R. Becker (American Chemistry Council)

MODERNIZING PROBLEM 

FORMULATION

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

• Transparent framework for integrating results - weight of evidence 

methodology – to evaluate mode(s) of action, cause and effect, etc.

• Accurate characterization of potential risks associated with exposures 

at environmental levels (including uncertainties)

• Independent peer review, responsiveness to scientific issues raised and 

accountability that these are addressed

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Weight of Evidence Framework for 

Integration of Lines of Evidence

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Outcome of the December 2012 Workshop organized by 

ACC’s Center for Advancing Risk Assessment Science and Policy 

http://arasp.americanchemistry.com/
Recommendations on Best Practices 

for WoE from Rhomberg et al. 2013 

• Articulating the central organizing 

elements

• Modernizing problem formulation

• Specific best practices for data 

acquisition, data evaluation, WoE 

(integration) and drawing conclusions

• Implementing Best Practices

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Modernizing Problem Formulation 

Improving the problem formulation phase is a key to 

making risk assessment: 

more 

scientifically 

accurate 

more practical 

more relevant for 

protecting human 

health and the 

environment

more useful for 

risk-managers 5
Steps Needed to Modernize Problem 

Formulation

Intended purpose of the assessment (incl. how outcomes will be 

used (which programs & for which RA & RM purposes)

Identify uses, sources and exposures, key potential 

exposure scenarios & populations 

Identify and summarize conclusions of recent relevant peer 

reviewed evaluations (e.g., ITER, ATSDR, NTP, IARC; journal 

publications)

Summarize the potential hazards of key concern for the 

assessment 6
Steps Needed to Modernize Problem 

Formulation

Building from the Preamble: articulate the specifics: lit 

search strategy, data evaluation protocols, etc.

Preliminary identification of hypothesized modes of 

action for production of these toxicities: absolutely 

necessary for cancer endpoint evaluations

Define the framework that will be used for study 

integration (e.g., WHO/IPCS Key Events DR Framework; 

Hypothesis-Based WoE Framework, etc.)

Articulate the key scientific issues that need to be addressed in 

the evaluation of the hypothesized Modes of Action 7
Stakeholder Meeting: 

Open and Frank Discussion

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Of the Problem Formulation 

documentation (analysis plan) 

Of the key scientific issues that need to be 

addressed in the assessment and 

specifically for evaluation of the 

hypothesized Modes of Action
Modernizing Problem Formulation: 

A Necessity 

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ARTICULATE SPECIFIC HYPOTHESES: 

Chloroform Example

Hypothesis A: : CHCl3 acts via 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 via 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) Modernize problem 

formulation – make MoA 

a central element 

(articulate specific 

hypotheses for each MoA)

2) A priori – detail the 

specific weight of 

evidence framework that 

will be used for 

integrating results

3) Use best practices for 

data acquisition, data 

evaluation, WoE, risk 

characterization, peer 

review, revision and 

finalization

4) Implement 

immediately and 

incorporate continuous 

improvement procedures 10

A Clear Path Forward for IRIS 
THANK YOU

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