Impacts of Selected Cumulative Pesticide ExposureRisk Projects

1
Impacts of Selected Cumulative Pesticide
Exposure/Risk Projects Crofton,K.M.1,
DeVito,M.J.1, Herr,D.W.1, Hughes,M.F.1,
Lowitt,A.2, Baetcke,K.2, Moser,V.C.1,
Padilla,S.1, Setzer,R.W.1, Gennings,C.4,
Tornero,R.3 1 NHEERL, 3NERL, Office of Research
and Development, and 2Office of Pesticide
Programs, U. S. Environmental Protection Agency,
4Virginia Commonwealth University, Richmond,
Virginia
Results/Conclusions
Pyrethroid Cumulative Risk Project
Carbamate Cumulative Risk Project

• Carbamates
• All carbamates produce dose- and time-dependent
  inhibition of cholinesterase and decreased motor
  activity.
• The experimental mixture data will provide
  critical data regarding potential interactions.
• Follow up with PBPK models allow integration of
  biological data over a wide range of potential
  exposure scenarios.

Science Questions

• Goal 2 Exposure to Dose to Response Assessment
  
• Develop PBPK model for individual pyrethroids
• Develop analytical procedures
• Develop, parameterize and validate PBPK model
• In vitro metabolism and dermal absorption of
  individual pyrethroids
• Scale to human exposure
• Limited in vivo studies to test PBPK model
• Develop PBPK model for mixtures of pyrethroids

• The carbamate studies are designed to
• Determine if the interaction of these seven
  pesticides in a mixture is dose-additive
  following acute exposure.
• Compare all cholinesterase assays using two
  different methods, a spectrophotometric method
  and a radiometric method.
• Use motor activity as an indicator of
  neurological and behavioral impact of the
  pesticides.
• Correlate the behavioral and neurochemical
  endpoints for a better understanding of the
  biological effect of various levels of
  cholinesterase inhibition.
• Approach
• First, collect data on the individual carbamates.
  
• Time-course of cholinesterase inhibition in both
  the brain and red blood cells.
• Dose-response assessment using brain and red
  blood cell cholinesterase inhibition as well as
  motor activity.
• The mixture studies will be conducted using a
  fixed-ratio ray design.
• This allows for testing along a range of mixture
  doses wherein the proportion of pesticides within
  the mixture is the same.
• One proportion tested will be based on projected
  environmental exposures from food, water, and
  air.
• Another proportion tested will be based on the
  relative potency of the pesticides
• We will also measure carbamate levels in tissues
  and work with PBPK modelers in NHEERL and NERL to
  develop a model for cumulative exposure to
  carbamate pesticides. This approach has important
  utility given the relative short biological
  half-lives of the chemicals. Such PBPK models are
  able to simulate intermittent and repeated
  exposures of humans to carbamate pesticides.

• What is the risk of exposure to mixtures of
  carbamate or pyrethroid insecticides?
• What are appropriate exposure paradigms, and
  what statistical models can be used to analyze
  these mixture data?

• Pyrethroids
• All pyrethroids produced dose-dependent
  depression in motor activity relative potencies
  ranged from 0.5 (?-cyhalothrin) to 70
  (resmethrin).
• These data suggest a common endpoint for use in
  cumulative risk calculations.
• In vitro clearance data improves PBPK rat model.

Research Goals
The FQPA requires consideration of cumulative
exposures in determining the risk from exposure
to pesticides with a common mode of action. The
current default for determining the cumulative
risk to pesticide mixtures assumes
dose-additivity of chemicals with a common
mode-of-action. Previous efforts to determine
cumulative risk of pesticides with a common mode
of action have been hampered by a number of
uncertainties. These obstacles include a lack of
neurotoxicology mixture studies, and the
unavailability of efficient statistical models
with which to analyze mixtures data. The
current effort has been developed based on past
work by NHEERL scientists in evaluating
environmentally relevant mixtures of PHAHs,
organophosphates (OP), and OP-carbamate
mixtures. Two ongoing efforts aim to decrease
the uncertainties in the cumulative risk
assessments for carbamate and pyrethroid
pesticides.
In Vitro Clearance of Pyrethroids
Impact and Outcomes

• Impact and Outcomes
• This work will generate data and models for use
  in determining the cumulative risk of carbamates
  and pyrethroids.
• These products will allow the Agency to conduct
  state-of-the-art cumulative assessments for
  carbamates and pyrethroids.
• Uncertainties in the cumulative risk assessments
  for these two economically important classes of
  pesticides will be reduced.

Dose-response assessment for motor activity and
cholinesterase activity for two carbamates. For
these pesticides, the magnitude of activity
decreases is greater than the cholinesterase
inhibition measured in the brain, illustrating
the importance of evaluating both endpoints.
Table 1. Carbamate pesticides, rat oral LD50 and
dosages used.

• Goal 1 Neurotoxicity Studies
• Dose response assessment for behavioral toxicity
  of pyrethroids
• Acute - Individual chemicals
• Develop relative potency factors (administered
  dose vs. tissue dose)
• Mixtures - Assess assumption of additivity
  (Gennings et al, 2004)

Generic PBPK model structure for pyrethroids
Pyrethroid Dose-effect Functions
Relative Potencies for Pyrethroids
Future Directions

• Specific aims
• To test the hypothesis of additivity.
• Test the effects of mixtures based on
  environmentally relevant exposures (relative
  doses based on known human exposures).
• Integrate the experimental neurotoxicology data
  with PBPK models and in vitro mechanistic data.

• Carbamates
• Conduct fixed-ray design mixture studies.
• Collect tissue level data for selected carbamates
  for use in kinetic modeling.
• Complete PBPK models for individual chemicals as
  well as mixture.
• Pyrethroids
• Complete PBPK models for single chemicals.
• Adjustment of relative potencies by tissue dose
  from the PBPK models, two of which have been
  completed.
• Develop PBPK model for mixtures.
• Assess dose additivity using tissue dose.
• Extrapolate model(s) to humans.
• All Chemicals
• Work with OPP and NERL staff to design mixtures
  of pyrethroids or carbamates based on food
  residue and household residue (non-food)
  exposures.
• Future work will include testing a series of
  relevant mixtures, and analyzing the
  neurotoxicology data for additivity.

References

• Gennings C, Carter WH Jr, Carney EW, Charles GD,
  Gollapudi BB, Carchman RA. (2004) A novel
  flexible approach for evaluating fixed ratio
  mixtures of full and partial agonists. Toxicol.
  Sci. 80134-150.
• ? Gray AJ, Rickard J (1982) The toxicokinetics of
  deltamethrin in rats after intravenous
  administration of a toxic dose. Pestic. Biochem.
  Physiol. 18205-215.

Dose-Response assessment of 7 Carbamate
Insecticides using Brain Cholinesterase
Inhibition as an Endpoint Brain cholinesterase
was assessed using two different methods, the
radiometric method (left panel) and the Ellman
method (right panel). The radiometric method is
superior for analysis of tissues from carbamate
treated animals because that method limits
reactivation and is less variable.