Risk assessment: the importance of genetic polymorphisms in man.
Many genetic polymorphisms in metabolism enzymes are important for the risk of cancer as shown in a large number of case-control studies. The relative risk estimates have shown large variations between such population studies. However, in most studies the relative risk estimates are in the range of 2. Some polymorphisms are effect modifiers, i.e. without exposure they have no consequence and the effect of exposure can appear independent of the genotype. Genetic polymorphisms in metabolism of environmental toxicants plays a significant role in exposures to traffic generated air pollution in Copenhagen, revealing statistically significant higher levels of chromosomal aberrations in non-smoking bus drivers with glutathion-S-transferase M1, GSTM1 null and N-acetyltransferase 2, NAT2 slow genotypes. Combined with cohort studies showing positive associations between high chromosomal levels and increased cancer risk, such results indicate effect modification regarding cancer risk. In risk assessment the safety 'factor' of 10 is generally accepted to allow for variation in individual susceptibility. Reviewing the literature justifies the factor of 10 when considering single polymorphisms. However in an individual with several susceptible metabolism genotypes as well as other determinants of susceptibility, e.g. defective DNA repair, poor-nutritional state, etc. the risk may increase far above a safety of 10.Historically, genetic polymorphisms have been taken into consideration in employment and currently the application in insurance situations is criticised.
Knudsen
L E
LE
Department of Environmental and Occupational Medicine, Institute of Public Health, University of Copenhagen, Blegdamsvej 3 DK-2200 Copenhagen N, Denmark. lisbeth.knudsen@pubhealth.ku.dk
Loft
S H
SH
Autrup
H
H
D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D004781:Environmental Exposure; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000235:genetics; D011110:Polymorphism, Genetic; D018570:Risk Assessment
D001191:Arylamine N-Acetyltransferase; D015415:Biomarkers; D005982:Glutathione Transferase; C478900:NAT2 protein, human