Aging and Toxic Response

1
Aging and Toxic Response B Sonawane1, M Evans2, M
DeVito2, L Birnbaum2, J Royland2, M Karstadt3, M
Okino4, K Thomas4, J Blancato4, A Geller2 U.S.
Environmental Protection Agency, Office of
Research and Development, 1NCEA, 2NHEERL,
3NHEERL/OPPT, 4NERL
Methods/Approach
Conclusions / Future Directions
Science Question

• Exposure Older adults may experience increased
  risk from environmental stressors due to
  different exposure or activity patterns.
• It is largely unknown whether older adults
  receive different levels, types, or durations of
  exposure compared to younger adults.
• Research into this area is needed to
  characterize the behavior/activity patterns and
  the microenvironments in which older adults live.
  Information is need for relevant subgroups of
  the aging population regarding their activities,
  geographic location, indoor and outdoor air
  exposure, dietary consumption, and data on
  pharmaceutical use and dietary supplements for
  use in source-to-dose exposure modeling.

Pharmacokinetics (PK) - the same external dose
may result in a different internal dose or
distribution to different target organs in older
than in younger adults

• Older adults are more susceptible than younger
  adults to adverse health effects associated with
  exposure to some environmental pollutants.
• To better understand this susceptibility, data
  and models are needed regarding 1)
  behavior/activity patterns and exposure to the
  pollutants in older adults microenvironments 2)
  changes in absorption, distribution, metabolism,
  and excretion with aging 3) alterations in
  reserve capacity that alter the bodys ability to
  compensate for the effects of environmental
  exposures.
• The variability present in the older adult
  population affects activity, exposure,
  pharmacokinetics, and health effects resulting
  from exposure. One of the challenges for this
  evolving research program is to determine which
  older adults are most susceptible and to which
  toxicants.

• What are the biological, behavioral, and
  geographical factors that make older adults more
  susceptible to the effects of environmental
  exposures?
• To what degree is susceptibility due to
  differential activity patterns and exposures to
  toxic environmental agents?
• How do aging-related alterations in
  pharmacokinetics and pharmacodynamics affect the
  susceptibility of older adults?
• Are specific subgroups of older adults more
  vulnerable if so, why?
• What are the high priority exposure and health
  effects for this sub-population?

Physiological changes with age affect these
compartments and processes
Criteria for Choosing Environmental Agents
Initial research will focus on compiling and
assessing existing exposure and activity data for
older adults in order to identify critical data
gaps. Research on exposure and activity across
the lifespan currently includes particulate
matter panel studies, the National Human Activity
Pattern Survey, the National Human Exposure
Assessment Study, and the Consolidated Human
Activity Database. The adequacy of these data
for use in source-to-dose risk assessment models
relevant to older adults will be assessed for
important chemical and biological stressors.
These data will be incorporated into the
Stochastic Human Exposure and Dose Simulation
(SHEDS) modeling system, coupled with the
Exposure-Related Dose Evaluation Model (ERDEM) to
predict the range and distribution of aggregate
and cumulative exposures to identify potentially
susceptible subgroups in the older adult
subpopulation. The information will also be used
to supplement the Exposure Factors Handbook.
Impact and Outcomes
Research Goals
Toxicants can affect one or more of these organs
and tissues

• The research of ORD scientists and grantees has
  been used by the Office of Childrens Health
  Protection to issue fact sheets and health
  advisories related to the air quality index to
  stakeholders in the older adult community
  (http//www.epa.gov/aging).
• ORD has raised the issue of environmental health
  of older adults through symposia to stakeholders
  in the aging community and health care providers
  
• National Council on Aging/American Society of
  Aging (2003)
• American Public Health Association (2003, 2004)
• National Gerontological Nursing Association
  (2004)
• CHEST (2004)
• Gerontological Society of America (2004)
• ORD has also provided expertise to
• Council on State and Territorial Epidemiologists
  (2003, 2004) for development of environmental
  health indicators relevant to older adults for
  their national surveys
• Institute of Medicine (2004) for their
  consideration of future issues in health
  promotion and disease prevention.
• ORDs research program on the exposures that the
  older adult population experiences and the
  subsequent PK and target organ responses will
  provide a better understanding of the
  environmental health risks associated with aging
  in healthy or compromised older adults. This, in
  turn, will provide a scientific rationale for
  decisions on how to appropriately incorporate the
  differential sensitivity of this heterogeneous
  sub-population into health promotion and
  intervention strategies to ameliorate risk from
  environmental exposures.

This research program will generate data on the
exposures that the older adult population
experiences and the subsequent pharmacokinetic
and target organ responses with the goal of
understanding the environmental health risks
associated with aging in healthy or compromised
older adults.
Concentration of Toxicant at the Biological
Target (e.g., receptor, tissue compartment, cell)
Changes in PK Processes with Aging that May
Affect Susceptibility

• Predictive Modeling
• Sensitivity analysis to identify the parameters
  that most affect outcomes, e.g., tissue
  dosimetry, toxicity, for prototype toxicants.
• Predict the magnitude of change in parameters
  necessary in order to have an impact in a dose/or
  response model.
• Address global and correlated changes in the
  model parameters affected by aging
• Collaboration with the Environmental and
  Occupational Health Sciences Institute, Rutgers
  University.
• Use these results to predict who in the older
  adult sub-population may be most susceptible
  based on known changes in PK with age, disease,
  pharmaceutical use
• Identify and prioritize specific areas of
  experimental research for refinement or
  additional data for the next generation of
  models.

Health Effects Research Determine the
contribution of changes in physiological
processes that limit the bodys ability to
maintain homeostasis and respond to injury to
aging-related susceptibility. Research by ORD
and its grantees on the respiratory and
cardiovascular effects of exposure to
particulates and the gastrointestinal effects of
water-borne pathogens has illustrated the
particular susceptibility of older adults to
these contaminants. Further research in ORD
will link exposures and toxicokinetic data to
aging-related changes in toxicodynamic functions
(Masoro, et al 2003 Geller and Zenick Ginsberg,
et al) that may make older adults more
susceptible to adverse health effects resulting
from these exposures. Some alterations in
reserve capacity that alter the bodys ability to
compensate for the effects of environmental
exposures Reduced repair, plasticity,
compensatory capacity Decreased efficacy of DNA
repair, mitochondrial DNA damage. altered gene
expression Reduced anti-oxidant capacity Altered
immune function Changes in neurotransmitter and
receptor levels, calcium homeostasis Health
effects will be measured in molecular, cellular,
animal and human models. Goal Model
age-related pharmacodynamic changes to identify
and prioritize those processes or mechanisms that
confer susceptibility to identify potentially
susceptible sub-groups of older adults.
References

• Evans, MV, et al. 2005. Development of a PBPK
  model to compare differences in disposition of
  TCE and metabolites in adult versus elderly rats.
  The Toxicologist (abstract).
• Geller, AM and Zenick, H submitted. Aging and
  the environment a research framework.
• Ginsburg, G, et al. submitted. PK and PD factors
  that can affect sensitivity to neurotoxic
  sequelae in the elderly.
• Hattis, D. and Russ, A 2003. Role of dosimetric
  scaling and species extrapolation in evaluating
  risks across life stages. II. PK dosimetric
  considerations in old age. Report to US EPA.
• Masoro, EJ, et al. 2003. A report on aging and
  toxic response issues relevant to risk
  assessment. EPA report EPA/600/P-03/004A.
• Royland, J.E. 2004. Abstracts Age-related
  susceptibility A genomics approach. The
  Toxicologist The Genomics of the Aged Brain
  Exp. Gerontol. Differential Gene Expression in
  the Murine Brain Brain Area vs. Age. J.
  Neurochem. 90 (Suppl. 1) 34.

Initial model Trichloroethylene (Evans, et al
2005) further work other volatile organics,
persistent bioaccumulative toxicants, pesticides
Hattis and Russ 2003 Geller and Zenick Ginsburg
et al