This report reviews the literature on the genotoxicity of mainstream tobacco smoke
and cigarette smoke condensate (CSC) published since 1985. CSC is genotoxic in nearly
all systems in which it has been tested, with the base/neutral fractions being the
most mutagenic. In rodents, cigarette smoke induces sister chromatid exchanges (SCEs)
and micronuclei in bone marrow and lung cells. In humans, newborns of smoking mothers
have elevated frequencies of HPRT mutants, translocations, and DNA strand breaks.
Sperm of smokers have elevated frequencies of aneuploidy, DNA adducts, strand breaks,
and oxidative damage. Smoking also produces mutagenic cervical mucus, micronuclei
in cervical epithelial cells, and genotoxic amniotic fluid. These data suggest that
tobacco smoke may be a human germ-cell mutagen. Tobacco smoke produces mutagenic urine,
and it is a human somatic-cell mutagen, producing HPRT mutations, SCEs, microsatellite
instability, and DNA damage in a variety of tissues. Of the 11 organ sites at which
smoking causes cancer in humans, smoking-associated genotoxic effects have been found
in all eight that have been examined thus far: oral/nasal, esophagus, pharynx/larynx,
lung, pancreas, myeoloid organs, bladder/ureter, uterine cervix. Lung tumors of smokers
contain a high frequency and unique spectrum of TP53 and KRAS mutations, reflective
of the PAH (and possibly other) compounds in the smoke. Further studies are needed
to clarify the modulation of the genotoxicity of tobacco smoke by various genetic
polymorphisms. These data support a model of tobacco smoke carcinogenesis in which
the components of tobacco smoke induce mutations that accumulate in a field of tissue
that, through selection, drive the carcinogenic process. Most of the data reviewed
here are from studies of human smokers. Thus, their relevance to humans cannot be
denied, and their explanatory powers not easily dismissed. Tobacco smoke is now the
most extreme example of a systemic human mutagen.