Computational Toxicology and Methods Development Laboratory
Background
In its efforts to provide public health guidance
to state and local health departments, other federal agencies, health
professionals, and the public on the health effects of environmental
pollutants, the Agency for Toxic Substances and Disease Registry
(ATSDR) relies on the latest advances in computational toxicology.
Housed within the Division of Toxicology and Environmental
Medicine, the Computational Toxicology
Laboratory (CompTox Lab) supports the agency mission by developing
and applying state-of-the-art computational toxicology methods such
as physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD)
modeling, quantitative structure-activity relationship (QSAR)
methods, and benchmark dose (BMD) models. The developed PBPK,
QSAR and BMD models are then implemented to determine and characterize
risks from exposure to hazardous substances.
CompTox Lab Services
PBPK models mathematically describe
absorption, distribution, storage, metabolism, and excretion of
chemicals as they are
introduced
into the body. The models help predict human toxicity following
exposure to hazardous substances. The most common modeling applications
involve predictions based on information derived from animals (across
species extrapolations) or exposure routes (across route extrapolations)
other than those being studied.
The current CompTox Lab library of PBPK models
includes the following chemicals:
- Trichloroethylene
- Carbon tetrachloride
- Dichloroethylene
- Methylene chloride
- Benzene
- Dioxin
- PCBs
- Lead
- Methyl mercury
- Chlorpyrifos
- Parathion
- Tetrachloroethylene
- Chloroform
- Vinyl chloride
- Acetone
QSAR techniques are used to estimate
the toxicity of poorly characterized substances based on comparisons to well-studied substances having similar chemical structures. TOPKAT, a commercially
available software, is used to predict toxicity endpoints based on chemical structure. The software predicts carcinogenicity in
male and female mice and rats, developmental toxicity, mutagenicity, log octanol/water partition coefficients, oral LD50s, and oral chronic
LOAELs in rats.
Benchmark dose (BMD) modeling is an
approach in which the dose response is modeled and the lower confidence
bound for a dose at a specified response level is calculated. BMD
is used to derive health guidance values by estimating the dose of a toxic substance without appreciable
risk or adverse health outcome. This is an alternative method to
the traditional threshold model approach (NOAEL/LOAEL) that is commonly
used for non-carcinogenic risk assessment of hazardous substances.
Highlights
Emergency response and Bioterrorism
- QSAR is currently being conducted on a subset of chemicals from
the CDC/ATSDR Chemical Terrorism List. Preliminary results suggest
QSAR may be useful for providing limited data for use in acute
exposure scenarios for chemical terrorism substances without available
toxicity data. We are investigating the potential use of this
data for establishing reoccupancy levels.
- In response to an urgent congressional request for information
on the toxicity of 2-chloro-6-fluorophenol (one of the chemicals
spilled at a chemical factory in New York), QSAR analysis conducted
in the CompTox Lab predicted the chemical to be a mild skin sensitizer
but noncarcinogenic and not a developmental toxicant. These results
were provided to the New York State Department of Health (DOH),
Bureau of Toxic Substance Assessment and follow-up consultations
ensued.
Research
- Based on a QSAR analysis performed by CompTox Lab scientists,
the National Toxicology Program (NTP) initiated a chronic carcinogenicity
study of a styrene-acrylonitrile trimer, a drinking water contaminant
in the Toms River area.
- International collaborations with TNO Nutrition and Food Research,Netherlands
continue using PBPK/PD models developed in the lab to investigate
the mechanisms of interaction between trichloroethylene, benzene,
lead, and methyl mercury.
- A PBPK/PD model was developed to predict the joint toxicity
between chlorpyrifos and parathion in the rat. The model simulations
indicated that additivity is obtained at oral levels below 0.08
mg/kg of each chemical.
- CompTox Lab scientists are collaborating with researchers at
University of Georgia to develop mechanistically based PBPK models
to investigate the interaction between perchlorate and PCBs.
Site-specific
- CompTox Lab faculty developed PBPK models for
36
PCB congeners. Models were used to assess the impact of contaminated
fish consumption on PCB blood levels in Anniston, Alabama. Results
show that the contribution of consumption of contaminated fish
to PCB blood levels is congener specific.
Children’s Health
- Child-based PBPK models for methylene chloride and tetrachloroethylene
were developed to determine if age-specific groups are more sensitive
to chemical exposures than adults. Thus far, results of the modeling
efforts show that neonates are 3 to 10-fold more susceptible to
chemical toxicity via inhalation and oral routes than adults exposed
to identical environmental conditions. Model validation data is
needed to complete these models.
Laboratory Goals
- Support ATSDRs mission by using state-of-the-art decision-support
tools for toxicologic evaluation of chemicals and their mixtures.
- Provide a scientifically credible, timely, and cost-effective
alternative to traditional toxicology testing.
Contact Information
For more information, contact
Agency for Toxic Substances and Disease Registry
Division of Toxicology and Environmental Medicine
1600 Clifton Road NE, Mailstop F-32
Atlanta, GA 30333
Phone: 1-800-CDC-INFO • 888-232-6348 (TTY)
Email: cdcinfo@cdc.gov
This page was updated on
08/07/2008