PRINCIPLES OF TOXICOLOGY

can be used during testing of potential mutagens in vitro. One of the most common involves the
monitoring of mutations in specific well-characterized gene loci, such as those coding for hypoxanthineguanine
phosphoribosyl transferase (HGPRT), thymidine kinase (TK), or ouabain resistance
(OVA r ). Mutagenic modification in the segments of the DNA coding for these proteins (enzymes)
results in an increased sensitivity of the cell, which can often be evaluated by the cell’s heightened
susceptibility to other agents (e.g., bromodeoxyuridine or 8-azaguanine).
As described in the section on in vivo mammalian testing, evaluations of sister chromatid exchange,
DNA repair activity, and chromosomal aberration through interpretation of metaphase spreads may be
applied to in vitro testing of mutagens. An additional procedure that has been correlated with chemical
mutagenicity is examination for cell culture transformation; following treatment with mutagens, some
cells in culture lose their normal, characteristic arrangement of monolayered attachment and begin to
pile up in a disorganized fashion. Two major drawbacks in looking for this feature are that considerable
expertise is necessary to interpret the results accurately and that the criteria for evaluation are more
subjective than for other mutagenicity assays.
A comparison of the sensitivity and specificity of selected short-term tests by two recognized
systems (National Toxicology Program (NTP) and Gene-Tox) is shown in Table 12.3.
12.5 OCCUPATIONAL SIGNIFICANCE OF MUTAGENS
Areas of Concern: Gene Pool and Oncogenesis
12.5 OCCUPATIONAL SIGNIFICANCE OF MUTAGENS 257
The potential significance of occupationally acquired mutations can be divided into two areas. The
first is concern for the protection of the human gene pool. This factor may represent the most significant
reason for genetic testing, but it is often underemphasized by nongeneticists involved with safety
evaluation because of the inability to demonstrate induced mutation in humans to date. The second
area is that of oncogenesis. The intimate relationship between the tumorigenic and genotoxic properties
of many chemicals (Figure 12.8) makes genetic testing a potentially powerful screening technique for
establishing priorities for future testing of chemicals of unknown cancer-causing potential. This factor
has been one of the primary driving forces behind the rapid expansion of genetic toxicology as a
discipline. Once again, however, the paucity of proved human carcinogens compared with the number
of demonstrated animal carcinogens suggests weaknesses in the process of extrapolating from animal
studies to human exposure in the workplace.
At the heart of the present legal and regulatory approach toward environmental and occupational
exposure to mutagens is the possibility that they may cause human genetic damage. Two important
assumptions underlie this central concept:
• Environmental or occupational mutagens may cause aneuploidy, chromosome breaks, point
mutations, or other genetic damage in humans
• Environmental or occupational mutagens that can be controlled by regulatory efforts
represent a significant component of total human exposure
Much of the interest in potential environmental and occupational mutagens is related to the prevalent
opinion that many cancers are initiated by a mutagenic event. This premise is supported by the strong
correlation between some specific occupational chemical exposures and cancer incidence in humans.
One good example is the relationship between liver cancer (angiosarcoma) and exposure to vinyl
chloride in some manufacturing operations. Another example is the respiratory tract cancers that may
be caused by exposure to bis(chloromethyl)ether.