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APPENDIX VI

TOXICOLOGICAL PROFILES OF THE METALS OF CONCERN FOR HUMAN HEALTH

Arsenic

Lowest Observed Adverse Effect Levels (LOAELs) for acute human exposure to arsenic are about 1 mg/kg/day (ATSDR 1993a). The oral RfD for arsenic is 0.3 µg/kg/day. The most likely human health effects of oral exposure to arsenic are gastrointestinal irritation, peripheral neuropathy, vascular lesions, anemia and a group of skin diseases. Acute ingestion of low levels of arsenic trioxide may cause nausea, vomiting and diarrhea; ingestion of higher concentrations (>70 mg) are usually fatal (Ariza et al. 1999). The data available on the acute effects of oral exposure to arsenic are mainly from case reports of fatal or near fatal exposures. It is likely that lower acute exposures could also produce characteristic signs of arsenic toxicity. For intermediate-duration exposure most oral LOAELs range from 0.05 to 0.5 mg/kg/day (ATSDR 1993a)

Little information is available on the effects due to dermal contact with inorganic arsenic. The chief effect is local irritation and dermatitis. A dermal NOAEL of 580 mg/L As⁺³ was identified for the guinea pig (ATSDR 1993a).

No studies were located regarding unusual susceptibility of any human population to arsenic. Given that the degree of arsenic toxicity may be influenced by the rate and extent of its methylation in the liver, it is likely that members of the population with a lower than normal methylating capacity will be susceptible to arsenic toxicity

Arsenic is also considered a carcinogen via the oral route. The U.S. EPA (1998) has derived an oral cancer potency factor of 0.0015 µg/kg/day based on an increased incidence of skin cancer in humans exposed to arsenic via their drinking water.

Cobalt

Oral exposure to cobalt (frequently cobalt chloride) by humans can cause nausea, vomiting, polycythemia and minor cardiovascular effects. An oral RfD of 60 µg/kg/day has been established by the U.S. EPA (1997) based on polycythemia in renally compromised and normal patients.

There are no data that indicate that cobalt causes cancer.

Cadmium

The primary toxicological endpoint following oral exposure to cadmium is proteinuria (i.e., excess protein in the urine). Gastrointestinal absorption is about 5 to 8% (Goyer 1996). Absorption is enhanced by dietary deficiencies of calcium, iron and protein and in women, low serum ferritin levels (Goyer 1996). Gastrointestinal effects have occurred at consumption of drinks containing approximately 16 mg per litre of cadmium (Nordberg 1972). Recovery was rapid with no long-term effects. Common symptoms of cadmium ingestion include nausea, vomiting, salivation, abdominal pain, cramps and diarrhea (ATSDR 1993b). The emetic dose is 0.07 mg/kg (ATSDR 1993b).

Skin contact with cadmium is not known to cause health effects in humans or animals (ATSDR 1993b).

Young children and populations with dietary deficiencies of calcium, iron, protein, and vitamin D have increased cadmium absorption from the gastrointestinal tract, making them potentially more susceptible to cadmium toxicity. Also, populations with kidney damage from causes unrelated to cadmium exposure, including diabetes, are expected to be more susceptible to cadmium-related nephrotoxicity.

Although cadmium is classified as a human carcinogen via inhalation, there are no data to indicate that cadmium can cause cancer following oral or dermal exposures.

Nickel

Oral exposure to nickel and nickel compounds can result in an increased incidence of allergic contact dermatitis, eczema and respiratory effects in humans.

There are no data to indicate that metallic nickel is carcinogenic.

Chromium

Ingestion of chromium (VI) can cause stomach upsets, ulcers, convulsions and kidney and liver damage. Death has also occurred after accidental chromium poisoning. A man died of severe gastrointestinal haemorrhage after ingesting 4.1 mg/kg of chromic acid (ATSDR 1993c). A boy died after ingestion of 7.5-mg/kg potassium dichromate (ATSDR 1993c). A woman who ingested a few grams of potassium dichromate experienced renal effects and regained renal function following dialysis. She also experienced decreased haemoglobin content and hematocrit, increased total white blood cell counts, reticulocyte counts and plasma haemoglobin.

Dermatitis in chromium-sensitive workers has been found to worsen after ingestion of 0.036-mg/kg chromium as potassium dichromate (ATSDR 1993c).

Acute oral exposure to chromium can cause dermal, ocular, immunological, gastrointestinal, haematological, renal, hepatic, neurological and cardiovascular effects. Respiratory, cardiovascular, haematological, hepatic and neurological effects in humans as a result of chromium ingestion have only been identified for extreme cases where death occurred or large amounts were ingested associated with occupational exposure.

Allergic chromium skin reactions readily occur with exposure and are independent of dose in allergic individuals (Goyer 1996). Eczema and dermatitis (ATSDR 1993c) characterize allergic skin reactions. Acute dermal exposure of humans to chromium (VI) compounds causes skin burns. Cases of such skin burns are a result of accidental occupational or therapeutic exposure.

Individuals who are sensitive to chromium may develop asthma as an anaphylactic response to inhaled chromium (ATSDR 1993c). Some individuals have less ability than others to reduce chromium (VI) in the bloodstream and are more likely to be affected by the adverse effects of chromium exposure (ATSDR 1993c). Based upon animal studies and occupational exposure studies, young people may be more susceptible to toxic effects of chromium than adults (ATSDR 1993c).

Lead

The level of lead causing a toxic effect is commonly expressed through blood lead levels. Studies have been conducted to correlate environmental lead levels with blood lead levels and slope factors have been developed to predict the increases in blood lead per unit lead concentration in environmental media (ATSDR 1993d). Slopes range between 0.0007 and 0.0068 µg/dL blood lead increase per mg/kg soil lead (ATSDR 1993d).

Lead is neurotoxic with varying symptoms. Exposure of children to high levels may cause encephalopathy and/or irreversible mental retardation (Goyer 1996). Symptoms of lead encephalopathy begin with lethargy, vomiting, irritability, loss of appetite and dizziness, progressing to ataxia, a reduced level of consciousness, which may progress to coma and death. Encephalopathy can occur at blood lead levels of 100-120 µg/dL in adults and 80-100 µg/dL in children (ATSDR 1993d).

In adults, lead neurotoxicity can result in depression, affective or schizophreniform-like psychosis, irritability, decreased libido, fatigue, anger, tension and interpersonal conflicts. Adults have been found to have overt neurological signs and symptoms at blood lead levels of 40-60 µg/dL (ATSDR 1993d). In children, neurobehavioural impairment has been associated with blood lead levels of 50 - 70 µg/dL (ATSDR 1993d).

At high levels of exposure, lead produces cardiac lesions and cardiac abnormalities (ATSDR 1993d).

Lead interferes with heme biosynthesis and has multiple haematology effects. In humans a LOAEL of 0.02 mg/kg/day was related to decreased δ-aminolevulenic acid dehydratase (ALAD) activity (ATSDR 1993d).

Acute lead-induced kidney damage in humans includes inclusion bodies, mitochondrial changes and damage to the proximal tubules (Fanconi's syndrome) which results in aminoaciduria, glucosuria and hyperphosphaturia. These effects appear to be reversible. Fanconi's syndrome is estimated to occur in approximately 1/3 of children at approximately 150 µg/dL (ATSDR 1993d). Nephropathy occurs in children at blood levels >80 µg/dL (ATSDR 1993d).

Colic, which is characterized by abdominal pain, constipation, cramps, nausea, vomiting, anorexia and weight loss is a symptom of individuals acutely exposed to high levels (40 to 200 µg/dL) of lead (ATSDR 1993d).

Children are at the greatest risk for experiencing lead-induced health effects. This is due to a number of factors: 1) young children (<5 years old) absorb ingested lead more efficiently (50% relative absorption) than adults (15% relative absorption); 2) behaviour such as thumb sucking and pica result in clevated transfer of lead-contaminated dust and dirt; 3) children have an immature detoxification enzyme system resulting in increased retention and body burdens of lead and 4) children have lower thresholds expressed as blood lead concentration for haematological and neurological effects (ATSDR 1993d).

Developing fetuses are at an increased risk due to the inherent susceptibility of the developing nervous systems and exposure arising from transplacental transfer of maternal lead. Toxic effects of lead exposure are exacerbated in individuals with inherited genetic diseases, such at thalassemia, which is characterized by an abnormality in the rate of haemoglobin synthesis. People with neurological dysfunction or kidney disease are unusually susceptible to lead exposure. The neurological system and the kidney are the targets of lead intoxication and as a result persons with neurological dysfunction or kidney disease may become overburdened at much lower threshold concentrations to elicit manifestations of lead intoxication (ATSDR 1993d).

Lead has been classified by the US EPA as a probable human carcinogen, but a quantitative cancer risk estimate was not derived due to the lack of understanding of the toxicological properties of lead. The US EPA also identified that neurobehavioural effects are a more sensitive and toxicologically relevant endpoint than cancer.