[Federal Register Volume 72, Number 191 (Wednesday, October 3, 2007)]
[Notices]
[Pages 56358-56360]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-19462]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES


National Toxicology Program (NTP); Host Susceptibility Program 
(HSP); Genetic Variation and the Basis for Individual Susceptibility to 
Environmental Toxicant Associated Disease: Request for Information

AGENCY: National Institute of Environmental Health Sciences (NIEHS), 
National Institutes of Health (NIH).

ACTION: Request for information.

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SUMMARY: The NTP is developing the Host Susceptibility Program (HSP), a 
new research program, to identify and functionally validate genes 
associated with environmental exposure. This program will make 
available NTP expertise and resources to investigate the genetic basis 
for population-level differences in susceptibility to environmental 
toxicants and/or disease based upon gene and environment interactions. 
This research will be designed to ultimately lead to a better 
understanding of why some individuals are more susceptible than others 
to exposure to an environmental toxicant resulting in disease and 
morbidity. Asthma, cardiovascular disease, cancer, diabetes, and 
obesity are examples of diseases associated with multiple interacting 
genes that are influenced by exposure to environmental agents. Through 
this Request for Information, extramural and intramural scientists are 
invited and encouraged to provide information and comment relevant to 
this proposed programmatic research approach in order to help guide 
further development and refinement of the goals of the NTP HSP. 
Information on this initiative can be submitted electronically through 
the HSP Request for Information Web site at: (http://ntp.niehs.nih.gov/go/32130 ) or by contacting Dr. John E. French (see FOR FURTHER 
INFORMATION CONTACT below).

DATES: The deadline for response is October 31, 2007.

ADDRESSES: Responses can be submitted electronically at the HSP Request 
for Information Web site: http://ntp.niehs.nih.gov/go/32130.

FOR FURTHER INFORMATION CONTACT: Other correspondence should be 
directed to Dr. John E. French, Host Susceptibility Program, NIEHS, 
P.O. Box 12233, MD EC-17, Research Triangle Park, NC 27709, (fax) 919-
541-0947, (email) [email protected]. Courier address: Dr. John E. 
French, Host Susceptibility Program, 111 T.W. Alexander Drive, Building 
101, Room F167, Research Triangle Park, NC 27709.

SUPPLEMENTARY INFORMATION: 

Background

    The NTP was established as a cooperative effort to (1) coordinate 
toxicology testing programs within the federal government, (2) 
strengthen the science base in toxicology, (3) develop improved testing 
methods, and (4) provide information about potentially toxic chemicals 
to health, regulatory, and research agencies, scientific and medical 
communities, and the public. To meet these goals, NTP designs and 
conducts large-scale laboratory animal research and testing programs 
and analyzes and reports their findings to assess potential hazards to 
human health from exposure to environmental chemicals.
    Recently, the NTP led and funded a haplotype mapping project with 
Perlegen Sciences to resequence 15 isogenic strains of mice selected 
for their potential genetic diversity. Along with the public sequence 
of isogenic C57BL/6J, analysis of 16 sequenced strains has revealed, 
conservatively, more than 8 million single nucleotide polymorphisms in 
this initial analysis of laboratory and wild-derived isogenic mouse 
strains (Frazer et al., 2007). Identification and analysis of mouse 
haplotypes will provide a valuable tool for haplotype-phenotype 
association studies in genetically diverse strains that can be used to 
predict human genetic variants of functional significance (http://mouse.perlegen.com/mouse/index.html ). Toward that goal, the NTP is 
developing a multidisciplinary research program on genetic 
susceptibility to environmental exposures. This effort will partner 
extramural and/or intramural researchers with NTP scientists by 
creating research partnerships using NTP R&D contract resources. This 
research program is not a funding opportunity or a grant program.
    The intent of HSP is to provide researchers access to NTP R&D 
contract resources and NTP expertise in public health toxicology. 
Participation by extramural and/or intramural scientists will be based 
on competitive peer

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review of proposed research projects. NTP scientists will work with 
extramural and/or intramural investigators to define and refine the 
most effective and cost-efficient experimental protocols for 
accomplishing the experimental aims and for linking environmental 
exposure with toxicity leading to disease. Development of approved 
projects will proceed sequentially from hypothesis through specific 
aims, based upon a consensus derived experimental plan. Continued 
support of research projects will depend upon satisfactory completion 
of each phase of the research plan.
    Via this partnership, extramural and/or intramural investigators 
will have access to NTP contract resources to investigate the 
relationship between exposure to environmental toxicants and 
development of quantitative measures of toxicity and disease, using 
genetically diverse experimental animal models. Using research 
partnerships, HSP scientists aim to develop the tools and means 
necessary to accomplish the multidisciplinary tasks that are often 
rate-limiting to individual research groups that may be interested in 
investigating environmental toxicant exposure and genetic 
susceptibility to disease and determining allelic variants of causally 
related genes and their potentially dysregulated signaling pathways. 
Once a project has been peer reviewed and approved, NTP staff will 
interact directly with the Principal Investigator(s) (PIs) of the 
approved projects to refine the research using NTP contracted 
resources. NTP R&D contractors will perform approved tasks under the 
direction of NTP staff. Those tasks necessary to accomplish the 
experimental aims of any particular study are expected to vary from 
project to project. In some cases, NTP may only support one or two key 
missing steps necessary to complement the research; in other cases, it 
may be necessary to supply the entire scope of experimental tasks 
needed to complete the specific aims. Examples of tasks that can be 
supported by NTP contracts and staff include, but are not necessarily 
limited to:
     Facilitating animal model selection (multiple-isogenic 
strains, heterogeneous, outbred stocks, etc.).
     Providing strain-specific data on absorption, 
distribution, metabolism, and excretion of metabolic products of 
environmental toxicants.
     Defining or optimizing of exposure route, dose and dose 
schedule of environmental toxicants using range-finding studies to 
determine quantitative measures of acute toxicity in vivo in an 
appropriate animal model.
     Quantitatively identifying variants of toxicity 
(phenotyping) in multiple isogenic strains, genetically engineered 
strains, and/or genetically defined outbred stocks.
     Developing appropriate experimental design protocols for 
toxicity, biomarkers, expression arrays, clinical and histopathology, 
and statistical analysis.
     Acquiring test agent(s) in quantities sufficient for non-
GLP acute and prechronic toxicity investigations, development of 
analytical methods for determination of quantity and purity of test 
substances, production and stability (storage) of dosage forms.
     Developing, optimizing, and conducting study and route 
specific toxicology and toxicity assays for correlation between 
toxicity and histopathologic determinants.
    Output from such collaborative research activities, which may 
include providing biological samples and/or data (genotyping, 
quantitative measures of toxicity, expression phenotypes, etc.), is to 
be made fully available to the originating principal investigator (or 
his/her replacement, in case of withdrawal) for continued support of 
the research project developed within the partnership. Data and samples 
are to be transferred to extramural or intramural collaborators under 
terms of a negotiated NIH Materials Transfer Agreement.

Information Requested

    The NTP is soliciting information from the extramural and 
intramural research communities on the strategies, resources, and tools 
necessary to enable this cooperative research program on genetic 
variation and individual susceptibility to environmental toxicant 
exposure and associated polygenic diseases to progress. Please respond 
online at the HSP Request for Information Web page (http://ntp.niehs.nih.gov/go/32130) to any or all of the following questions by 
October 31, 2007.
    1. In general, what are the utility and limitations of using model 
organisms (e.g., multiple strains of isogenic mice, heterogeneous mouse 
stocks, etc.) to investigate and establish the genetic determinants of 
biological response?
    2. Are there particular environmental toxicants associated with 
human disease where this research approach is immediately applicable 
and useful to the identification of causally related genes and their 
allelic variants?
    3. Similarly, are there particular physiologic or pathogenic 
pathways and/or disease endpoints for which the proposed research 
approach is likely to be especially insightful in advancing our 
understanding of gene-environment interactions?
    4. What computational, statistical, and bioinformatic methodologies 
might be particularly useful for determining toxicity phenotypes and 
identifying associated genes, pathways, and networks?
    5. What high-data content technologies, platforms, and statistical 
approaches might be particularly valuable and critical to elucidating 
the genetic basis for toxicity and disease based upon the experience 
and knowledge gained over the past decade?
    6. Are there high-throughput assays and screens using cell-based 
systems that might be employed to examine the role of genetic variation 
in human exposure?
    7. Are in vitro and in vivo assays and genetic models for 
functional validation of genes useful in permitting orthologous human 
genes and their allelic variants to be identified and tested in large-
scale human populations with defined environmental exposures?
    8. Is the competitive research partnership approach described for 
the HSP using NTP R&D expertise in toxicology and contract resources 
viable and of general interest to researchers interested in these 
questions? Why or why not?
    9. Are there specific concerns over intellectual property or 
research collaboration issues in a research partnership that should be 
addressed and negotiated?
    All responses to individual questions within this Request for 
Information are optional. The information collected will be analyzed 
and considered for use in the further development of the NTP HSP. The 
summarized data (without identifiers) may appear in internal reports. 
Although the NIH will provide safeguards to prevent the release of 
identifying information, there is no guarantee of confidentiality. This 
Request for Information is for planning purposes and should not be 
construed as a solicitation for applications or as an obligation on the 
part of the Government. The Government will not pay for the preparation 
of any information submitted or for the Government's use of that 
information. Acknowledgement of receipt of responses will not be made, 
nor will respondents be notified of the Government's assessment of the 
information received. No basis for claims against the Government shall 
arise as a result of response to this Request for Information, or in 
the

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Government's use of such information as part of our evaluation process.

Reference

    Frazer, K.A., E. Eskin, H.M. Kang, M.A. Bogue, D.A. Hinds, E.J. 
Beilharz, R.V. Gupta, J. Montgomery, M.M. Morenzoni, G.B. Nilsen, 
C.L. Pethiyagoda, L.L. Stuve, F.M. Johnson, M.J. Daly, C.M. Wade, 
and D.R. Cox. A sequence-based variation map of 8.27 million SNPs in 
inbred mouse strains. Nature 2007 July 29 Epub.

    Dated: September 24, 2007.
Samuel H. Wilson,
Acting Director, National Institute of Environmental Health Sciences 
and National Toxicology Program.
[FR Doc. E7-19462 Filed 10-2-07; 8:45 am]
BILLING CODE 4140-01-P