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Applications of Toxicogenomic
     Technologies to Predictive Toxicology
            and Risk Assessment
	        The new field of toxicogenomics presents a potentially powerful set of tools to better
understand health effects from exposures to toxicants in the environment. However, realizing
the potential of this nascent field to improve public health decisions will require a concerted
effort to generate data, to make use of existing data, and to study data in new ways—an ef-
fort requiring funding, interagency coordination, and data management strategies.



     T
               he Human Genome Project has
               been one of the most important
               biological research projects of
all time. The project produced a complete
sequence of the chemical makeup of genetic
information contained in the DNA in human
cells. It also supported the development of
many new “genomic technologies,” including
research tools that allow scientists to look
at the complete set of genes in a single            and legal concerns.
experiment (see Box 1). These technologies                This National Research Council re-
allow scientists to study, for example, what        port, produced at the request of the National
combinations of genes lead to susceptibility to     Institute of Environmental Health Sciences
particular diseases, such as cancer.
       Now, scientists are applying genomic       Box 1. Genomics refers to an array of methods to
                                                  study genes and genomes, including:
technologies to study the potentially adverse
                                                     • gene sequencing, which applies various bio-
effects of pharmaceutical drugs and indus-
                                                         chemical and bioinformatics tools to study the
trial and environmental chemicals on human               DNA of organisms.
health. The new science of toxicogenomics            • genotype analysis that looks at genetic varia-
provides valuable information on the effects             tion between individuals and in populations.
of drugs and chemicals at a molecular level,         • epigenetics that studies reversible changes in
providing a more complete understanding of               gene function that can be passed from parent to
their potential toxic effects. Integrating such          child.
information into risk assessments could sig-      Transcriptomics (or gene expression profiling) is the
nificantly enhance public health and regula-      study of mRNA—the intermediary step between genes
tory decisions.                                   and proteins that indicates genes that are active (as op-
       However, leveraging the potential of       posed to dormant or silent).
toxicogenomics will require a coordinated         Proteomics is the study of proteomes, which are col-
effort to generate more data, make multiple       lections of proteins. Proteins carry out the functions
uses of existing data sources, and study data     encoded by genes.
in new ways, perhaps on a scale approach-         Metabolomics is the study of the products of biologi-
ing that of the Human Genome Project.             cal processes. Such products change in response to
Toxicogenomics also raises some ethical           such things as nutrition, stress, and disease states.
(NIEHS), provides a broad overview of the benefits                   For example, gene expression profiling shows
of toxicogenomics, the challenges in achieving                 how exposures to chemicals cause cells in the body
them, and potential approaches to overcoming the               to turn on some genes and turn off others, which
challenges.                                                    can change the proteins that are produced by the
                                                               cell (see figure below for information on genes and
Potential to Enhance Toxicology                                proteins). The on-off pattern of the many genes in
                                                               cells varies for different chemicals, creating a char-
      Genes—sections of a person’s DNA in the
                                                               acteristic pattern or “signature”—the genetic calling
nucleus of cells that code for cellular functions—
                                                               card of the toxicant. Proteomics and metabolomics
are essential to the development of the human body
                                                               allow comparable analysis of protein and metabolite
and the maintenance of bodily processes through-
                                                               changes.
out life. Not all genes are “expressed,” or actively
                                                                     Potential applications of toxicogenomics in-
involved in a cellular function, at all times. Instead,
                                                               clude improved methods for screening potential tox-
genes may be “turned on” and “turned off” in
                                                               icants, monitoring individuals’ exposures to specific
response to environmental agents or other factors
                                                               toxicants, tracking cellular responses to different
during a person’s lifetime. Such changes in gene ex-
                                                               exposure levels, assessing the mechanisms by which
pression can adversely affect bodily processes and
                                                               toxicants cause diseases, and predicting variability
cause illness.
                                                               in individuals’ sensitivity to various toxicants.
      Traditional toxicology typically evaluates re-
sponses such as death, disease causation, or micro-
scopic changes in the cells of animals and people.
                                                               Use of Toxicogenomics in Risk Assessment
Toxicogenomics produces molecular-level data                         This report recommends that regulatory agen-
about genes and how specific toxicants affect gene,            cies enhance efforts to incorporate toxicogenomic
protein, and metabolite patterns. Toxicogenom-                 data into risk assessment. However, these data are
ics enables investigators to link toxicant-specific            not currently ready to replace existing required
molecular changes with responses in cells, tissues,            testing regimens in risk assessment and regulatory
and organisms.                                                 toxicology. The report recommends that toxi-
                                                                              cogenomic technologies be further
                                                                              developed to increase capabilities in
                                                                              the following areas:
                                                                              Exposure Assessment: Toxicogenom-
                                                                              ics should be developed further to
                                                                              identify genetic patterns associated
                                                                              with exposure to individual chemicals
                                                                              and, perhaps, to chemical mixtures.
                                                                              Standardized methods for identifying
                                                                              these signatures will be needed.
            NA




                                                                           Hazard Screening: Toxicogenomics
          mR




                                                                           should be developed further to en-
                                                                           able rapid screening of the potential
                                                                           toxicity of chemicals for drug devel-
                                                                           opment purposes and for determining
                                                                           the toxicity of chemicals found in the
                                                                           environment. Upon validation and de-
                                                                           velopment of adequate databases, tox-
                                                                           icogenomic screening methods should
                                                                           be integrated into relevant chemistry
A genome is all of the DNA in an organism. Genes contained within this DNA regulatory and safety programs.
code for proteins, which perform cellular functions. When a person is exposed
to chemicals, cells in the body respond by switching on some genes and          Variability in Susceptibility: Suscep-
switching off others, thus changing the proteins that are produced by the cell. tibility to toxic effects of chemical
exposures varies from person to person. Toxi-                                               Microarrays are one
cogenomic technologies offer the potential to use                                           of the primary tools
genetic information to identify susceptible subpopu-                                        of toxicogenom-
lations and assess differences in susceptibility in                                         ics. A microarray
                                                                                            is a chip, based on
larger populations. Toxicogenomics would then be                                            those used by the
able to inform regulatory processes to susceptibility                                       electronics industry,
within a population.                                                                        that can “look” at
                                                                                            thousands of human
Mechanistic Information: Toxicogenomics can
                                                                                            genes simultaneously.
offer insight on the mechanisms by which chemi-                                             Using microarrays,
cal exposures cause diseases. Tools and approaches                                          scientists can literally
for elucidating the mechanisms involved in toxic re-                                        see which genes are
sponses should continue to be developed to enhance                                          activated, repressed,
risk assessment.                                                                            or unchanged by a
                                                                                            chemical.
Cross-Species Extrapolation: Traditional toxicology
makes use of animal studies, but animal-to-human           possible to date about the potential effects of expo-
toxicity extrapolations introduce uncertainty into risk    sure to toxic substances in early development.
assessment. Toxicogenomics offers the potential to         Mixtures: Humans are frequently exposed to mul-
significantly enhance the confidence of such extrapo-      tiple chemicals, and it is difficult to determine the
lations by using human cells. Using toxicogenomics         effect of each chemical in a mixture. It is unlikely
to analyze species differences in toxicity will help ex-   that toxicogenomic signatures will be able to deci-
plain some of the molecular bases for such differences.    pher all interactions among complex mixtures, but
Dose-Response Relationships: Toxicogenomics has            it should be possible to use mechanism-of-action
the potential to improve understanding of dose-re-         data to design toxicogenomic experiments to better
sponse relationships—the understanding of how a            inform this area of study.
given level of exposure to a toxicant affects toxic
responses in an individual. This understanding is          The Need for a “Human Toxicogenomics
particularly useful for evaluating the effects of low      Initiative”
levels of exposure.                                              The report notes that toxicogenomic technolo-
Developmental Exposures: Relatively little is              gies have matured to the point where they are widely
known about the health impacts of fetal and early          accepted by the scientific community and viewed as
life exposures to many chemicals in current use.           producing high-quality data. In order to realize the
Because of their sensitivity, toxicogenomic tech-          full potential of toxicogenomic technologies, how-
nologies are expected to reveal more than has been         ever, the report recommends that NIEHS and other
Box 2. Human Toxicogenomics Initiative (HTGI)
      The report recommends that NIEHS cooperate with other stakeholders in exploring the feasibility and objec-
tives of a “Human Toxicogenomics Initiative” (HTGI). The initiative should include:
1.  reation and management of a large, public database for storing and integrating the results of toxicoge-
   C
   nomic analyses with conventional toxicity-testing data.
2.  ssembly of toxicogenomic and conventional toxicological data on a large number (hundreds) of com-
   A
   pounds into a single database. This includes the generation of new toxicogenomic data from humans and
   animals for a number of compounds on which other types of data already exist, as well as the consolida-
   tion of existing data.
3.  reation of a national biorepository for storing human clinical and epidemiological samples.
   C
4.  urther development of bioinformatics tools (e.g., software, analysis, and statistical tools).
   F
5.  onsideration of the ethical, legal, and social implications of collecting and using toxicogenomic data and
   C
   samples.
6.  oordinated subinitiatives to evaluate the application of toxicogenomic technologies to the assessment of
   C
   risks associated with chemical exposures.
stakeholders explore the feasibility and objectives of      viduals from being dissuaded from participating
a “Human Toxicogenomics Initiative (HTGI).”                 in research or undergoing the genetic testing that
      The most important focuses of such an initia-         is the first step in individualized risk assessment
tive would be to collect more data on chemicals us-         and risk reduction. The protection of individuals
ing toxicogenomics and to create a public database.         should be considered when developing large-scale
This public database would facilitate sharing and           biorepositories and databases. Additionally, special
use of the volumes of data, which will vastly exceed        efforts should be made to address the impacts of
the data involved in the Human Genome Project.              toxicogenomic research and findings on vulnerable
More data on a large number of compounds are                populations.
needed so that comparisons can be made and data                    Toxicogenomics is likely to play a role in
can be mined to identify important relationships.           occupational, environmental, and pharmaceutical
      The Human Toxicogenomics Initiative would             regulation and litigation. Regulatory agencies and
support data collection and coordinate the creation         courts should give appropriate weight to the valida-
and management of a large-scale database that would         tion, replication, consistency, sensitivity and speci-
use systems biology approaches and tools to integrate       ficity of methods when deciding whether to rely on
the results of toxicogenomic analyses with conven-          toxicogenomic data.
tional toxicity-testing data. The resulting publicly-
accessible HTGI data resource would strengthen              Education and Training in Toxicogenomics
the utility of toxicogenomic technologies in toxicity             It is essential that education and training in
assessment and thus enable better prediction of health      toxicogenomics become a continuous, ongoing
risks associated with existing and newly developed          process that reflects the rapid developments in new
compounds (see Box 2).                                      toxicogenomic technologies. Education and training
                                                            programs relevant to toxicogenomic applications in
Ethical, Legal, and Social Issues
                                                            predictive toxicology will require cross-discipline
      The report also addresses the ethical, legal,         collaboration. Information about the scientific and
and social implications of toxicogenomics. When             ethical, legal, and social issues toxicogenomics
toxicogenomic data are linked to clinical and               involves should be communicated to the general
epidemiological information, it is critical that the        public, susceptible subgroups, health profession-
privacy, confidentiality, and security of individuals’      als, government regulators, attorneys and judges,
information be adequately protected. Safeguarding           the media, scientists in training, scientists on the
this information will advance important individual          periphery of toxicogenomics, and institutions that
and societal interests, and will also prevent indi-         participate in toxicogenomics research.

Committee on Applications of Toxicogenomic Technologies to Predictive Toxicology: David C. Christiani
(Chair), Harvard School of Public Health; Cynthia A. Afshari, Amgen, Inc.; John M. Balbus, Environmental
Defense; James S. Bus, The Dow Chemical Company; Bruce F. Demple, Harvard School of Public Health;
Linda E. Greer, Natural Resources Defense Council; Sharon L.R. Kardia, University of Michigan, Ann Arbor;
George D. Leikauf, University of Pittsburgh Graduate School of Public Health; Daniel C. Liebler, Vanderbilt
University School of Medicine; Gary E. Marchant, Arizona State University College of Law; John Quack-
enbush, Harvard School of Public Health; Kenneth S. Ramos, University of Louisville; Mark A. Rothstein,
University of Louisville School of Medicine; Raymond E. Stoll, Stoll  Associates, LLC; Roger G. Ulrich,
Calistoga Pharmaceuticals Inc.; Helmut Zarbl, University of Medicine and Dentistry of New Jersey; Marilee
Shelton-Davenport (Study Director) and Karl Gustavson (Program Officer), National Research Council.
This report brief was prepared by the National Research Council based on the committee’s
report. For more information or copies, contact the Board on Environmental Studies and
Toxicology at (202) 334-3060 or visit http://nationalacademies.org/best. Copies of Applications of
Toxicogenomic Technologiess to Predictive Toxicology and Risk Assessment are available from the
National Academies Press, 500 Fifth Street, NW, Washington, D.C. 20001; (800) 624-6242; www.
nap.edu.

           Permission granted to reproduce this brief in its entirety with no additions or alterations.
                                   © 2007 The National Academy of Sciences

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Toxicogenomic technologies final

  • 1. Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment The new field of toxicogenomics presents a potentially powerful set of tools to better understand health effects from exposures to toxicants in the environment. However, realizing the potential of this nascent field to improve public health decisions will require a concerted effort to generate data, to make use of existing data, and to study data in new ways—an ef- fort requiring funding, interagency coordination, and data management strategies. T he Human Genome Project has been one of the most important biological research projects of all time. The project produced a complete sequence of the chemical makeup of genetic information contained in the DNA in human cells. It also supported the development of many new “genomic technologies,” including research tools that allow scientists to look at the complete set of genes in a single and legal concerns. experiment (see Box 1). These technologies This National Research Council re- allow scientists to study, for example, what port, produced at the request of the National combinations of genes lead to susceptibility to Institute of Environmental Health Sciences particular diseases, such as cancer. Now, scientists are applying genomic Box 1. Genomics refers to an array of methods to study genes and genomes, including: technologies to study the potentially adverse • gene sequencing, which applies various bio- effects of pharmaceutical drugs and indus- chemical and bioinformatics tools to study the trial and environmental chemicals on human DNA of organisms. health. The new science of toxicogenomics • genotype analysis that looks at genetic varia- provides valuable information on the effects tion between individuals and in populations. of drugs and chemicals at a molecular level, • epigenetics that studies reversible changes in providing a more complete understanding of gene function that can be passed from parent to their potential toxic effects. Integrating such child. information into risk assessments could sig- Transcriptomics (or gene expression profiling) is the nificantly enhance public health and regula- study of mRNA—the intermediary step between genes tory decisions. and proteins that indicates genes that are active (as op- However, leveraging the potential of posed to dormant or silent). toxicogenomics will require a coordinated Proteomics is the study of proteomes, which are col- effort to generate more data, make multiple lections of proteins. Proteins carry out the functions uses of existing data sources, and study data encoded by genes. in new ways, perhaps on a scale approach- Metabolomics is the study of the products of biologi- ing that of the Human Genome Project. cal processes. Such products change in response to Toxicogenomics also raises some ethical such things as nutrition, stress, and disease states.
  • 2. (NIEHS), provides a broad overview of the benefits For example, gene expression profiling shows of toxicogenomics, the challenges in achieving how exposures to chemicals cause cells in the body them, and potential approaches to overcoming the to turn on some genes and turn off others, which challenges. can change the proteins that are produced by the cell (see figure below for information on genes and Potential to Enhance Toxicology proteins). The on-off pattern of the many genes in cells varies for different chemicals, creating a char- Genes—sections of a person’s DNA in the acteristic pattern or “signature”—the genetic calling nucleus of cells that code for cellular functions— card of the toxicant. Proteomics and metabolomics are essential to the development of the human body allow comparable analysis of protein and metabolite and the maintenance of bodily processes through- changes. out life. Not all genes are “expressed,” or actively Potential applications of toxicogenomics in- involved in a cellular function, at all times. Instead, clude improved methods for screening potential tox- genes may be “turned on” and “turned off” in icants, monitoring individuals’ exposures to specific response to environmental agents or other factors toxicants, tracking cellular responses to different during a person’s lifetime. Such changes in gene ex- exposure levels, assessing the mechanisms by which pression can adversely affect bodily processes and toxicants cause diseases, and predicting variability cause illness. in individuals’ sensitivity to various toxicants. Traditional toxicology typically evaluates re- sponses such as death, disease causation, or micro- scopic changes in the cells of animals and people. Use of Toxicogenomics in Risk Assessment Toxicogenomics produces molecular-level data This report recommends that regulatory agen- about genes and how specific toxicants affect gene, cies enhance efforts to incorporate toxicogenomic protein, and metabolite patterns. Toxicogenom- data into risk assessment. However, these data are ics enables investigators to link toxicant-specific not currently ready to replace existing required molecular changes with responses in cells, tissues, testing regimens in risk assessment and regulatory and organisms. toxicology. The report recommends that toxi- cogenomic technologies be further developed to increase capabilities in the following areas: Exposure Assessment: Toxicogenom- ics should be developed further to identify genetic patterns associated with exposure to individual chemicals and, perhaps, to chemical mixtures. Standardized methods for identifying these signatures will be needed. NA Hazard Screening: Toxicogenomics mR should be developed further to en- able rapid screening of the potential toxicity of chemicals for drug devel- opment purposes and for determining the toxicity of chemicals found in the environment. Upon validation and de- velopment of adequate databases, tox- icogenomic screening methods should be integrated into relevant chemistry A genome is all of the DNA in an organism. Genes contained within this DNA regulatory and safety programs. code for proteins, which perform cellular functions. When a person is exposed to chemicals, cells in the body respond by switching on some genes and Variability in Susceptibility: Suscep- switching off others, thus changing the proteins that are produced by the cell. tibility to toxic effects of chemical
  • 3. exposures varies from person to person. Toxi- Microarrays are one cogenomic technologies offer the potential to use of the primary tools genetic information to identify susceptible subpopu- of toxicogenom- lations and assess differences in susceptibility in ics. A microarray is a chip, based on larger populations. Toxicogenomics would then be those used by the able to inform regulatory processes to susceptibility electronics industry, within a population. that can “look” at thousands of human Mechanistic Information: Toxicogenomics can genes simultaneously. offer insight on the mechanisms by which chemi- Using microarrays, cal exposures cause diseases. Tools and approaches scientists can literally for elucidating the mechanisms involved in toxic re- see which genes are sponses should continue to be developed to enhance activated, repressed, risk assessment. or unchanged by a chemical. Cross-Species Extrapolation: Traditional toxicology makes use of animal studies, but animal-to-human possible to date about the potential effects of expo- toxicity extrapolations introduce uncertainty into risk sure to toxic substances in early development. assessment. Toxicogenomics offers the potential to Mixtures: Humans are frequently exposed to mul- significantly enhance the confidence of such extrapo- tiple chemicals, and it is difficult to determine the lations by using human cells. Using toxicogenomics effect of each chemical in a mixture. It is unlikely to analyze species differences in toxicity will help ex- that toxicogenomic signatures will be able to deci- plain some of the molecular bases for such differences. pher all interactions among complex mixtures, but Dose-Response Relationships: Toxicogenomics has it should be possible to use mechanism-of-action the potential to improve understanding of dose-re- data to design toxicogenomic experiments to better sponse relationships—the understanding of how a inform this area of study. given level of exposure to a toxicant affects toxic responses in an individual. This understanding is The Need for a “Human Toxicogenomics particularly useful for evaluating the effects of low Initiative” levels of exposure. The report notes that toxicogenomic technolo- Developmental Exposures: Relatively little is gies have matured to the point where they are widely known about the health impacts of fetal and early accepted by the scientific community and viewed as life exposures to many chemicals in current use. producing high-quality data. In order to realize the Because of their sensitivity, toxicogenomic tech- full potential of toxicogenomic technologies, how- nologies are expected to reveal more than has been ever, the report recommends that NIEHS and other Box 2. Human Toxicogenomics Initiative (HTGI) The report recommends that NIEHS cooperate with other stakeholders in exploring the feasibility and objec- tives of a “Human Toxicogenomics Initiative” (HTGI). The initiative should include: 1. reation and management of a large, public database for storing and integrating the results of toxicoge- C nomic analyses with conventional toxicity-testing data. 2. ssembly of toxicogenomic and conventional toxicological data on a large number (hundreds) of com- A pounds into a single database. This includes the generation of new toxicogenomic data from humans and animals for a number of compounds on which other types of data already exist, as well as the consolida- tion of existing data. 3. reation of a national biorepository for storing human clinical and epidemiological samples. C 4. urther development of bioinformatics tools (e.g., software, analysis, and statistical tools). F 5. onsideration of the ethical, legal, and social implications of collecting and using toxicogenomic data and C samples. 6. oordinated subinitiatives to evaluate the application of toxicogenomic technologies to the assessment of C risks associated with chemical exposures.
  • 4. stakeholders explore the feasibility and objectives of viduals from being dissuaded from participating a “Human Toxicogenomics Initiative (HTGI).” in research or undergoing the genetic testing that The most important focuses of such an initia- is the first step in individualized risk assessment tive would be to collect more data on chemicals us- and risk reduction. The protection of individuals ing toxicogenomics and to create a public database. should be considered when developing large-scale This public database would facilitate sharing and biorepositories and databases. Additionally, special use of the volumes of data, which will vastly exceed efforts should be made to address the impacts of the data involved in the Human Genome Project. toxicogenomic research and findings on vulnerable More data on a large number of compounds are populations. needed so that comparisons can be made and data Toxicogenomics is likely to play a role in can be mined to identify important relationships. occupational, environmental, and pharmaceutical The Human Toxicogenomics Initiative would regulation and litigation. Regulatory agencies and support data collection and coordinate the creation courts should give appropriate weight to the valida- and management of a large-scale database that would tion, replication, consistency, sensitivity and speci- use systems biology approaches and tools to integrate ficity of methods when deciding whether to rely on the results of toxicogenomic analyses with conven- toxicogenomic data. tional toxicity-testing data. The resulting publicly- accessible HTGI data resource would strengthen Education and Training in Toxicogenomics the utility of toxicogenomic technologies in toxicity It is essential that education and training in assessment and thus enable better prediction of health toxicogenomics become a continuous, ongoing risks associated with existing and newly developed process that reflects the rapid developments in new compounds (see Box 2). toxicogenomic technologies. Education and training programs relevant to toxicogenomic applications in Ethical, Legal, and Social Issues predictive toxicology will require cross-discipline The report also addresses the ethical, legal, collaboration. Information about the scientific and and social implications of toxicogenomics. When ethical, legal, and social issues toxicogenomics toxicogenomic data are linked to clinical and involves should be communicated to the general epidemiological information, it is critical that the public, susceptible subgroups, health profession- privacy, confidentiality, and security of individuals’ als, government regulators, attorneys and judges, information be adequately protected. Safeguarding the media, scientists in training, scientists on the this information will advance important individual periphery of toxicogenomics, and institutions that and societal interests, and will also prevent indi- participate in toxicogenomics research. Committee on Applications of Toxicogenomic Technologies to Predictive Toxicology: David C. Christiani (Chair), Harvard School of Public Health; Cynthia A. Afshari, Amgen, Inc.; John M. Balbus, Environmental Defense; James S. Bus, The Dow Chemical Company; Bruce F. Demple, Harvard School of Public Health; Linda E. Greer, Natural Resources Defense Council; Sharon L.R. Kardia, University of Michigan, Ann Arbor; George D. Leikauf, University of Pittsburgh Graduate School of Public Health; Daniel C. Liebler, Vanderbilt University School of Medicine; Gary E. Marchant, Arizona State University College of Law; John Quack- enbush, Harvard School of Public Health; Kenneth S. Ramos, University of Louisville; Mark A. Rothstein, University of Louisville School of Medicine; Raymond E. Stoll, Stoll Associates, LLC; Roger G. Ulrich, Calistoga Pharmaceuticals Inc.; Helmut Zarbl, University of Medicine and Dentistry of New Jersey; Marilee Shelton-Davenport (Study Director) and Karl Gustavson (Program Officer), National Research Council. This report brief was prepared by the National Research Council based on the committee’s report. For more information or copies, contact the Board on Environmental Studies and Toxicology at (202) 334-3060 or visit http://nationalacademies.org/best. Copies of Applications of Toxicogenomic Technologiess to Predictive Toxicology and Risk Assessment are available from the National Academies Press, 500 Fifth Street, NW, Washington, D.C. 20001; (800) 624-6242; www. nap.edu. Permission granted to reproduce this brief in its entirety with no additions or alterations. © 2007 The National Academy of Sciences