Minimal Risk Level Derivation for Cadmium : Acute and Intermediate Duration Exposures

The Agency for Toxic Substances and Disease Registry (ATSDR) lists cadmium as one of its priority hazardous substances. The agency conducted a comprehensive literature review of cadmium and used the information to develop a toxicological profile that identified the full range of health effects associated with exposure to cadmium. It included an assessment that identified screening levels, termed health guidance values or minimal risk levels (MRLs), below which adverse health effects are not expected. In this paper, we describe how MRLs for cadmium are derived. For the acute inhalation MRL, the traditional no observed adverse effect level or lowest observed adverse effect level (NOAEL/LOAEL) approach is used; for the oral intermediate MRL, the benchmark dose (BMD) approach is used. MRLs were developed for the most sensitive route-specific end points, other than mortality and cancer that were sufficiently supported and justified by the data. These included an acute duration (1–14 day exposure) inhalation MRL of 0.03 μg Cd/m for alveolar histiocytic infiltration and focal inflammation in alveolar septa and an intermediate duration (15–365 day exposure) oral MRL of 0.5 μg Cd/kg/day for decreased bone mineral density JOURNAL OF EXPERIMENTAL AND CLINICAL TOXICOLOGY ISSN NO: Coming soon Research DOI : coming soon Corresponding Author: : Obaid Faroon, Division of Toxicology and Human Health Sciences, Agency for Toxic Substances and Disease Registry, Atlanta, Georgia. Email:0xs0@cdc.gov, Phone: 770-488-3320


Introduction
Toxicological profiles are used to help protect people's health. They identify potential adverse health effects caused by exposure to chemicals, particularly priority environmental pollutants. The Agency for Toxic such as minimal risk levels (MRLs) [1]. An MRL is an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk for adverse non-cancer health effects over a specified duration of exposure. Thus, MRLs are based on the concept that a threshold level of exposure exists, below which no non-cancer health effect is likely to occur.
Therefore, an exposure level protective against the most sensitive effect would also be protective against all other effects. ATSDR health assessors and other responders use these substance-specific estimates to identify contaminants and potential health effects that might be of concern at hazardous waste sites. MRLs serve as screening levels; they are not intended to define clean-up or action levels for ATSDR or other agencies.
Uncertainty factors are used with the point of departure to compensate for data gaps, study duration, species differences, human variability, and other physiological phenomenon [2]. While  Starting in the early 1920s, it became apparent that cadmium fumes were acutely toxic after numerous workers had died after short exposures to presumably high exposures to airborne cadmium oxide [8]. As in metal fume fever, initial symptoms of cadmium fume overexposure were usually mild pulmonary edema that rapidly progressed to severe edema and pneumonitis [9,10]. Similarly, studies have reported that acute exposure to cadmium can cause lung damage in animals [11][12][13][14][15].
Cadmium Oral Toxicity: The major sources of oral exposure to cadmium in humans are typically food and incidental ingestion from contaminated hands [16,17]. anemia, liver disease, and nerve or brain damage [20][21][22]. Even lower levels of exposure for extended periods can make bones fragile, so that they are easier to break [23,24]. Relative and absolute lung weights were significantly increased at 0.26 mg (only in males), 0.88 mg, and 2.6 mg Cd/m 3 . Histological changes occurred only in the respiratory tract; Table 1 shows the incidence rates.
These data were determined to be suitable for deriving the acute inhalation MRL for cadmium.

Intermediate oral MRL Derivation
The

Results and Discussion
Acute Inhalation MRL derivation Because the alveolar histiocytic infiltration incidence data shown in Table 1   Other studies that reported adverse health effects starting at higher doses lend support to this MRL.
Reproductive effects in rats exposed to 8-12 mg Cd/kg/ day included necrosis and atrophy of seminiferous tubules and decreased sperm count and motility [33,53]. Neurological effects in rats exposed to 3.1 mg or 9 mg Cd/kg/day included decreased motor activity [22,54], whereas 5 mg Cd/kg/day increased their passive avoidance [55]. At approximately 3 mg Cd/kg/day, liver necrosis and anemia occurred [29]. Immunological effects included greater susceptibility to lymphocytic leukemia virus in mice exposed to 1.9 mg Cd/kg/day as cadmium chloride in drinking water for 280 days [56].
Vesiculation of the renal proximal tubules occurred in rats exposed to 1.18 mg Cd/kg/day as cadmium chloride in drinking water for 40 weeks [28]. Decreases in bone strength occurred in young rats exposed to 0.8 mg Cd/ kg/day as cadmium chloride in drinking water for 4 weeks (Ogoshi [57]. Administration to rats by gavage of 0.5 mg Cd/kg/day on gestation days 1-21 resulted in decreased glomerular filtration rates and increased urinary fractional excretion of phosphate, magnesium, potassium, sodium, and calcium in their 60 day old offspring [30].

Conclusions
In compliance with the Comprehensive  AIC = Akaike's information criterion; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the benchmark dose; sd1 = a 1 standard deviation change from the control.