# Presentation: 757082

## Aging and Toxic Response

**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

- 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?

**Research Goals**

**Methods/Approach**

**Impact and Outcomes**

**Conclusions / Future Directions**

**Science Question**

- 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.

-  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 body’s 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.

-  The research of ORD scientists and grantees has been used by the Office of Children’s 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.
-  ORD’s 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.

**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.*

**Physiological changes with age affect these compartments and processes**

**Criteria for Choosing Environmental Agents**

**Concentration of Toxicant at the Biological Target**
**(e.g., receptor, tissue compartment, cell)**

| Existing human or animal models |
| --- |
| Chemical/physical properties, e.g., lipophilicity |
| Metabolic activation / deactivation, transporters |
| Receptor-mediation |
| Outcome-based criteria (toxicities) |
| Critical dose-metric |

**Toxicants can affect one or more of these organs and tissues**

| Additional Sources of Variability |
| --- |
| Genetic predisposition |
| Disease Status |
| Lifestyle |
| Cumulative Exposure |
| Nutrition |
| Occupation |

**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.

-  **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.**

**Health Effects Research: Determine the contribution of changes in physiological processes that limit the body’s 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 body’s 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.

**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**

| Absorption | • Minor changes in gastric absorption; reduced gastric acid production
• Changes in dermal absorption, barrier function
• Reduced lung volume, elasticity |
| --- | --- |
| Distribution | •Change in body composition
  Decreased total body water in older adults 
  Decreased muscle mass, increased relative adipose level 
• Plasma protein binding  – decrease in plasma albumin (acidic compounds), increase in α1-glycoprotein (basic compounds)
• Potential for increased permeability of blood-brain barrier with concurrent disease (diabetes, hypertension, cerebrovascular ischemia) |
| Metabolism | • Reduced liver volume and liver blood flow
• Minor effects on Phase I and II metabolism in healthy aging
 Significant metabolic changes with age-associated diseases 
 Decline in specific cytochrome P450 content
• Polypharmacy - interactions of environmental toxicants with therapeutic compounds, herbal supplements, and diet due to shared metabolic pathways, and/or induction or inhibition of metabolic enzymes and/or transporters. |
| Elimination | • Reduced renal function
      Reduced blood flow           Reduced glomerular filtration
      Reduced renal MFO activity, inducibility
• Reduced biliary excretion
• Reduced pulmonary excretion |

- 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.

- 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

**Changes in PK Processes with Aging that May Affect Susceptibility**