychowski and Goldsmith, 1992)
 
 


Fig. 2. Kinds of Biological Markers (Jendrychovski and Goldsmith, 1992)

These biomarkers can be divided into markers of exposure, markers of effect, and markers of susceptibility.
 

Biomarkers of Exposure

These biomarkers can be divided into internal dosimeters and biologically effective dose. They are connected with several different types of exposure. In our studies foetal exposure to chlorinated pesticides has been shown to correlate with embryonal measurements of chlorinated pesticides (Rosival et al., 1983). A higher level of placental contamination by organochlorine compounds was observed in an industrial locality as compared to a similar or even higher placental contamination by heavy metals in a rural area.
    Histochemically, the presence of heavy metals in the placenta could be detected, in particular in the syncytiotrophoblast (Reichrtová, 1995). This refers also to other chlorinated substances (e.g. PCBs).
Measurement of bone lead in epidemiologic studies has proved to be useful in exposure assessment studies, i.e., in spotting factors that contribute most to retained body lead burden, and in investigating cumulative lead exposure as a risk factor for poor health outcomes such as hypertension, kidney impairment, cognitive impairment, behavioural disturbances, and adverse reproductive outcomes (Hu, 1998).
    Biological Tolerance Values (BAT) are defined as maximum permissible quantity of a chemical compound, its metabolites, or any deviation from the norm of biological parameters effected by these substances in occupationally exposed persons. They are established, as a rule for blood and urine, the knowledge of action mechanisms is needed.
Examples of biological monitoring for selected agents, e.g. lead (lead in blood and urine ZPP, zinc protoporphyrin), cadmium (cadmium in urine or blood), mercury (mercury in urine), organophosphates (red cell or serum cholinesterase activity), benzene (total phenol or muconic acid in urine, benzene in expired air), trichlorethylene (TCE), trichloracetic acid in urine (TCA) (trichloroacid in urine, TCE in end-expired air). Biological monitoring follows several goals: the detection of exposed workers at an early stage before significant adverse effects have occurred; quantifying or classifying exposure for epidemiologic studies and identifying variations in susceptibility with workers and population.
 

Biomarkers of Effect

These biomarkers can be categorised based on their relationship to health status – from normal health, to health impairment, or to overt disease (Bearer, 1998).
    There are many biomarkes of effect, e.g. hematological toxicity, immunotoxicity, reproductive toxicity (International Programme on Chemical Safety, 1993). Regarding other biomarkers of effect entails this group also biomarkers at the genomic level, e.g. cytogenetic markers (Evans, 1984), chromosome aberrations (Evans, 1984), sister chromatid exchange (Tucker et al., 1993), micronuclei (Heddle et al., 1991). Markers of gene expression include assays for detection of mRNA or for detection of proteins (Barrett et al., 1997). Methodologies for examining gene expression by the detection of the encoded proteins all depend on the development of antibodies that are theoretically specific for the identification of the protein of interest (Barret et al., 1997).
    In a study directed towards the documenting of the possibilities offered by the detection of genetic changes in human populations, the Comet Assay technique was used. Workers exposed to polycyclic aromatic hydrocarbons at a chemical plant showed significantly increased numbers of DNA breaks as compared to two control groups. The results have confirmed that this method is suitable for the monitoring of biological responses to occupational exposure (Šrám, 1998).
    The Comet Assay has been modified by incubating DNA of individual cells with specific repair enzymes which detect certain types of DNA lesions (Collins et al., 1995). This way, the method is not only suitable for the detection of direct breaks but also of other types of DNA lesions, in particular oxidative DNA lesions and large DNA adducts. This significantly extends the number of applications of the method in research, in particular concerning genotoxicology, molecular epidemiology, diagnosis and therapy as in studying basic processes in the cell.
    Potential uses of biomarkers of effect are of disease prognosis, and as adjuncts to other biomarkers in providing refinements of epidemiology and risk assessment.
    Most of the biological biomarkers of effect especially at the genomic level are still experimental tools whose utility remains to be established.
 

Biomarkers of susceptibility

A marker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability to respond to the challenge of exposure to a specific xenobiotic substance. Some people are susceptible because of inborn differences of metabolism, physiological characteristics, their nutritional status, or absorption characteristics. For example, the measurement of airway reactivity to inhaled bronchoconstrictors can be used as a biomarker of susceptibility. Increased non-specific airway reactivity is a characteristic of most asthmatics and can play a role in disease activity. This marker can also relate to induced variations in absorption, metabolism, and response to environmental agents.
The concept of biomarkers of susceptibility encompasses enzymes of activation and detoxification, repair enzymes, and changes in target molecules for toxic chemicals. Objectives of use are as follows: evaluation of interindividual variation, repair enzymes, and changes in target variation of risk, determination of the role of genetic variations and improvement of the detection of environmental hazards.
    Methods for studying phenotyping expression concern the use of probe drugs in vivo (metabolic polymorphisms can be identified by determining the metabolic ratio) and in vitro. There are also other methods (polymorphisms of xenobiotic-metabolizing enzymes can be detected at other phenotypic levels). Variations in the activities of the xenobiotic metabolising enzymes by polymorphic changes can influence the genotoxic effects.
    According to Barrett et al. (1997) the following recommendations are made: phenotyping should be continued along with genotyping, the combined impact of all relevant genes for a given exposure needs to be assessed, better kinetic characterisation of enzyme substrate and inhibitor specificity must be determined, a better understanding of the regulation of enzyme expression by environmental agents is needed, the value of intermediate markers of exposure such as DNA adducts should be studied. A future approach will be to use information obtained from analysis populations of interethnic groups.
    The identification of valid biomarkers that indicate exposure, effect, or susceptibility is a complicated process involving studies in animals, refinements in laboratory assays, and studies in special human populations e.g. workers and children.
    Validation and use of biomarkers in such areas as asthma, respiratory disease, cancer, and neurodevelopmental effects would hasten progress in understanding modes of exposure and risk assessment for children (Bearer, 1998). Other examples are biomarkers of leukaemia risk: benzene as a model (Smith and Zhang, 1998), biomarkers for assessing human female reproductive health (Lasley, and Overstreet, 1998), and bone lead as a new biomarker of lead dose (Hu, 1998).
    An integral part of the use of biomarkers of susceptibility are ethical, social and legal issues surrounding studies of susceptibility (e.g. genetic screening of workers, the right of the subjects to be informed, confidentiality, duties of the research, etc.). This problem raises further questions as follows (Loffredo et al., 1998). Should employers be able to transfer chemically sensitive workers to jobs with lower exposure levels rather than reducing exposure levels to a safe level for all? Could employers expose more resistant workers to higher exposure level? In cases of alleged chemical injury, would lawyers misuse knowledge of genetic susceptibilities? It is a comprehensive and extremely sensitive issue and technological progress continues to challenge our sense of what may be deemed “wrong” or “morally appropriate”, respectively.
    In order to translate the results of the genetic research into opportunities for treating and preventing disease and promoting health, population-based epidemiologic studies are increasingly needed.
Human genome epidemiology is an intersection between molecular epidemiology and genetic epidemiology. The topics addressed range from population-based epidemiologic research on gene variants to the evaluation of genetic test services (Khoury and Dorman, 1998).
    One of the important goals of human genome epidemiology is to assess the magnitude of disease risk associated with gene-gene and gene-environment interactions in different populations. The consequence of this approach is the Environmental Genome Project (EGP). It is an activity of the National Institute of Environmental Health Sciences (NIEHS) in the U.S.A. to characterise the variations in important human genes and to relate these differences to the susceptibility of humans to chemical and physical agents (e.g. ionising radiation) in the environment.
    The main goal of EGP is to enhance population-based research toward identifying environmental exposure-disease relationships. This will lead also to prevention and intervention strategies in combination with primary prevention measures (reducing or eliminating of environmental exposures). In connection with this further identification of the non genetic factors — occupational, environmental and food exposure, life styles and infectious diseases that influence the hypothesis whether the altered susceptibility genes lead to disease — is a great potential to prevention.
    The Environmental Genome Project, which is to complement the Human Genome Project seeks to determine genetic sequence diversity data for the U. S. population on more than 200 genes known to control susceptibility to environmentally linked diseases, and to develop a central database of polymorphisms of these genes (Albers, 1997). On the basis of epidemiological studies, it will be determined how polymorphisms account for the increased risk of or resistance to disease upon exposure to specific chemicals. The project will also look at environmental factors ranging from diets to effects of chemical mixtures.
    According to Olden´s estimation (Albers, 1997) more than 200 candidate genes are under consideration for the study from several broad classes.
    It concerns genes controlling the distribution and metabolism of chemicals, genes for the DNA repair pathways, genes for the cell cycle/cell death control system including apoptosis, genes for metabolism of nucleic acid precursors, and genes for signal transduction systems controlling the expression of genes in other classes.
About 100 candidate genes (metabolism and detoxification) regulate cytochrome P450s, N-acetyl transferase, glutathione S-transferases, glucuronyl tranferases, sulphotransferases, metallothioneins, and variants of the enzyme paraoxonases (exposure to organophosphates) with difficulty in breaking down nerve gas sarin and related organophosphates. Variations in alcohol dehydrogenase genes have been linked to alcohol-related diseases and cancer.
There are many more genes that can be tested but there are great economic constraints (e.g. the cost to sequence the “environmental” genes in 1,000 people will be about $ 60 million). Perhaps the greatest advances have developed from the associations between exposure, polymorphisms in carcinogen-metabolising genes (Suk and Collman, 1998). The important enzymatic pathways involved in carcinogen metabolism concern two categories: oxidation, reduction, and hydrolysis are termed phase I reactions, whereas conjugation and synthesis are phase II reactions.
Phase I enzymes mainly involve the cytochrome P450 group, but also include N-acetyltransferase, important in metabolic activation. Phase II enzymes (e.g. glutathione S-transferases) are involved in detoxification reactions and help the body dispose of carcinogens in lung, brain, and bladder cancers, and other diseases. Another very common phase II reaction concerns sulfotransferases to form another common phase II reaction for phenols is the conjugation with sulfate to form sulfate monoesters. Methylation is generally not a quantitatively important metabolic pathway for xenobiotics, but is an important pathway in the intermediary metabolism of both N- and O- containing catechols and amines (Borchardt,1980).
    Among the most studied genotypes are human glutathione transferases especially in relation to the genetic polymorphism of glutathione 5-transferase M 1 (GSTM 1).
    The effect of GSTM 1 and N-acetyl transferase 2 was seen in coke workers on mutagenicity of urine and of glutathione S-transferase T 1 on the chromosomal aberrations in subjects from the 1.3-butadiene monomer production unit. Effects of genotypes on DNA adducts were found from lung tissue of autopsy donors and from placentas of mothers living in an air-polluted regions, protein adducts in smokers, SCE in smokers and non smokers and Comet Assay parameters in postal workers (Šrám, 1998).
    If the genetic polymorphism responsible for detoxification pathways is known it is reasonable to suggest that subjects lacking these genes should not be employed in occupations in which certain types of exposures are likely to occur. Ethical questions must be addressed if knowledge about individual genotypes is to be used to prescribe preventive measures among specific groups.
    Regarding methods for studying genetic polymorphisms, identification of novel genetic polymorphisms and genotyping of populations is of great importance.
    Advances in the areas of molecular genetics and molecular epidemiology now make it possible to study genetic polymorphisms of the enzymes used to metabolise xenobiotic compounds, presymptomatic genetic changes (e.g. somatic mutations) associated with increased risk disease, and other genetic markers of susceptibility. The capability studying the RNA species present in the tissue samples permits to study tissue specific gene expression. The advent of new technologies, polymerase chain reaction (PCR) now makes it possible to detect specific genotypes and specific RNA species in extremely low concentrations. PCR technology alone greatly increases the potential of obtainable data from very small amounts of banked tissue of any type as long as its preparation and preservation conditions are compatible with PCR analysis (Lee et al., 1995).
    An Environmental and Biological Specimen Bank was established in 1998 in the premises of the Institute of Preventive and Clinical Medicine in Bratislava (Slovak Republic). This is the first Specimen Bank in Central and Eastern European Countries. Its aim is to provide a broadly acknowledged basis for environmental and biological monitoring, identification of trends in environmental pollution, as well as to identify new environmental chemicals. The development of sample banks is also important to speed the identification and validation of markers.
    As for ambient air pollution Whyatt (1998) measured the amount of PAHs bound to DNA (PAH-DNA adducts) in maternal and umbilical blood cells. Results indicate, that PAH-induced DNA damage in mothers and newborns is increased by ambient air pollution. In the fetus, this damage appears to be enhanced by the P450A1 (CYP1A1) Mspl polymorphism. Genetic damage in newborns associated with environmental PAHs raises concern about carcinogenic risks from in utero exposure to this widespread contaminant.
    With regard to other candidate genes there are about 50 DNA repair genes. The inability to repair such mistakes can cause skin and other cancers.
    Chemical receptor genes include ones that modify pathways related to toxic response, e.g. Ah receptors, estrogen receptors, progesterone receptors, and endocrine disrupter pathways.
Variations in genes in neurotoxicology, reproductive, and developmental toxicology are also strong candidates.
Genes involved in nutrition pathways or the metabolism of nutrients (e.g. vitamins and minerals) account for another 25 candidates. Certain polymorphisms in nutrient pathways contribute to diseases such as cirrhosis and liver cancer. Steroid metabolism genes involved in the synthesis of estrogen, progesteron, and testosterone account for some 25 candidates (Albers, 1997).
    Characterisation of the variability in response to a contaminant requires the analysis of several susceptibility factors. Recent results in determining genetic susceptibility are discussed by Suk and Collman (1998) and Whyatt at al., (1998). Lead constitutes a rare example where the dose-response relationship has been thoroughly studied epidemiologically. In children lead exposure is manifested in impaired behavioural, cognitive, and motor functions (Grassman, 1996). Currently, deficits are thought to occur with blood lead levels (BLLs) below 10 µg/dl (Šov?ikova et al., 1997), and the calculated threshold of less than 1 µg/dl (Schwartz, 1994).
    A specific example of research in the characterization of a genetic polymorphism of a commonly occurring gene now leads us to begin to understand the relationship between lead exposure levels and cognitive impairment in susceptible subpopulations in children. An enzyme of the heme biosynthesis pathway, delta-aminolevulinate dehydratase (ALAD) is a protein that is encoded by a gene in the 9 q 34 chromosome locus. It is polymorphic in the population, with two common alleles, ALAD-1 a ALAD-2. This structure results in three distinct genotypes, ALAD 1-1 1-2, and 2-2, which are distributed in the population (Suk and Collman, 1998). It is hypothesised that individuals with the ALAD-2 allele could be more susceptible to lead exposure if the ALAD subunit binds lead more tightly ALAD-1 subunit (Astrin et al., 1987). Individuals with the ALAD 1-2 and 2-2 allele might have higher blood lead concentrations as well as higher total body burden, making them more likely to show clinical and subclinical manifestations of low-level exposure (Suk and Collman, 1998).
    Interactions between the ALAD polymorphism, developmental stage, dietary deficiencies, and gender are possible. As a result, the most susceptible population cannot be identified.
    Genetic polymorphisms in metabolic enzyme activity add an important dimension of variability. Depending on the particular chemical, this may serve as a protective factor of increased susceptibility to toxic effects (e.g. epoxide hydrolyse and fetal hydantoin syndrome — Graeter and Mortensen, 1996).
    Response variability can be analysed in large cohorts with uniform exposure. Future approaches to risk assessment may employ mechanistic models where the variability in the intermediate steps between exposure and health outcome are modelled using a combination of animal and human in vivo and in vitro endpoints.
 

CONCLUSIONS

Despite recent extraordinary advance in cellular and molecular biology that has enhanced our understanding of the basis for human disease, the approaches for incorporating this information into risk assessment and risk management activities are still in their infancy (Preston, 1996). Determining how to incorporate the influence of genetic susceptibility and sensitivity into the process is particularly difficult. Therefore the projects including gene-environment interactions have great public health implications. It is the basis for understanding how chemical agents interact and providing data to prevent and not just treat final-stage disease.
    A great challenge not only to EGP, but also to other activities regarding genetic problems and human health is in the area of their ethical, legal, and social implications. These issues are complex and many-layered and we should foster an open dialogue on these implications with both scientific and non-scientific communities.
    The complex interplay between genes and environment represents also a great challenge to scientists, and it is also an important opportunity to reduce the burden of disease and disfunctions on humans.
 

REFERENCES


ALBERS, J. W. (1997). “Understanding Gene – Environment.” Environ. Health Perspect. 105: 578–580.

ASTRIN, K. H. et al. (1987). “Delta-aminolevulinic acid dehydratase isozymes and lead toxicity.” Ann. N. Y. Acad. Sci. 514: 23–29.

BARRETT, J. C. et al. (1997). 12th Meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals: Susceptibility to Environmental Hazards. Environ. Health Perspect. 105: Suppl. 4, 694–737.

BEARER, C. F. (1998). “Biomarkers in pediatric environmental health: A cross-cutting issue.” Environ. Health Perspect. 106: Suppl. 3, 813–816.

BORCHARDT, R. T. (1980). “N- and O-methylation.” In: Enzymatic Basis of Detoxication. (J. B. Jacoby, ed.) Academic Press, New York, pp. 43–62.

COLLINS et al. (1995). “The comet assay modified to detect DNA base oxidation, and repair of DNA damage in cellular and subcellular systems.” J. Cell. Biochem. (Suppl), 347.

ELLSWORTH, D. L. et al. (1997). “Impact of Human Genome Project on epidemiological research.” Epidemiol. Rev. 19: 3–13.

EVANS, H. J. (1984). “Human peripheral blood lymphocytes for the analysis of chromosome abberations in mutagen tests”. In: Handbook of Mutagenicity Test Procedures, 2nd ed. (B. J. Kilbey, M. Legator, W. Nichols, C. Ramel, eds.) Elsevier Amsterdam, pp. 405–427.

GOEDDE, H. W. (1986). “Ethnic differences in reactions to drugs and other xenobiotics: Outlook of a geneticist”. In: Ethnic Differences in Reactions to Drugs and Xenobiotics (W. Kalow, H. W. Goedde, D. P. Agarwal, eds). Alan R. Liss, New York, pp. 9–14.

GRAETER, L. J., and MORTENSEN, M. E. (1996). “Kids are different: developmental variability in toxicology.” Toxicology. 111: 15–20.

GUENGERICH, F. P. (1998). “The Environmental Genome Project: Functional analysis of polymorphisms.” Environ. Health Perspect. 106: 365–368.

HEDDLE, J. A. et al. (1991). “Micronuclei as an index of cytogenetic damage: past, present, and future.” Environ. Mol. Mutagen. 18: 277–291.

HOLTZMAN, N. A., and ANDEREWS, L. B. (1997). “Ethical and legal issues in genetic epidemiology.” Epidemiol. Rev. 18 : 163–174.

HU, H. (1998). “Bone lead as a new biologic marker of lead dose: Recent findings and implications for public health.” Integrated Approaches for Studying Hazardous Substances. 106: Suppl. 4, 961–967.

INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY (1993). “Biomarkers and risk assessment concepts and principles”. In: Environmental Health Criteria 155. World Health Organization, Geneva.

JENDRYCHOWSKI, W., and GOLDSMITH, J. (1992). “Health effects of environmental contaminants.” In: Kryzanowski, J. K. (ed.) Seminars of Environmental Epidemiology. WHO. Bilthoven. pp. 7–33.

KHOURY, M. J. (1997). “Genetic epidemiology and the future of disease prevention and public.” Epidemiol. Rev. 19: 175–180.

KHOURY, M. J., and DORMAN, J. S. (1998). “The Human Genome Epidemiology Network.” Am. J. Epidemiol. 148: 1–3.

KÖTELES, G. J. (1998). “The human lymphocyte micronucleus assay.” Centr. Eur. J. Occup. Environ. Med. 2: 12–30.

LASLEY, B. L., and OVERSTREET, J. W. (1998). “Biomarkers for assessing human female reproductive health.” Integrated Approaches for Studying Hazardous Substances. 6. Suppl 4, 955–960.

LEE, L. W., GRIFFITH, J., ZENICK, H., and HULKA, B. S. (1995). “Human tissue monitoring and specimen banking: Opportunities for exposure assessment, risk assessment, and epidemiologic research.” Environ. Health Perspect. 103: Suppl. 3, 3–8.

LOFFREDO, CH. A. (1998). “The Environmental Genome Project: Suggestions and concerns.” Environ. Health Perspect. 106:A 368.

OLDEN, K. O. (1994). Vision for the Future. National Institute of Environmental Health Sciences. USA.

REICHRTOVÁ, E. (1995). “Human placenta quality in ecologically different regions. Part 2-P Placental structural changes and cord blood IgE level.” Toxicol. Letters 78 (Suppl.):69–70.

ROSIVAL, L. et al. (1983). “Transplacental passage of pesticides into human embryo.” Czechoslovak Medicine 5: 1–7.

SCHWARTZ, J. (1994). “Low-level lead exposure and children’s IQ: a meta-analysis and search for a threshold.” Environ. Res. 65:42–55.

SMITH, M. T., and ZHANG, L. (1998). “Biomarkers of leukemia risk: Benzene as a model.” Integrated Approaches for Studying Hazardous Substances 106: Suppl. 4, 937–946.

SOVCIKOVA, E. et al. (1997). “Effects on the mental and motor abilities of children exposed to low levels of lead in Bratislava.” Toxic Subst. Mech. 16:221–236.

ŠRÁM, R. J. (1998). “Effect of glutathione S-transferase M1 polymorphisms on biomarkers of exposure and effects.” Environ. Health Perspect. 106: Suppl. 1, 231–239.

SUK, A., and COLLMAN, G. W. (1998). “Genes and the environment: Their impact on children’s health.” Environ. Health Perspect. 106: Suppl. 3, 817–820.

TARCHER, A. B., and CALABRESE, E. J. (1992). “Enhanced susceptibility to environmental chemicals.” In: Principles and Practices of Environmental Medicine. (Tarcher, A. B., ed.) Plenum Medical Book Co. New York, London, 189–213.

TRICHOPOULOS, D. et al. (1996). “What causes cancer?” Sci. Am. 88:496–509.

TUCKER, J. D. et al. (1993). “Sister-chromatid exchange: Second report of the Gene-Tox program.” Mutat. Res. 297:101–180.

VESELL, E. S. (1987). “Pharmacogenetic perspectives on susceptibility to toxic industrial chemicals.” Br. J. Ind. Med. 44:505.

WHYATT, R. et al. (1998). “Relationship between ambient air pollution and DNA damage in polish mothers and newborns.” Environ. Health Perspect. 106: Suppl. 3, 821–826.

Received: 30 December 1998
Accepted: 26 February 1999

Posted:  December 1999
| Back |