# Presentation: 780636

## Robert  L.  Sielken  Jr.,  Ph.D.  

- President
- Sielken  &  Associates  Consulting  Inc.
- 3833  S.  Texas  Avenue,  Suite  230
- Bryan,  TX  77802
- Tel:  979-846-5175;  Fax:  979-846-2671;  Email:  SielkenAssoc@aol.com

- Scientific  Issues
- Associated  with  the  Agency’s  Evaluation  of  the
- Toxicity  Profile  of  Chlorpyrifos

- September  16,  2008

- FIFRA  Scientific  Advisory  Panel  (SAP)  Meeting

## Area  of  Focus:    

- Question  6.
- Points  of  Departure  (PoD)  for  Risk  Assessment

-     There  are  weaknesses  associated  with  each  of  EPA’s  three  proposed  options.
-     An  alternative  to  EPA’s  three  proposed  options  needs  to  be  developed.

## For  Chlorpyrifos:  

- should    be    determined  in  an  appropriate  and  relevant  manner
- and  reflect  biological  significance  and  not  just  statistical  significance.

- Critical  Event:
-     	First  Adverse  Effect
-     	or  Known  Precursor

- Need  to  Account  for  the  Difference  Between  Known  Precursors:
-        (a)  Known  Precursor  that  leads  to  an  Adverse  Effect  with  Certainty
-        (b)  Known  Precursor  that  MIGHT  lead  to  an  Adverse  Effect

- For  Chlorpyrifos:
-      AChE  Inhibition  is  a  Surrogate  for  the Critical  Event:
-     	Candidates:  Brain  or  RBC  or  Heart  AChE  Inhibition

- Candidates  are  Not  necessarily  Precursors.
- Utility  and  Reliability  as  a  Surrogate  Differs  Among  Candidates.
- Relationship  Between  Surrogate  and  Adverse  Effects  Differs   Among  Candidates.

## February  2008  SAP  endorsed

- 	Brain  as  a  Better  Surrogate  than  RBC

## For example, 

- 	Brain  or  RBC  or  Heart  AChE  Inhibition

- Both
- 	Utility  and  Reliability  as  a  Surrogate
- 	and
- 	Relationship  Between  Surrogate  and  Adverse  Effects
- differs  with  the  response  level:
- For example,
- 	10%  for  Brain
- 	30%  for  RBC

## If    NOAELs    are    used    at    all,  

- they    should    be    determined  in  an  appropriate  and  relevant  manner
- and  reflect  biological  significance  and  not  just  statistical  significance.

- While  NOAELs  are  limited  to  one  of  the  experimental  doses,
- it  is  not  true  that  NOAELs  do  not  reflect  experimental  variability.
- Statistical  Significance  reflects  experimental  variability.

- NOAELs  can  play  an  important  role
- --  when there are insufficient data for dose-response modeling
- --  when the dose-response modeling involves unwarranted assumptions
- --  when the benchmark response (BMR) level is too far from the range of experimental responses
- --  when the BMD is highly dependent of the choice of the dose-response model
- --  when the BMDL is highly dependent on the choice of the statistical procedure to use

## Then  BMDs  are  preferred  over  NOAELs.

- When there are sufficient data for dose-response modeling
- When the dose-response modeling does not involve unwarranted assumptions
- When the benchmark response (BMR) level is near the range of experimental responses
- When the BMD is relatively independent of the choice of the dose-response model
- When the BMDL is not highly dependent on the choice of the statistical procedure to use

## BMDs  should  be  duration-route-population  specific  

- 	and  be  determined  from  duration – route - population  specific  data.

| Duration | Route | Population |
| --- | --- | --- |
| Acute | Oral | Adults |
|  |  | Females 13 to 50 |
|  |  | Pregnant Females |
|  |  | Fetuses |
|  |  | Post-Natal/Infants |
|  |  | Children |
| Acute | Dermal | Adults |
|  |  | Females 13 to 50 |
|  |  | Pregnant Females |
|  |  | Fetuses |
|  |  | Post-Natal/Infants |
|  |  | Children |
| Acute | Inhalation | Adults |
|  |  | Females 13 to 50 |
|  |  | Pregnant Females |
|  |  | Fetuses |
|  |  | Post-Natal/Infants |
|  |  | Children |
| Chronic | Oral | Adults |
|  |  | Females 13 to 50 |
|  |  | Pregnant Females |
|  |  | Fetuses |
|  |  | Post-Natal/Infants |
|  |  | Children |
| Chronic | Dermal | Adults |
|  |  | Females 13 to 50 |
|  |  | Pregnant Females |
|  |  | Fetuses |
|  |  | Post-Natal/Infants |
|  |  | Children |
| Chronic | Inhalation | Adults |
|  |  | Females 13 to 50 |
|  |  | Pregnant Females |
|  |  | Fetuses |
|  |  | Post-Natal/Infants |
|  |  | Children |

-     Duration-route-population  specific  exposures  can  be  appropriately  aggregated.
-                 Total  MOE  =  1  /  {  ∑  [  1  /  Duration-route-population  specific  MOE  ]  }
-     Uncertainty  Factors  and  any  FQPA  Factor  can  be  used  after  the  Total  MOE  is  calculated
- 	to  determine  what  Total  MOE  is  acceptable.

- Duration
- = acute,  short  term,  intermediate  term,  chronic
- Route = oral,  dermal,  inhalation
- Population = infants,  children,  adults,  ...

## Betancourt and Carr (2004):

- near the range of experimental responses
- so that
- the BMD is relatively independent
- of the choice of the dose-response model.

- There  are  numerous  pitfalls  in  the  calculation  of  BMDs  and  BMDLs
- which  EPA  has  NOT  avoided.

## Several Aspects of EPA’s BMD and BMDL Calculations are NOT Transparent.

- EPA’s Issue Paper does not document several key components of these calculations:

- a)  The dose-response model used.

- b)  The confidence limit procedure used to determine the BMDL.

- d)  The software being used.

- c)  The assumptions being made.

- Different forms of exponential models.

- Asymptotic Normality or Likelihood Ratio

- Restricted models and restricted parameters.

- PROAST from RIVM in the Netherlands.
- EPA’s BMDS 2.0 beta version which is publically available
- as of April 2008 but the exponential model doesn’t work.
- EPA’s DR Utils – a collection of “subroutines” and not a complete
- working program.

- e)  The specific data values used  -- not just a superset.

- There  are  numerous  pitfalls  in  the  calculation  of  BMDs  and  BMDLs
- which  EPA  has  NOT  avoided.

## Different combinations of alternatives for (a), (b), (c), and (d)

- EPA’s Issue Paper does not document several key components of these calculations:

- a)  The dose-response model used.

- b)  The confidence limit procedure used to determine the BMDL.

- d)  The software being used.

- c)  The assumptions being made.

- are used for different BMDs and BMDLs.
- No Transparency and No Consistency.

- There  are  numerous  pitfalls  in  the  calculation  of  BMDs  and  BMDLs
- which  EPA  has  NOT  avoided.

## EPA’s documents found the need  to clarify that EPA was combining studies.  For example, on page 4 in EPA-HQ-OPP-2005-0162-0505.pdf, EPA states that 

- EPA’s documents found the need  to clarify that EPA was combining studies.  For example, on page 4 in EPA-HQ-OPP-2005-0162-0505.pdf, EPA states that
- “This figure illustrates a place where the Agency’s analysis regarding the BMD50 estimates may not have been clear in the Issue Paper presented to the SAP.  The BMD50 values for PND11 provided in Table 5 of the Issue Paper are from a combined analysis across studies.  Specifically, the following sentence can be found in the Agency’s Issue Paper: ‘The Agency also calculated the BMD50 for the EPA PND11 and PND17 studies (Table 5).’  This sentence should read, ‘The Agency also calculated the BMD50 for the PND11 (combined analysis of EPA and FMC studies) and PND17 studies (EPA only)  (Table 5).’”

- Several Aspects of EPA’s BMD and BMDL Calculations are NOT Transparent.

- There  are  numerous  pitfalls  in  the  calculation  of  BMDs  and  BMDLs
- which  EPA  has  NOT  avoided.

## Pool Data 

- EPA’s New
- Analysis of Combined Studies:

- Pool Data
- from Studies 1 & 2

- Analyze Pooled Data

- Result for Pooled Data

- There  are  numerous  pitfalls  in  the  calculation  of  BMDs  and  BMDLs
- which  EPA  has  NOT  avoided.

## EPA’s New Analysis of Combined Studies:  Does Restricted Modeling

- Several Aspects of EPA’s BMD and BMDL Calculations are NOT Transparent.

- Fitted Models when Models are Restricted
- vs.
- Fitted Models when Models are Unrestricted

- BMD(B)
- Unrestricted

- BMD(A) = BMD(B)
- Restricted

- BMD(A)
- Unrestricted

- Restricted Model

- Unrestricted Model

- Unrestricted Model

- EPA’s New Analysis of Combined Studies:  Does Restricted Modeling

## Several Aspects of EPA’s BMD and BMDL Calculations are NOT Transparent.

- Examples

- Betancourt and Carr (2004):

- Pools
- Females (Repeat PND1-6)
- and
- Males (Acute PND1)

- Reports
- Male BMD10 and BMDL10
- and
- Female BMD10 and BMDL10

- Restricts Modeling
- to have the Same Power

- EPA-HQ-OPP-2008-0274-0011.2.pdf

- There  are  numerous  pitfalls  in  the  calculation  of  BMDs  and  BMDLs
- which  EPA  has  NOT  avoided.

## BMD and BMDL Estimates for a Specific 
Endpoint, Route, Exposure Duration, Sex and Age 
Should Not be Restricted
by Data Unrelated to the Specific 
Endpoint, Route, Exposure Duration, Sex and Age

- Endpoint, Route, Exposure Duration, Sex and Age
- Should Not be Restricted
- by Data Unrelated to the Specific
- Endpoint, Route, Exposure Duration, Sex and Age

- HOWEVER, in the document in the Docket
- EPA-HQ-OPP-2008-0274-0011.2.pdf,
- EPA fits the Acute-Exposure Male PND1 Brain AChE in Betancourt and Carr (2004) Restricting the Power of the Model to be Identical to the Power of the Model for Repeated-Exposure Female PND1-6.

- Several Aspects of EPA’s BMD and BMDL Calculations are NOT Transparent.

- There  are  numerous  pitfalls  in  the  calculation  of  BMDs  and  BMDLs
- which  EPA  has  NOT  avoided.

## Several Aspects of EPA’s BMD and BMDL Calculations are NOT Transparent.

- Examples

- Timchalk et al. (2006), RBC, PND12

- Pools
- Females (3 Hour)
- and
- Males (6 Hour)

- Reports
- “Grouped” BMD10 and BMDL10

- EPA-HQ-OPP-2008-0274-0011.4.pdf
- = EPA-HQ-OPP-2008-0274-0023.pdf

- Restricts Modeling
- to have the Same Power

- There  are  numerous  pitfalls  in  the  calculation  of  BMDs  and  BMDLs
- which  EPA  has  NOT  avoided.

## Several Aspects of EPA’s BMD and BMDL Calculations are NOT Transparent.

- Examples

- Timchalk et al. (2006), Brain, PND12

- Pools
- Females (3 Hour)
- and
- Males (6 Hour)

- Reports
- Male (not “Grouped”)
- BMD10 and BMDL10

- EPA-HQ-OPP-2008-0274-0011.7.pdf
- = EPA-HQ-OPP-2008-0274-0023.6.pdf

- Restricts Modeling
- to have the Same Power

- There  are  numerous  pitfalls  in  the  calculation  of  BMDs  and  BMDLs
- which  EPA  has  NOT  avoided.

## Several Aspects of EPA’s BMD and BMDL Calculations are NOT Transparent.

- Examples

- Timchalk et al. (2006), RBC, PND17

- Pools
- Females (3 Hour)
- and
- Males (6 Hour)

- Reports
- Male (not “Grouped”)
- BMD10 and BMDL10

- EPA-HQ-OPP-2008-0274-0023.7.pdf

- Restricts Modeling
- to have the Same Power

- There  are  numerous  pitfalls  in  the  calculation  of  BMDs  and  BMDLs
- which  EPA  has  NOT  avoided.

## Even though EPA claims that they are using dose-response models that are 

- SIMILAR to those used previously and reviewed by the FIFRA SAP,
- the application of this methodology needs to be reviewed
- on a CASE – BY – CASE basis

- The reasonableness and scientific validity of an application of a general approach
- depends upon how well the approach’s underlying assumptions and requirements
- are satisfied in the case at hand.
- These assumptions and requirements were not discussed for chlorpyrifos.
- Although previous SAPs may have reviewed the general approach that EPA
- is taking to combine data from multiple studies into a single dose-response analysis,
- the scientific appropriateness of that methodology must be reviewed on a case-by-case basis.
- No such review was presented by EPA for carbofuran.  No review was conducted by the SAP.

- There  are  numerous  pitfalls  in  the  calculation  of  BMDs  and  BMDLs
- which  EPA  has  NOT  avoided.

##     Dermal  studies  are  generally  the  best  source  of  dermal  BMDs.  

-     Dermal  studies  are  generally  the  best  source  of  dermal  BMDs.

- 	Too  much  opportunity  for  introducing
- 	unnecessary  uncertainty  and  multiple  conservatisms
- 	if  an  oral  study  and  a  dermal  absorption  factor
- 	are  used  instead  of  a  dermal  study.

- Route  Specificity  can  be  critical.

##     Human  data  are  preferable  to  animal  data.

## Conclusions:  Part 1

-     An  alternative  to  EPA’s  three  proposed  options  needs  to  be  developed.
-     February  2008  SAP  endorsed  Brain  as  a  Better  Surrogate  than  RBC
-     If  NOAELs  are  used  at  all,  they  should  be  determined  in  an  appropriate  and  relevant  manner
- 	and  reflect  biological  significance  and  not  just  statistical  significance.
-     If  appropriate  conditions  are  met,  then  BMDs  are  preferred  over  NOAELs.
-     BMDs  should  be  duration – route - population  specific  and  be  determined  from
-                 duration – route - population  specific  data.
-     Duration – route - population  specific  exposures  can  be  appropriately  aggregated.
-                 Total  MOE  =  1  /  {  ∑  [  1  /  Duration-route-population  specific  MOE  ]  }
-     Uncertainty  Factors  can  be  used  after  the  Total  MOE  is  calculated
- 	to  determine  what  Total  MOE  is  acceptable.
-     BMDs  should  reflect  adverse  effects  and  biologically  significant  changes.
- 	The  benchmark  response  (BMR)  level  needs  to  be  appropriately  selected.

- For example,
-     	10%  for  Brain
-     	30%  for  RBC

## Conclusions:  Part 2

-     Several  Aspects  of  EPA’s  BMD  and  BMDL  Calculations  are  NOT  Transparent.
- 	The dose-response model used.
-                    The confidence limit procedure used to determine the BMDLs.
- 	The assumptions being made.
- 	The software being used.
- 	The specific data being used.
-      EPA  needs to clarify  what  they  are  doing  when  they  “combine  studies”.
- EPA is pooling dissimilar data.
- EPA is doing restricted modeling.
- EPA is NOT consistent.
-      EPA’s  methodology  needs  to  be  reviewed  on  a  Case – by – Cases  basis.
-     Dermal  studies  are  generally  the  best  source  of  dermal  BMDs.
- 	Too  much  opportunity  for  introducing  unnecessary  uncertainty  and  multiple  conservatisms
- 	if  oral  study  and  dermal  absorption  factor  are  used  instead  of  a  dermal  study.
-     Human  data  are  preferable  to  animal  data.

## Thank  You