PRINCIPLES OF TOXICOLOGY - Biology East Borneo

14.6 TOXICOLOGY OF SELECTED METALS 339The current daily oral RfD for cadmium is 5 × 10 –4 mg/kg for water sources, in comparisonto 1 × 10 –3 mg/kg daily from food sources. The USEPA has categorized cadmium as a Class B1carcinogen (probable human carcinogen), by inhalation only.ChromiumChromium is a naturally occurring element, which is found in the environment in three major valencestates: elemental chromium (0), trivalent chromium (+3), and hexavalent chromium (+6). Chromium(+3) occurs naturally in the environment, while chromium (+6) and chromium (0) typically aregenerated 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 ofhuman activities. The most stable form of the chromium compounds is the trivalent state, the naturallyoccurring form. The hexavalent form is uncommon in a natural setting and is easily reduced to thetrivalent form by environmental processes.The three major forms of chromium differ dramatically in their potential for causing effects onhuman 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 atthe site of contact, such as ulcers of the skin, irritation of the nasal mucosa, perforation of the nasalseptum, 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 ofexposure or potential health effects.The respiratory tract in humans is a major target of chromium inhalation exposure. Occupationalexposure to chromium (+6) and/or chromium (+3) in a number of industries has been associated withrespiratory effects. Irritant effects, decreased pulmonary function, and perforation of the nasal septumhave been noted in workers exposed to chromium. Chronic exposure to chromium compounds havealso resulted in adverse respiratory effects in animals.There is little evidence of reproductive effects of chromium in humans, but there is some evidencethat chromium has adverse reproductive effects in certain animal species. There is conflicting humanand animal evidence of developmental toxicity following inhalation, oral, or dermal exposure tochromium. 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) compoundshave been shown to cross the placenta and to induce neural tube defects and lethality in mice, cleftpalates and lethality in hamsters, and a variety of abnormalities in chick embryos. Allergic contactdermatitis 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 bacterialgenotoxicity assay systems and were positive for all endpoints. The genotoxicity data support thehypothesis that chromium (+6) is not genotoxic per se, but that chromium genotoxicity is mediated bythe intracellular reduction of chromium (+6) to chromium (+3), which may be the ultimate genotoxicform of chromium. Paradoxically, chromium (+3) does not induce DNA damage, even though it bindsto DNA in vitro and in vivo.Unlike many chemical carcinogens, the majority of information on chromium-induced carcinogenesiscomes from human epidemiology studies of occupationally exposed workers rather than fromanimal studies. Lung cancer is considered to be an occupational hazard for workers exposed tochromium (+6) in a wide variety of industrial and commercial occupations. Studies indicate thatworkers in industries that use chromium can be exposed to concentrations of chromium two orders ofmagnitude higher than exposure to the general population. There is a good correlation between thedose of chromium, expressed as a function of concentration and time of exposure, and the relative riskof developing lung cancer, which has been calculated to be as much as 30 times that of appropriatecontrols. 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 developinggastrointestinal cancer.