PRINCIPLES OF TOXICOLOGY

The current daily oral RfD for cadmium is 5 × 10 –4 mg/kg for water sources, in comparison
to 1 × 10 –3 mg/kg daily from food sources. The USEPA has categorized cadmium as a Class B1
carcinogen (probable human carcinogen), by inhalation only.
Chromium
14.6 TOXICOLOGY OF SELECTED METALS 339
Chromium is a naturally occurring element, which is found in the environment in three major valence
states: elemental chromium (0), trivalent chromium (+3), and hexavalent chromium (+6). Chromium
(+3) occurs naturally in the environment, while chromium (+6) and chromium (0) typically are
generated by industrial processes.
Natural geologic sources represent a component of chromium present in the environment. However,
chromium is released to the environment in much larger and more concentrated amounts as a result of
human activities. The most stable form of the chromium compounds is the trivalent state, the naturally
occurring form. The hexavalent form is uncommon in a natural setting and is easily reduced to the
trivalent form by environmental processes.
The three major forms of chromium differ dramatically in their potential for causing effects on
human health. Trivalent chromium is an essential nutrient required for normal energy metabolism.
Hexavalent chromium is irritating, and short-term high-level exposure can result in adverse effects at
the site of contact, such as ulcers of the skin, irritation of the nasal mucosa, perforation of the nasal
septum, and irritation of the gastrointestinal tract, as well as adverse effects in the kidney and liver.
Exposure to metallic chromium is less common and is not well characterized in terms of levels of
exposure or potential health effects.
The respiratory tract in humans is a major target of chromium inhalation exposure. Occupational
exposure to chromium (+6) and/or chromium (+3) in a number of industries has been associated with
respiratory effects. Irritant effects, decreased pulmonary function, and perforation of the nasal septum
have been noted in workers exposed to chromium. Chronic exposure to chromium compounds have
also resulted in adverse respiratory effects in animals.
There is little evidence of reproductive effects of chromium in humans, but there is some evidence
that chromium has adverse reproductive effects in certain animal species. There is conflicting human
and animal evidence of developmental toxicity following inhalation, oral, or dermal exposure to
chromium. There is no evidence that exposure to chromium has any developmental effects in humans.
However, studies indicate that chromium may be teratogenic in animals. Chromium (+6) compounds
have been shown to cross the placenta and to induce neural tube defects and lethality in mice, cleft
palates and lethality in hamsters, and a variety of abnormalities in chick embryos. Allergic contact
dermatitis in sensitive individuals can result from exposure to chromium compounds.
Chromium (+6) compounds have been tested in a wide range of in vivo, cell culture, and bacterial
genotoxicity assay systems and were positive for all endpoints. The genotoxicity data support the
hypothesis that chromium (+6) is not genotoxic per se, but that chromium genotoxicity is mediated by
the intracellular reduction of chromium (+6) to chromium (+3), which may be the ultimate genotoxic
form of chromium. Paradoxically, chromium (+3) does not induce DNA damage, even though it binds
to DNA in vitro and in vivo.
Unlike many chemical carcinogens, the majority of information on chromium-induced carcinogenesis
comes from human epidemiology studies of occupationally exposed workers rather than from
animal studies. Lung cancer is considered to be an occupational hazard for workers exposed to
chromium (+6) in a wide variety of industrial and commercial occupations. Studies indicate that
workers in industries that use chromium can be exposed to concentrations of chromium two orders of
magnitude higher than exposure to the general population. There is a good correlation between the
dose of chromium, expressed as a function of concentration and time of exposure, and the relative risk
of developing lung cancer, which has been calculated to be as much as 30 times that of appropriate
controls. The principal forms of chromium-induced cancer are lung carcinomas and, to a lesser extent,
nasal and pharyngeal carcinomas. There also is some evidence for an increased risk of developing
gastrointestinal cancer.