Presenting Uncertainty in the Context of Toxicological, Biological Monitoring and Exposure Information. William H.

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1 Presenting Uncertainty in the Context of Toxicological, Biological Monitoring and Exposure Information William H. Farland, PhD, ATS

2 Presenting Risk Information and Uncertainty Concerns regarding how uncertainty and risks are communicated and understood by the general public and decision-makers Recent approaches for improvements have been proposed and utilized. Examples: Intergovernmental Panel on Climate Change (IPCC) adopted an approach that provides the public with a likelihood scale that clearly defines the probabilities associated with each outcome. The Health and Environmental Sciences Institute (HESI) recently published the results of a multi-sector Risk Assessment in the 21st Century (RISK21) initiative which provides a highly visual representation of estimates of risk with the goal of widening risk communication efforts beyond technical experts

3 Presenting Risk Information and Uncertainty Health risk information is necessarily complex and subject to interpretation. Risk assessors continue to struggle with how to best array and present data within IRIS and similar data repositories. Solutions should encompass approaches that assist the risk assessor to demonstrate inherent uncertainty in the data and the derived risk values

4 Example of Risk Values Comparison Table: Carbon Tetrachloride

5 Example of Reference Dose Comparison Table: Carbon Tetrachloride

6 Presenting Toxicological Information Visually Appropriately designed visual aids can improve comprehension of risks associated with different medical treatments, screenings, and lifestyles Using IRIS as the example, we provide a working model of a visualization approach for cancer/non-cancer risks to help put relationships in context. A series of figures that capture different types of information. Allows for inclusion of exposure information, e.g. environmental levels, intake levels, biomonitoring equivalents (BE s), where appropriate. Gives risk managers and others the opportunity to put toxicity values (reference doses or cancer probabilities) in the context of exposure. 6

7 Presenting Toxicological Information Visually Intended for use by a risk assessor for explanatory purposes In describing relationships, it may appear that each toxicity value is known with certainty and represents a bright line between safe and unsafe. Although toxicity value point estimates are often used in this manner, it is important to note that the true definition, at least for an IRIS value, recognizes that the value could be a range that spans an order of magnitude of uncertainty. 7

8 Dose (mg/kg/day) Oral Noncancer Basic Figure The range for the values are not on scale but are allowing the visualization of the uncertainty between the POD and the risk value. Point of Departure (POD) Uncertainty Factor (UF) The dose-response point that marks the beginning of a low-dose extrapolation. This point can be the lower bound estimate on dose for an estimated incidence or a change in response level from a dose-response model (BMD), or a NOAEL or LOAEL for an observed incidence, or change in level of response. Uncertainty Factors can range from 0 to 3000 (maximum). The possible types of UFs are: interspecies uncertainty (UF A ); intraspecies variability (UF H ); subchronic to chronic extrapolation (UF S ); use of a LOAEL in absence of a NOAEL (UF L ); database incomplete (UF D ) Reference Value The shading in the figure represents a decrease in the value and the potential risk of effects; higher value (darker shade) to a lower value (lighter shade). An estimate of an exposure for a given duration to the human population (including susceptible subgroups that is likely to be without an appreciable risk of adverse health effects over a lifetime. It is derived from a BMDL, NOAEL, LOAEL or suitable point of departure, with uncertainty/variability factors applied to reflect limitations of the data used. Durations include acute, short-term, subchronic, and chronic and are defined individually in this glossary.

9 Carbon tetrachloride: Oral Noncancer (USEPA) mg/kg-day Chosen PODs BMDL 2x-ADJ = 3.9mg/kg-day for elevated serum SDH activity Based on subchronic oral rat study Alternative PODs Alternative PODs NOAEL = 1 mg/kg-day (EPA) LOAEL = 10 mg/kg-day for liver lesions (EPA) 3.9 BMDL 2x-ADJ (EPA) 4x10-3 RfD (EPA) 1000-fold UF Uncertainty Factor is based on default 10-fold for intraspecies differences (UF H ), 10-fold for interspecies extrapolation (UF A ), 3 for subchronic to chronic extrapolation (UF S ) UF = 10x10x3x3 = 1000 RfD = RfD = 3.9 mg/kg-day (BMDL 2x-ADJ ) 1000 (UF) mg/kg-day

10 Carbon tetrachloride: Oral Noncancer (RIVM) mg/kg-day Chosen POD NOAEL = 1 mg/kg-day for liver effects Based on a rat subchronic oral study Alternative PODs Alternative PODs LOAEL 10 mg/kg-day for liver lesions (RIVM) 1 NOAEL (RIVM) 4x10-3 TDI (RIVM) 250-fold UF The basis for the uncertainty factor was not provided. RfD = RfD = 1 mg/kg-day (NOAEL) 250(UF) mg/kg-day

11 100-fold UF 30-fold UF 100-fold UF Carbon tetrachloride: Inhalation mg/m Noncancer Comparison* BMCL 10(HEC) (EPA) 6.4 NOAEC ADJ (RIVM) 5.8 NOAEL HEC (ATSDR) 0.19 cmrl (ATSDR) 0.1 RfC (EPA) mg/m cmrl (ATSDR) 0.1 RfC (EPA) 0.06 TCA (RIVM) 0.06 TCA (RIVM) *represents available alternative reference values

12 Carbon Tetrachloride: Comparison to Background and BE Equivalent Concentration µg/l mg/m RfC (EPA) A BE is defined as the concentration or range of concentrations in a biological matrix that is consistent with a health-based exposure guidance value e.g RfD or RSD 0.19 BE Background Range (ATSDR) <LOD (0.005) Background (NER)

13 Oral Carcinogenic Basic Figure Dose (mg/kg/day) The range for the values are not on scale but are allowing the visualization of the uncertainty between the POD and the risk value. Point of Departure (POD) The dose-response point that marks the beginning of a low-dose extrapolation. This point can the lower limit on Effective dose 10 (LED 10 ) which is the 95% lower confidence limit of the dose of a chemical needed to produce an adverse effect in 10 percent of those exposed to the chemical, relative to control. It can also be the Effective dose 10 (ED 10 ), which is the dose corresponding to a 10% increase in an adverse effect, relative to the control response. An oral slope factor is an upper bound, approximating a 95% confidence limit, on the increased cancer risk from a lifetime oral exposure to an agent. This estimate, usually expressed in units of proportion (of a population) affected per mg/kg-day, is generally reserved for use in the low-dose region of the doseresponse relationship, that is, for exposure corresponding to risks less than 1 in 100. The shading in the figure represents a decrease in the value and the potential risk of effects; higher value (darker shade) to a lower value (lighter shade). Risk Specific Dose = Target Risk/CSF Cancer Hazard Classification Cancer Classifications: There are five recommended US EPA standard hazard descriptors: Carcinogenic to Humans, Likely to Be Carcinogenic to Humans, Suggestive Evidence of Carcinogenic Potential, Inadequate Information to Assess Carcinogenic Potential, and Not Likely to Be Carcinogenic to Humans. Other Agencies such as IARC and RIVM use other cancer classification descriptions.

14 mg/kg-day Carbon tetrachloride: Oral Cancer (USEPA) Chosen POD LED 10, lower 95% bound on exposure at 10% extra risk: 1.54 mg/kg-day Alternative POD Alternative POD ED 10, central estimate of exposure at 10% extra risk: 2.27 mg/kg-day 1.54 (EPA) 1.4x10-4 (EPA) Likely to be carcinogenic to humans Risk Specific Dose (RSD): 1.4x 10-4 mg/kg-day Oral slope factor: 7x10-2 per mg/kgday Alternative Oral Slope Factor Target Organ: liver Species: Mouse (Nagano et al., 2007b; JRBC, 1998) Extrapolation method: multistage model, linear extrapolation from LED10 Classification: likely to be carcinogenic to humans Other Agency Classifications RSD Calculation Divide 1E-5 (1 in 100,000 (E-5) risk level) by the slope factor of 7E-2 per (mg/kg)-day Alternative Oral Slope Factor If ED10 was used the Oral slope factor: 4x10-2 per mg/kgday IARC Cancer classification: 2B (possible carcinogenic to humans)

15 Summary Visual display of key risk information: Provides a general sense of the strength of the available data and confidence in the overall assessment; Reminds us of the uncertainty in the values displayed; Provides for useful comparisons with other derived values and exposure levels; and Provides an educational tool for presenting this information to non-risk assessors. All models (of communication) are wrong (for some audiences), but some are useful! (With apologies to George Box)

16 Co-Authors Nancy Beck, American Chemistry Council Judy Lakind, LaKind Associates Patricia Nance, Toxicology Excellence for Risk Assessment (TERA) Ted Simon, Ted Simon, LLC