Savannah River Site Health Effects Subcommittee (SRSHES) Meeting

Final Meeting Minutes
January 10, 2002

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In general, heavy metals are attracted to sulfur, often have charged ions that easily bind to other molecules, and result in various oxidation states. The kidney serves as a target organ for toxins due to its extremely high blood flow of 25% of cardiac output. As a result, heavy metals that enter the blood stream will travel to the kidney. The primary function of the kidney is to concentrate waste products, including heavy metals. Transport and binding sites in the kidney are present in proximal tubules and metals may alter the structure of the protein and membrane. These changes may result in longterm residual effects. Waste products filter through the nephrons of the kidney, collect in a duct, travel to the urine and are eventually excreted. The majority of heavy metals elicit adverse effects in proximal tubules. Uranium and mercury cause toxicity in the same portion of the proximal tubules.

In general, heavy-metal toxicity differs among individuals based on age, dose and genetic predisposition to disease. In particular, effects from the five heavy metals most commonly in the environment are outlined as follows:

• Lead toxicity primarily causes nausea, vomiting and other gastrointestinal (GI) effects in adults, but more serious impacts of central nervous system (CNS) dysfunction and IQ deficits occur in children. Epidemiologic studies that demonstrated effects to children were the main reason lead was removed from gasoline in the United States. Lead toxicity also causes anemia in both adults and children, but this condition probably affects females more frequently than males. High-dose chronic exposure will produce kidney toxicity in the proximal tubules, but these impacts are not immediately seen at low enough doses. Regeneration can occur in approximately 30-90 days; however, effects can appear 20-50 years post-exposure. Persons on farms and other rural areas typically receive lower exposures of lead than those in urban areas. High-level exposures primarily result from smelting and other occupational sources, but children who consume paint chips can receive high doses as well. Effects to the kidney can be seen with a blood lead level of 50-65 µg/dL. In addition to age, dose and genetics, lead toxicity also differs by form. For example, tetraethyl lead in gasoline has an extremely high bioavailability rate and will cause more adverse effects than inorganic lead on wheel weights.
  
• Arsenic toxicity causes increased pigmentation and thickening of the skin, facial swelling as well as nausea, abdominal pain, diarrhea and other GI upsets at high doses. Arsenic in drinking water can cause increased skin cancer, but high-dose acute poisoning can result in death to the kidney tubules, other cells or the exposed individual. All U.S. regulatory limits for non-cancer effects from arsenic are based on a study completed in Taiwan several decades ago. However, these data are controversial due to the age, methodology and population of the study.
  
• Cadmium toxicity primarily impacts the proximal tubule in the kidney. This effect results in increased calcium and protein in the urine, which may have implications for people with osteoporosis. At high doses of cadmium, GI disturbances occur and regeneration is possible. The most common sources of exposure to persons are from Nickel-Cadmium (Ni-Cad) batteries.
  
• Mercury toxicity primarily impacts the kidney, but CNS dysfunction, excessive excitement, intention tremors, and other behavioral abnormalities are more common. Mercury toxicity is also associated with pain in the feet and hands and can contribute to kidney disease. Depending on the dose, the kidney may regenerate. Mercury is primarily excreted in the urine, but it can be detected in the urine and blood depending on the time interval between exposure and biological sampling.
  
• Uranium toxicity can injure or cause death to proximal tubules in the kidney. For a 150- pound adult, depending on the dose the kidney may regenerate, ATSDR uses 0.002 mg/kg/day as the minimum risk level for uranium.

Exposure limits of heavy metals established by regulatory agencies are considered to be safe because modifying and safety factors are incorporated into models to account for sensitive populations, racial/ethnic groups or other differences among persons. Examples of site-specific research on heavy metals are outlined as follows. A study was completed at Fernald that found statistically significant elevations of both kidney and bladder disease in 8,496 persons, but evidence of excess diabetes mellitus was not detected. A study was conducted among 2,627 individuals at the Oak Ridge Reservation to determine potential effects from mercury to the community. Of the 2.4 million pounds of mercury released, 500,000 pounds were discharged to a waterway that runs through the site. Data showed no statistical differences in the mean adjusted urinary mercury levels between exposed and non-exposed groups and no evidence of excess mercury in hair between consumers and non-consumers of fish. Although hair analysis was used for the Oak Ridge study and research at other sites, the American Medical Association opposes this methodology in determining the need for medical therapy.

Chelation is another controversial area because the therapy should only be used to treat heavy-metal poisoning. For example, an elevated blood lead level in children is defined as 10 µg/dL and above, but chelation therapy should not be administered unless the level is 100 µg/dL and higher. Dr. Markiewicz encouraged SRSHES to contact him by telephone at 404/498-0335 or e-mail at kvm4@cdc.gov to obtain web site addresses for studies or additional information on heavy metals. In the meantime, however, he raised the possibility of making a follow-up presentation that would more narrowly focus on effects from heavy metals most frequently detected at SRS. More details on the Fernald and Oak Ridge studies could be included in the presentation.

Discussion.
Mr. Renard appreciated Dr. Markiewicz’s offer to present mercury toxicity data from other sites in the future, but he noted that fish advisories and other information on mercury have already been collected for the SRS region. He explained that SRSHES was most interested in mercury toxicity due to the high rates of kidney dialysis in the region. In addition to these data, Dr. Markiewicz hoped epidemiologic studies of mercury in blood, hair and urine would be conducted in the future to detect elevated levels and increases in kidney disease. Associating mercury exposure and kidney disease is extremely difficult with existing evidence. Dr. Wilson added that heavy metal toxicity is not the cause for virtually any of the kidney disease cases among his patients in the SRS region. Diabetes has been found to be the major culprit of kidney disease, particularly among blacks.

Dr. McClain followed up on this comment and asked for more details about the relationship between genetic predisposition and heavy-metal toxicity. Dr. Markiewicz confirmed that the race/ethnicity or genetic composition of an individual can cause heavy metals to react differently. The Human Genome Project, genetic markers, and other advances in molecular biology will eventually allow scientists to analyze an individual’s genetic composition and estimate the probability of disease development from heavy metal exposure.

Dr. Umansky questioned whether access to care could play a role in toxicity differences among racial/ethnic groups. For example, persons of color generally seek care at a later time in the disease progression than whites. As a result, preventive strategies would be less effective in these populations. Dr. Markiewicz agreed that lack of access to care is a concern in the United States, but improper diagnosis of heavy-metal poisoning is a common occurrence as well. In an effort to address this issue, ATSDR is educating physicians and emergency room personnel about the importance of taking an environmental history on patients. Ms. Leslie Todorov of NCEH noted that research on detoxification systems among different racial/ethnic groups is new and cutting-edge. She pointed out that more solid data need to be collected before assumptions can be made.