Report assesses health implications of perchlorate ingestion

01/25/05

WASHINGTON -- A new report by the National Academies' National Research Council on the health effects of perchlorate, a chemical that in high doses can decrease thyroid function in humans and that is present in many public drinking-water supplies, says daily ingestion of up to 0.0007 milligrams per kilogram of body weight can occur without adversely affecting the health of even the most sensitive populations. That amount is more than 20 times the "reference dose" proposed by the U.S. Environmental Protection Agency in a recent draft risk assessment.

Environmental releases of perchlorate -- a component of rocket fuel and fireworks -- have been discovered in 35 states, and more than 11 million people have perchlorate in their drinking water at concentrations of 4 parts per billion or higher. As it considers a first-ever national standard for acceptable levels of perchlorate in drinking water, EPA has issued a series of draft risk assessments, each containing a reference dose upon which a standard could be based. Controversies over the scientific conclusions reached in the risk assessments, however, led the federal government to request that the National Research Council review the issue.

The most recent EPA risk assessment, published in 2002, proposes a daily reference dose of 0.00003 milligrams per kilogram (mg/kg) of body weight, which the agency said would correspond to a drinking-water concentration of 1 part per billion based on certain assumptions about body weight and daily water consumption. The committee that wrote the Research Council report did not include a corresponding drinking-water concentration with its reference dose because the assumptions that are used to derive drinking-water standards involve public-policy choices that were beyond the committee's charge.

Perchlorate inhibits the thyroid's uptake of iodide, which is essential for the production of thyroid hormones. One potential consequence of that effect is low thyroid hormone production, or hypothyroidism. EPA has predicted that an ultimate consequence of that effect is the development of thyroid tumors -- a conclusion the agency based on the occurrence of a few thyroid tumors in rats exposed to perchlorate. The committee disagrees with EPA's conclusion and thinks that perchlorate exposure is unlikely to lead to thyroid tumors in humans. Humans are much less susceptible to disruption of thyroid function or formation of thyroid tumors than rats, and therefore the way rats responded to perchlorate exposure is not a good indicator of how humans would react.

In the past, high doses of perchlorate were used to treat patients with hyperthyroidism, or excessive thyroid hormone production, but a few patients had serious adverse reactions, and the use of perchlorate in this manner was largely abandoned. More recently, patients with hyperthyroidism have been treated effectively and safely with moderate doses of perchlorate for up to two years. Perchlorate has been administered to healthy subjects in doses ranging from 0.007 mg/kg to 9.2 mg/kg per day with no changes in thyroid hormone production to suggest any adverse effect on thyroid function. On the basis of these and other studies, the committee concluded that a perchlorate dose of more than 0.4 mg/kg per day would be required to adversely affect thyroid hormone production and cause hypothyroidism. However, the dose required to cause hypothyroidism in pregnant women, infants, children, and people with low iodide intake or pre-existing thyroid dysfunction might be lower.

There have been studies on the health effects of human populations exposed to perchlorate, but they were studies in which data were available for geographic areas, not for individuals. Relationships observed at the geographic level may not apply at the individual level, and therefore such studies cannot provide direct evidence of causation. They can support a possible association between two events, however, which allowed the committee to reach some conclusions based on those studies. In particular, the committee found that the available evidence is not consistent with an association between exposure to perchlorate in the drinking water at concentrations up to 120 parts per billion during pregnancy and changes in thyroid hormone production in normal-birth weight, full-term newborn infants. The evidence is insufficient to determine whether or not there is an association between perchlorate exposure and adverse neurodevelopmental outcomes in children.

Because of the weaknesses in the studies of the health effects in human populations exposed to perchlorate in the environment, the committee recommended against using them to determine a reference dose. Rather, it recommended using a 2002 clinical study in which groups of healthy men and women were administered perchlorate in daily doses ranging from 0.007 mg/kg to 0.5 mg/kg for 14 days. The study found no statistically significant inhibition of iodide uptake by the thyroid at the 0.007 mg/kg daily dose. The findings in this study are supported by the results in four other studies of healthy subjects, including a six-month study. The committee recommended that an uncertainty factor of 10 be applied to the 0.007 mg/kg per day level to protect the fetuses of pregnant women who might have hypothyroidism or iodide deficiency. This results in the 0.0007 mg/kg per day reference dose recommended in the report.

One committee member, concerned over the adequacy of the data, dissented and thought that an additional uncertainty factor of three should be applied. The rest of the 15-member committee responded by pointing out that the key study examined the effects of four dose levels in a total of 37 subjects, and that four other studies had remarkably similar results. The committee was unanimous in all other findings and recommendations.

The committee emphasized that the reference dose should be based on inhibition of iodide uptake by the thyroid in humans, which is not an adverse effect but the key biochemical event that precedes any health effects caused by perchlorate exposure. The committee called this a "conservative, health-protective approach to perchlorate risk assessment." It also suggested studies that have the potential to more precisely define "safe" perchlorate exposures. Future findings could result in the need to adjust the reference dose recommended in the report, the committee acknowledged.

The study was sponsored by the U.S. Environmental Protection Agency, the U.S. Department of Defense, the U.S. Department of Energy, and NASA. The National Research Council is the principal operating arm of the National Academy of Sciences and the National Academy of Engineering. It is a private, nonprofit institution that provides science and technology advice under a congressional charter. A committee roster follows.

Copies of HEALTH IMPLICATIONS OF PERCHLORATE INGESTION will be available later this winter from the National Academies Press; tel. 202-334-3313 or 1-800-624-6242 or on the Internet at HTTP://WWW.NAP.EDU. Reporters may obtain a pre-publication copy from the Office of News and Public Information (contacts listed above).

[ This news release and report are available at HTTP://NATIONAL-ACADEMIES.ORG ]

NATIONAL RESEARCH COUNCIL
Division on Earth and Life Studies
Board on Environmental Studies and Toxicology

COMMITTEE TO ASSESS THE HEALTH IMPLICATIONS OF PERCHLORATE INGESTION

RICHARD B. JOHNSTON JR., M.D. (CHAIR)
Associate Dean
Research Development;
Professor
Department of Pediatrics
University of Colorado School of Medicine; and
Executive Vice President for Academic Affairs
National Jewish Medical and Research Center
Denver

STACY BRANCH, D.V.M., PH.D.
Consultant and Owner
Djehuty Biomed Consulting; and
Adjunct Associate Professor
Department of Animal Science
School of Agriculture and Environmental Science
North Carolina Agricultural and Technical University
Clayton

GREGORY BRENT, M.D.
Professor of Medicine and Physiology
David Geffen School of Medicine
University of California, Los Angeles;
Chief
Endocrinology and Diabetes Section; and
Director of Fellowship Program
Endocrinology, Metabolism, and Diabetes Section
VA Greater Los Angeles Healthcare System
Los Angeles

ROSALIND BROWN, M.D.
Director of Clinical Trials Research
Endocrine Division
Children's Hospital
Boston

CHARLES C. CAPEN, D.V.M.,
PH.D.
Distinguished University Professor
Ohio State University
Columbus

DAVID COOPER, M.D.
Professor of Medicine - Endocrinology
Johns Hopkins University School of Medicine;
Professor of International Health
Johns Hopkins University Bloomberg School of Public Health;
Director
Thyroid Clinic
Johns Hopkins Hospital; and
Director
Division of Endocrinology
Sinai Hospital of Baltimore
Baltimore

RICHARD CORLEY, PH.D.
Staff Scientist, Biomonitoring and Biological Modeling Group
Pacific Northwest National Laboratory
Richland, Wash.

LINDA D. COWAN, PH.D.
George Lynn Cross Research Professor
Department of Biostatistics and Epidemiology
University of Oklahoma Health Sciences Center
Oklahoma City

JAMES C. LAMB IV, PH.D., J.D.
Senior Vice President
The Weinburg Group, Inc.
Washington, D.C.

GEORGE LAMBERT, M.D.
Director
Center for Childhood Neurotoxicology and Exposure Assessment
Environmental and Occupational Health Sciences Institute
Rutgers University
Piscataway

R. MICHAEL MCCLAIN, PH.D.
Toxicology Consultant
McClain Associates; and
Adjunct Professor
Environmental and Occupational Health Sciences Institute
University of Medicine and Dentistry of New Jersey
Randolph

SUSAN L. SCHANTZ, PH.D.
Professor of Toxicology
University of Illinois
Urbana-Champaign

DALENE STANGL, PH.D.
Director
Institute of Statistics and Decision Sciences, and
Professor of Statistics and Public Policy
Duke University
Durham, N.C.

LYNETTE STOKES, M.P.H., PH.D.
Chief
Bureau of Hazardous Material and Toxic Substances
Environmental Health Administration
Department of Health
Washington, D.C.

ROBERT D. UTIGER, M.D.
Clinical Professor of Medicine
Harvard University School of Medicine
Boston

STAFF

ELLEN MANTUS, PH.D.
Study Director

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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