**R. Becker (American**  **Chemistry Council)**  

# MODERNIZING PROBLEM **FORMULA**

**TION** December 13, 2013

## Key Scientific Improvements

**Needed in IRIS**

• **Problem formulation, including plan for conducting the assessment** 

• **Data acquisition protocol** 

• **Data evaluation protocols for each major type of study: epi, animal tox,**  **mechanistic for determining quality & reliability**

• **Tr ansparent fr** **amework for integr ating results**  **- weight of ev**  **idence methodology**  **– to evaluate mode(s) of action, cause and effect, etc.** 

• **Accur ate char** **acterization of potential risks associated with exposures at env**  **ironmental levels (including uncertainties)** 

• **Independent peer rev iew**  **, responsiveness to scientific issues r aised and**  **accountability that these are addressed** 2

## We **ight of Ev idence Fr**  **amework for Integr**  **ation of Lines of Ev**  **idence**

3 **Outcome of the December 2012**  **Wo rkshop**  **organized by ACC’**  **s Center for Advancing Risk**  **Assessment Science and P olicy** 

http ://arasp.americanchemistry .com/

## Recommendations on Best Pr **actices for W** **oE from Rhomberg et al. 2013**

• **Articulating the centr** **al organizing**  **elements**

• **Modernizing problem formulation** 

• **Specific best pr** **actices for data**  **acquisition, data evaluation,**  **Wo E**  **(integr ation)**  **and dr awing conclusions** 

• **Implementing Best Pr actices**  4

## Modernizing Problem **Fo rmulation**  **Improv ing the problem formulation phase is**  **a key**  **to making**  **risk assessment:**



## mor **e scien**  **tifically accur**  **ate mor**  **e pr actic**  **al**

**mor e r**  **elev an**  **t f or**  **pr ot**  **ecting human**  **health and the en**  **vir onment**  **mor e use**  **ful f or** 

**risk -**  **manag er**  **s** 5

## Steps Needed to Modernize Problem **Fo rmulation** 

**In tended**  **purpose of the assessment**  **(incl. how outcomes will be**  **used (which pr**  **ogr ams & f** **or which RA & RM purposes) Identify uses,**  **sour ces and e**  **xposur es,**  **ke y pot**  **ential ex**  **posur e scenarios & popula**  **tions Identify and summariz**  **e conclusions of r**  **ecent r elevant peer**  **reviewed evaluations (e. g., ITER, A**  **TSDR, NTP**

**, IARC; journal publica**  **tions) Summariz**  **e the potential haz ards of k**  **ey concern f** **or the assessment**  6

## Steps Needed to Modernize Problem **Fo rmulation** 

**Building fr om the Pr**  **eamble: articula te**  **the specifics: lit sear**  **ch str ategy** 

**, da ta**  **evaluation protocols, etc. Pr**  **eliminary iden tifica**  **tion of h ypothesiz**  **ed modes of action f** **or pr oduction of these to**  **xicities: absolutely necessary f** **or cancer endpoint ev alua**  **tions Define the fr**  **amework tha t will be used f** **or study integr**  **at ion (e.**  **g., WHO/IPCS K ey E**  **vents DR Fr amework;**  **Hypothesis -**  **Based Wo**  **E Fr amework, etc.)**  **Articula te the k**  **ey scientific issues tha t need to be addr**  **essed in**  **the evalua tion of the h**  **ypothesiz ed**  **Modes of Action** 7

## Stakeholder Meeting:

**Open and Fr**

**ank Discussion**

8 

### Of the Pr **oblem Fo**  **rmula tion**  **documen tat**  **ion (analysis plan) Of the**  **ke y**  **scien tific issues tha**  **t need to be**  **addr essed**  **in the assessmen**  **t and specifically**  **fo r e**  **va luation**  **of the hy**  **pothesiz ed Modes of**  **Action**

## Modernizing Problem **Fo rmulation:** 

**A Necessity** 

9 

### AR **TICULA TE**  **SPECIFIC HYPOTHESES: Chloroform Example**  **Hypothesis A**  **: : CHCl3 acts v**  **ia a mutagenic MoA, a MOA**  **which entails a linear**

**, non -**  **threshold dose -**  **response, to**  **produce a cancer risk to humans at typical exposure levels....**  **Hypothesis B: CHCl3 acts v ia a cytotoxic MoA, a MOA**  **which entails a**  **non -**  **linear**

**, threshold dose**  **- response,**  **such that cancer risk to humans**  **only arises at cytotoxic exposure**  **levels ....** **1) Moderniz e problem** 

**fo rmulation**  **– mak**  **e MoA a cen**  **tr al elemen**  **t (articulat**  **e specific hy**  **potheses f or each MoA)**  **2) A priori –**  **detail the specific w**  **eigh t of**  **evidence fr amework that**  **will be used f or**  **in te**  **gr ating results** 
**3) Use best pr actices f** **or data acquisition, dat**  **a evaluation, W** **oE, risk char**  **act eriz**  **ation, peer review**  **, revision and finaliz**  **ation 4) Implemen**  **t immediat**  **ely and incorpor**  **ate continuous**  **impr ovemen**  **t procedures** 10 

## A **Clear P ath F** **orward for IRIS**

# THANK **YOU**

11