Request for Information (RFI): The Impact of Environmental Lead Exposure on Cognition and Bone Function

Notice Number: NOT-TW-15-002

Key Dates
Release Date: February 10, 2015
Response Date: June 30, 2015

Related Announcements
None

Issued by
Fogarty International Center (FIC)
National Institute on Aging (NIA)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Environmental Health Sciences (NIEHS)

Purpose

The above components of the NIH are requesting information regarding the potential of lead exposure earlier in life to contribute to the loss of cognition and bone function later in life. 

Background
In December 2013, the G8 Health Ministries convened a Dementia Summit in London (G8).  The summit participants called upon member countries to strengthen efforts to better meet the challenges that dementia presents to society.  In 2010 dementia affected more than 35 million persons worldwide and the number is expected to double over the next 20 years.  This challenge has resulted in major research investments to identify risk factors for dementia that would allow the development of new therapies and strategies to delay the onset of dementia.  In this regard, common neurodegenerative pathologies do not explain most of the variation in cognitive decline with age (Boyle, 2013).  One factor that is known to cause cognitive loss early in life has not been so well studied to determine whether it contributes to cognitive loss later in life.  That factor is environmental lead exposure.

Lead exposure in the United States generally increased from the end of World War II through the mid 1970’s, largely the result of use of lead in gasoline as an octane booster combined with the increased number of automobiles in use. This exposure began to decrease following the phase out and eventual elimination of lead in gasoline, as a result of regulatory actions by the U.S. EPA.  At the time these regulations were promulgated over 200,000 tons of lead were consumed as gasoline antiknock additives each year. In large part as a result of these regulations to eliminate lead additives in gasoline, the number of children with elevated blood lead levels in the U.S. population decreased by about 98%. Blood lead levels in adults also decreased. Anyone living during the period 1945-1980 accumulated much more lead in their bodies than would otherwise have been the case. Some population groups had substantial elevations in blood lead, such as police officers, professional drivers, parking attendants and garage mechanics. Children exposed to deteriorating lead paint had even greater blood lead levels.  Many of these persons are now entering the later periods of life with associated risk of Alzheimer’s disease and loss of cognitive functions. There is concern that increased lead body burdens may contribute to the loss of cognitive function later in life, and evidence has clearly shown that lead reduces cognitive function early in life.

A similar situation is believed to have occurred in most other countries since use of lead in gasoline was widespread before the U.S. EPA took action.  Subsequent to the EPA lead regulation most other countries also eliminated the use of leaded gasoline but not until there already had been widespread over exposure to lead in the general population.  In this regard, an editorial in Neurology called attention to the need to more fully understand the effects of cumulative lead exposure on cognition (Weisskopf 2006).  In addition, primates fed a lead-rich formula as infants 23 years later developed tauopathy, an Alzheimer’s Disease-like pathology (Bihaqi 2013).

Apart from the potential impact of environmental lead exposure on cognition there is also concern that since most lead stored in the body is found in bone, that such exposure may adversely impact bone function later in life.  Among these concerns are: the possible impact on bone density of lead accumulated in bone; the possible adverse impact of lead stored in bone on the success of bone grafts; and the possibility that lead accumulated in bone could be a risk factor for bone fractures.  Many postmenopausal women in particular take bisphosphonate medication to prevent osteoporosis, and little is known about the interplay between these medications and mobilizations of lead from bone.

Information Requested
In view of the above, NIH is requesting information from the scientific community in the following topic areas and also unique opportunities to conduct studies in these areas:

  • Measures of Lead Body Burden in Aging Persons:
  • Measures of blood lead in aging adults
  • Measures of bone lead in aging adults
  • Urban/rural differences in bone lead levels
  • Measures of lead levels in bone samples from hip and knee replacements
  • Measures of blood lead in postmenopausal women
  • Measures of brain tissue lead in aging adults now decreased
  • Correlations between Lead Exposure and Cognitive Function
  • Correlations between blood lead levels and tests of cognitive function/Alzheimer’s Disease
  • Correlations between bone lead levels and tests of cognitive function/Alzheimer’s Disease
  • Cognitive function/Alzheimer’s Disease in persons previously employed in the lead industries
  • Cognitive function in persons with a history of high exposure to lead-containing automobile exhausts
  • Correlations between bone or blood lead levels and brain images associated with Alzheimer’s Disease and cognitive function
  • History of childhood lead exposure and risk of Alzheimer’s Disease and/or cognitive loss later in life
  • Impact of lead exposure on future risk of cognitive loss and/or Alzheimer’s Disease
  • Correlations between brain lead levels and earlier tests of cognitive function in aging adults now deceased

Effects of Lead on Bone Structure and Function:

  • Correlations between bone lead levels and risk of bone fracture
  • Impact of bone lead levels on success of bone grafts
  • Effects of bone lead levels on measures of bone density
  • Determining the half-life of lead contamination in bone
  • Impact of lead levels on vitamin D and PTH metabolism
  • Impact of lead on kidney function (once lead is mobilized from bone can the kidneys eliminate it?)
  • Effects of lead on bone formation and bone quality

Effects of strategies to prevent osteoporosis on lead mobilization from bone:

  • Effect of calcium supplements on lead release from bone
  • Effect of vitamin D supplementation on lead release from bone
  • Effect of bisphosphonate use on lead release from bone and on bone functioning
  • Effect of exercise on lead release from bone

General

  • Ongoing studies of Alzheimer’s Disease progression that could yield useful data with the addition of more information about prior lead exposure
  • Genetic factors that may increase the risk of cognitive loss associated with lead exposure
  • Collections of brain tissue in studies of Alzheimer’s Disease pathology that might also be sampled for lead content
  • Collections of bone tissues that might also be sampled for lead content
  • Case-control studies comparing blood lead or bone lead measurements in persons with and without Alzheimer’s Disease
  • Case-control studies comparing lead levels in bone samples from hip and knee replacements in persons with Alzheimer’s Disease compared to bone samples from matched controls without Alzheimer’s Disease (preferably age and gender matched)
  • Estimates of populations at risk from Alzheimer’s Disease as a result of accumulated lead exposure
  • Models for investigating developmental lead neurotoxicity as a risk factor in adult neurodegenerative disease
  • Longitudinal studies of the rate at which lead is lost from bone and what happens to lead stored in bone during bone remodeling

Responses

Responses will be accepted through June 30, 2015.  Please email your responses to the above inquiries to: FICleadcognitionandbonefunction@mail.nih.gov

In your response, please also provide a contact name and email address to enable potential follow-up communication by NIH staff. 

This request is for information and planning purposes only and should not be construed as a solicitation or as an obligation on the part of the Federal Government. The NIH does not intend to make any awards based on responses to this RFI or to otherwise pay for the preparation of any information submitted or for the Government's use of such information.

The NIH will use the information submitted in response to this RFI at its discretion and will not provide comments to any responder's submission. However, responses to the RFI may be reflected in future funding opportunity announcements. The information provided will be analyzed and may appear in reports. Respondents are advised that the Government is under no obligation to acknowledge receipt of the information received or provide feedback to respondents with respect to any information submitted.  No proprietary, classified, confidential, or sensitive information should be included in your response. The Government reserves the right to use any non-proprietary technical information in any resultant solicitation(s).

References
G8 Dementia Summit Communique. Published 11 December 2013. https://www.gov.uk/government/publications/g8-dementia-summit-agreements/g8-dementia-summit-communique

Boyle PA, Wilson RS, Yu L, Barr AM, Honer WG, Schneider JA, Bennett DA. Much of late life cognitive decline is not due to common neurodegenerative pathologies. Ann Neurol. 2013 Sep;74(3):478-89.

Weisskopf MG, Myers G. Cumulative effect of lead on cognition: is bone more revealing than blood? Neurology. 2006 Nov 14;67(9):1536-7.

Bihaqi SW, Zawia NH. Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb). Neurotoxicology. 2013 Dec;39:95-101.

Inquiries

If you have specific inquires about this RFI, direct them to:

Kenneth Bridbord, M.D., MPH
Fogarty International Center (FIC)
Telephone: 301-496-1415
Email: bridbork@ficod.fic.nih.gov