PRINCIPLES OF TOXICOLOGY

Several metals preferentially target the central nervous system. A neurological condition similar to
Parkinson’s disease, characterized by strange behavior and a “masklike” facial expression, is often
the result of chronic, high level exposure to manganese. Lead intoxication may result in learning
problems, behavioral disorders, hyperexcitability, or lethargy and ataxia. Chronic exposure to mercury
can produce hyperexcitability and even psychosis. This latter symptom was identified as “mad hatter’s
syndrome” in the nineteenth century due to its prevalence among hatmakers exposed to mercury
compounds used in the hat felting process. Table 14.2 lists principal target organ toxicities for selected
metals.
Carcinogenicity
A few metals, such as beryllium, cadmium, hexavalent chromium, and some nickel compounds have
been demonstrated to be carcinogenic in humans and experimental animals, primarily by the inhalation
route. Arsenic is classified as a human carcinogen by IARC (International Association for Research
on Cancer), but evidence for carcinogenicity in animals is not conclusive. The opposite is true for lead,
shown to be carcinogenic in animals but not in humans. Other metals, such as copper, zinc, and mercury,
have no demonstrated carcinogenic potential. Table 14.3 lists metals that have been demonstrated to
be carcinogenic or possibly carcinogenic in humans and animals.
Of the metals that are known or suspected carcinogens, some have shown the effect to be confined
to specific forms. For instance, hexavalent chromium is a known human carcinogen by inhalation,
while trivalent chromium does not appear to be carcinogenic by any route. Likewise, nickel carcinogenicity
has been demonstrated for the sulfide compound, but evidence for the carcinogenic potential
of other nickel species is less certain.
Route specificity is also an interesting observation related to metal carcinogenic potential. Cadmium
and hexavalent chromium are carcinogenic by inhalation only, while arsenic and beryllium
exhibit broader carcinogenic potential by the inhalation, oral, and perhaps the dermal route.
Each carcinogenic metal seems to have a unique mechanism of action. Hexavalent chromium is
converted to trivalent chromium in cells and forms tightly bound adducts with DNA and proteins. The
biologically active carcinogens are likely the reactive intermediates of chromium (+6) reduction.
Nickel ions accumulate within cells, generating oxygen radicals that appear to be the cause of the
TABLE 14.3 Classifications of Selected Metals Known or Suspected to be Carcinogenic to Humans
Metal USEPA IARC ACGIH/OSHA
Arsenic Human carcinogen a
Human carcinogen Human carcinogen
Beryllium Probable human
carcinogen b
Probable human
carcinogen
Suspected human
carcinogen
Cadmium Probable human Probable human Suspected human
carcinogen
carcinogen
carcinogen
Chromium (VI only) Human carcinogen d
Human carcinogen Human carcinogen
Cobalt Not classified Possible human
carcinogen c
Animal carcinogen
Lead Probable human Possible human Animal carcinogen
carcinogen
carcinogen
Nickel Human carcinogen d
(refinery dust and
nickel subsulfide)
Human carcinogen Human carcinogen
a
Human carcinogen = adequate evidence of carcinogenic potential in humans.
b
Probable or suspected human carcinogen = equivocal evidence of carcinogenic potential in humans, with adequate evidence of
carcinogenicity in animals.
c
Possible human carcinogen = equivocal evidence of carcinogenic potential in humans.
d Inhalation route only.
14.4 TOXICITY OF METALS 333