8 research outputs found
An Upper Bound for Exposure Variability
Presented at the Annual Society of Toxicology meetin
Dose response from high throughput gene expression studies and the influence of time and cell line on inferred mode of action by ontologic enrichment
<table><tbody><tr>
<td>Presented
at the Annual Society of Toxicology meeting</td></tr></tbody></table
Risk-Based High-Throughput Chemical Screening and Prioritization using Exposure Models and in Vitro Bioactivity Assays
We present a risk-based
high-throughput screening (HTS) method
to identify chemicals for potential health concerns or for which additional
information is needed. The method is applied to 180 organic chemicals
as a case study. We first obtain information on how the chemical is
used and identify relevant use scenarios (e.g., dermal application,
indoor emissions). For each chemical and use scenario, exposure models
are then used to calculate a chemical intake fraction, or a product
intake fraction, accounting for chemical properties and the exposed
population. We then combine these intake fractions with use scenario-specific
estimates of chemical quantity to calculate daily intake rates (iR;
mg/kg/day). These intake rates are compared to oral equivalent doses
(OED; mg/kg/day), calculated from a suite of ToxCast in vitro bioactivity
assays using in vitro-to-in vivo extrapolation and reverse dosimetry.
Bioactivity quotients (BQs) are calculated as iR/OED to obtain estimates
of potential impact associated with each relevant use scenario. Of
the 180 chemicals considered, 38 had maximum iRs exceeding minimum
OEDs (i.e., BQs > 1). For most of these compounds, exposures are
associated
with direct intake, food/oral contact, or dermal exposure. The method
provides high-throughput estimates of exposure and important input
for decision makers to identify chemicals of concern for further evaluation
with additional information or more refined models
Rapid Prototyping of Physiologically-Based Toxicokinetic (PBTK) Models
Presented at the Annual Society of Toxicology meetin
Risk-Based High-Throughput Chemical Screening and Prioritization using Exposure Models and in Vitro Bioactivity Assays
We present a risk-based
high-throughput screening (HTS) method
to identify chemicals for potential health concerns or for which additional
information is needed. The method is applied to 180 organic chemicals
as a case study. We first obtain information on how the chemical is
used and identify relevant use scenarios (e.g., dermal application,
indoor emissions). For each chemical and use scenario, exposure models
are then used to calculate a chemical intake fraction, or a product
intake fraction, accounting for chemical properties and the exposed
population. We then combine these intake fractions with use scenario-specific
estimates of chemical quantity to calculate daily intake rates (iR;
mg/kg/day). These intake rates are compared to oral equivalent doses
(OED; mg/kg/day), calculated from a suite of ToxCast in vitro bioactivity
assays using in vitro-to-in vivo extrapolation and reverse dosimetry.
Bioactivity quotients (BQs) are calculated as iR/OED to obtain estimates
of potential impact associated with each relevant use scenario. Of
the 180 chemicals considered, 38 had maximum iRs exceeding minimum
OEDs (i.e., BQs > 1). For most of these compounds, exposures are
associated
with direct intake, food/oral contact, or dermal exposure. The method
provides high-throughput estimates of exposure and important input
for decision makers to identify chemicals of concern for further evaluation
with additional information or more refined models
Risk-Based High-Throughput Chemical Screening and Prioritization using Exposure Models and in Vitro Bioactivity Assays
We present a risk-based
high-throughput screening (HTS) method
to identify chemicals for potential health concerns or for which additional
information is needed. The method is applied to 180 organic chemicals
as a case study. We first obtain information on how the chemical is
used and identify relevant use scenarios (e.g., dermal application,
indoor emissions). For each chemical and use scenario, exposure models
are then used to calculate a chemical intake fraction, or a product
intake fraction, accounting for chemical properties and the exposed
population. We then combine these intake fractions with use scenario-specific
estimates of chemical quantity to calculate daily intake rates (iR;
mg/kg/day). These intake rates are compared to oral equivalent doses
(OED; mg/kg/day), calculated from a suite of ToxCast in vitro bioactivity
assays using in vitro-to-in vivo extrapolation and reverse dosimetry.
Bioactivity quotients (BQs) are calculated as iR/OED to obtain estimates
of potential impact associated with each relevant use scenario. Of
the 180 chemicals considered, 38 had maximum iRs exceeding minimum
OEDs (i.e., BQs > 1). For most of these compounds, exposures are
associated
with direct intake, food/oral contact, or dermal exposure. The method
provides high-throughput estimates of exposure and important input
for decision makers to identify chemicals of concern for further evaluation
with additional information or more refined models
Risk-Based High-Throughput Chemical Screening and Prioritization using Exposure Models and in Vitro Bioactivity Assays
We present a risk-based
high-throughput screening (HTS) method
to identify chemicals for potential health concerns or for which additional
information is needed. The method is applied to 180 organic chemicals
as a case study. We first obtain information on how the chemical is
used and identify relevant use scenarios (e.g., dermal application,
indoor emissions). For each chemical and use scenario, exposure models
are then used to calculate a chemical intake fraction, or a product
intake fraction, accounting for chemical properties and the exposed
population. We then combine these intake fractions with use scenario-specific
estimates of chemical quantity to calculate daily intake rates (iR;
mg/kg/day). These intake rates are compared to oral equivalent doses
(OED; mg/kg/day), calculated from a suite of ToxCast in vitro bioactivity
assays using in vitro-to-in vivo extrapolation and reverse dosimetry.
Bioactivity quotients (BQs) are calculated as iR/OED to obtain estimates
of potential impact associated with each relevant use scenario. Of
the 180 chemicals considered, 38 had maximum iRs exceeding minimum
OEDs (i.e., BQs > 1). For most of these compounds, exposures are
associated
with direct intake, food/oral contact, or dermal exposure. The method
provides high-throughput estimates of exposure and important input
for decision makers to identify chemicals of concern for further evaluation
with additional information or more refined models
An Intuitive Approach for Predicting Potential Human Health Risk with the Tox21 10k Library
In vitro–in vivo extrapolation
(IVIVE) analyses translating
high-throughput screening (HTS) data to human relevance have been
limited. This study represents the first report applying IVIVE approaches
and exposure comparisons using the entirety of the Tox21 federal collaboration
chemical screening data, incorporating assay response efficacy and
quality of concentration–response fits, and providing quantitative
anchoring to first address the likelihood of human in vivo interactions
with Tox21 compounds. This likelihood was assessed using a maximum
blood concentration to in vitro response ratio approach (<i>C</i><sub>max</sub>/AC<sub>50</sub>), analogous to decision-making methods
for clinical drug–drug interactions. Fraction unbound in plasma
(<i>f</i><sub>up</sub>) and intrinsic hepatic clearance
(CL<sub>int</sub>) parameters were estimated in silico and incorporated
in a three-compartment toxicokinetic (TK) model to first predict <i>C</i><sub>max</sub> for in vivo corroboration using therapeutic
scenarios. Toward lower exposure scenarios, 36 compounds of 3925 unique
chemicals with curated activity in the HTS data using high-quality
dose–response model fits and ≥40% efficacy gave “possible”
human in vivo interaction likelihoods lower than median human exposures
predicted in the United States Environmental Protection Agency’s
ExpoCast program. A publicly available web application has been designed
to provide all Tox21−ToxCast dose-likelihood predictions. Overall,
this approach provides an intuitive framework to relate in vitro toxicology
data rapidly and quantitatively to exposures using either in vitro
or in silico derived TK parameters and can be thought of as an important
step toward estimating plausible biological interactions in a high-throughput
risk-assessment framework