# Beyond the RfD: Broad Application of a Probabilistic Approach to Improve Chemical Dose-Response Assessments for Noncancer Effects

Weihsueh A. Chiu, Daniel A. Axelrad, Chimeddulam Dalaijamts, Chris Dockins, Kan Shao, Andrew J. Shapiro, and Greg Paoli

Environ Health Perspect (2018)
DOI: http://dx.doi.org/10.1289/ehp3368
PMID: 29968566

### Publication

#### Abstract

**BACKGROUND:**
The National Academies recommended risk assessments redefine the traditional noncancer Reference Dose (RfD) as a probabilistically derived risk-specific dose, a framework for which was recently developed by the World Health Organization (WHO).

**OBJECTIVES:**
Our aim was to assess the feasibility and implications of replacing traditional RfDs with probabilistic estimates of the human dose associated with an effect magnitude M and population incidence I (HDMI).

**METHODS:**
We created a comprehensive, curated database of RfDs derived from animal data and developed a standardized, automated, web-accessible probabilistic dose-response workflow implementing the WHO framework.

**RESULTS:**
We identified 1,464 RfDs and associated endpoints, representing 608 chemicals across many types of effects. Applying our standardized workflow resulted in 1,522 HDMI values. Traditional RfDs are generally within an order of magnitude of the HDMI lower confidence bound for I=1% and M values commonly used for benchmark doses. The greatest contributor to uncertainty was lack of benchmark dose estimates, followed by uncertainty in the extent of human variability. Exposure at the traditional RfD frequently implies an upper 95% confidence bound of several percent of the population affected. Whether such incidences are considered acceptable is likely to vary by chemical and risk context, especially given the wide range of severity of the associated effects, from clinical chemistry to mortality.

**CONCLUSIONS:**
Overall, replacing RfDs with HDMI estimates can provide a more consistent, scientifically rigorous, and transparent basis for risk management decisions, as well as support additional decision contexts such as economic benefit-cost analysis, risk-risk tradeoffs, life-cycle impact analysis, and emergency response.

### Figures

#### Figure 1. Comparison of traditional and probabilistic definitions of the Reference Dose (RfD), along with definition of the output of probabilistic dose–response framework, HDMI.

Top: the definitions of the traditional and probabilistic RfDs are compared in terms of the equations used to derive them and the textual definition. The arrows show how the probabilistic RfD is more precisely defined quantitative by replacing: “deleterious effects” with a specific magnitude of effect in terms of degree of harm (italic underline, in green), the “estimate” of the dose “likely” to be without these effects with a specific statistical confidence bound (bold italic, in purple), and protecting “sensitive subpopulations” by a specific population incidence level (bold italic underline, in red). Additionally, the conceptual basis of the HDMI is displayed graphically as being based on individual dose-response curves for different percentiles of the population (lower left), along with its definition as the “Human dose associated with an effect of magnitude M and population incidence I” (lower right). Note: NOAEL, No Observed Adverse Effect Level; UFA, traditional uncertainty factor for animal-to-human extrapolation; UFH, traditional uncertainty factor for human variability; BMDM, benchmark dose for a magnitude of effect M; UFA,BW, probabilistic factor for interspecies body weight (BW) scaling (Figure 4); UFA,BW, probabilistic factor for interspecies toxicokinetic (TK) and toxicodynamic (TD) differences (after BW scaling); UFA,BW, probabilistic factor for human variability in sensitivity for a population incidence I. Adapted from WHO/IPCS (2014).

- Figure 1 (297 KB)

#### Figure 2. Overview of curation of toxicity values and probabilistic dose–response workflow.

Blue boxes relate to the identification, curation, and extraction of chemical reference doses (RfDs); orange boxes relate to the automated workflow for replacing RfDs with probabilistic dose-response estimates. Note: The number of probabilistic dose-response estimates (1,522) exceeds the number of endpoints-specific RfDs (1,464) because some RfDs did not specific whether a continuous or dichotomous endpoint was used, so both possibilities were evaluated in the probabilistic approach (see Figure 3B). CI, Confidence Interval; POD, Point of Departure; UF, Uncertainty factor; HDMI, Human dose associated with an effect of magnitude M and population incidence I.

- Figure 2 (147 KB)

#### Figure 3. Details of (A) toxicity value curation and data extraction and (B) assignment of conceptual model based on type of effect.

Note: BMD, Benchmark Dose; BMDL, Benchmark Dose Lower Confidence Limit; BMR, Benchmark Response; CASRN, Chemical Abstracts Service Registry Number; ED50, Effective Dose for a 50% response; LOAEL, Lowest Observed Adverse Effect Level; MRL, Minimal Risk Level; NOAEL, No Observed Adverse Effect Level; POD, Point of Departure; RfD, Reference Dose; SD, Standard Deviation; SE, Standard Error; UF, Uncertainty factor. See WHO/IPCS (2014) and Chiu and Slob (2015) for detailed definitions and descriptions of each conceptual model.

- Figure 3 (386 KB)

#### Figure 4. Details of uncertainty factor probability distributions assigned.

Note: BMD, Benchmark Dose; BMDL, Benchmark Dose Lower Confidence Limit; BMDU, Benchmark Dose Upper Confidence Limit; BW, Body Weight; ED50, Effective Dose for a 50% response; LOAEL, Lowest Observed Adverse Effect Level; NOAEL, No Observed Adverse Effect Level; POD, Point of Departure; P50, median of the distribution = Geometric mean of lognormal distribution; P95/P50, ratio between the 95th percentile and the median of the distribution = (Geometric standard deviation of lognormal distribution)1.6449; RfD, Reference Dose; SD, Standard Deviation; TD, Toxicodynamic; TK, Toxicokinetic; UFL, Uncertainty Factor for LOAEL-to-NOAEL.

- Figure 4 (420 KB)

#### Figure 5. Characteristics of the database of references doses (RfDs).

(A) Distribution of toxicological effects, including continuous endpoints, dichotomous endpoints, and endpoints that could be either continuous or dichotomous. (B) Distribution of types of points of departure (POD), including NOAEL (no observed adverse effect level), LOAEL (lowest observed adverse effect level), and BMDL (benchmark dose lower confidence limit). (C) Distribution of composite uncertainty factors (UFs) applied across RfDs, depending on source (IRIS, Integrated Risk Information System; OPP, Office of Pesticide Programs; ATSDR, Agency for Toxic Substances and Disease Registry; PPRTV, Provisional Peer-reviewed Toxic Values; HEAST, Health Effects Assessment Summary Tables).

- Figure 5 (183 KB)

#### Figure 6. Chemical space coverage of reference doses (RfDs).

The chemical properties of chemicals from the database of RfDs was compared to 32,464 structures in the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP) “prediction” dataset from Mansouri et al. (2016), based on chemical descriptors generated from chemistry development kit (CDK) (Guha 2007). (A) 3-D plot of coverage based on first three principal components; (B)–(E) Coverage comparisons based on easily interpretable descriptors Octanol:Water Partition Coefficient (ALogP), Molecular Weight (MW) in Daltons, and Topological Polar Surface Area (TopoPSA) in angstroms squared. (B) is a 3D plot, and (C)–(E) are histograms comparing the distributions of compounds for each descriptor.

- Figure 6 (564 KB)

#### Figure 7. Results of automated probabilistic dose-response workflow applied to 1,522 chemicals and endpoints.

(A) Comparison of traditional and probabilistic values: traditional POD (grey+), traditional RfD (grey×); HDMI median (black diamond); HDMI upper 95% confidence (black open triangle); HDMI lower 95% confidence=probabilistic (black open downward triangle).

(B) Boxplots of degree of uncertainty in HDMI (ratio between upper-tail 95% confidence bound and lower-tail 95% confidence bound), for different types of PODs (number “n” of PODs of each type is also shown). Each boxplot includes the interquartile range (box), median (line in box), 95% confidence interval (whiskers), and values outside 95% confidence interval (black dots).

(C) Contribution to overall uncertainty from each potential source of uncertainty, for the types of PODs.

(D) Dose-response functions, derived by estimates of HDMI at varying levels of incidence I, with exposure converted to a probabilistic hazard quotient through division by the probabilistic RfD.

LOAEL, Lowest Observed Adverse Effect Level;

NOAEL, No Observed Adverse Effect Level;

BMDL, Benchmark Dose Lower Confidence Limit;

TK/TD, Toxicokinetic and Toxicodynamic;

BW, Body Weight scaling;

POD, Point of Departure;

UF, Uncertainty Factor;

HDMI, Human dose associated with an effect of magnitude M and population incidence I;

RfD, Reference Dose;

HQ, Hazard Quotient.

- Figure 7 (656 KB)

#### Figure 8. Comparison of results of traditional and probabilistic dose-response assessment.

(A) Scatterplot of traditional RfD versus probabilistic RfD, defined as shown in Figure 1 for I=1%. Grey solid line denotes equality, and grey dashed lines denote 10 times greater or less. (B) Comparison of traditional RfD in terms of the uncertainty distribution of HDMI, expressed as the percent confidence that I<1% at exposures equal to the traditional RfD, shown as a frequency histogram and a boxplot. The boxplot displays the interquartile range (box), median (line in box), 95% CI (whiskers), and values outside 95% confidence interval (black dots). (C) Predicted incidence at the traditional RfD (median=black dots, 90% CI=vertical grey lines). (D) Dose-response functions, derived by estimates of HDMI at varying levels of incidence I, with exposure converted to a traditional hazard quotient through division by the traditional RfD. CI, Confidence Interval; HQ, Hazard Quotient; RfD, Reference Dose.

- Figure 8 (192 KB)

#### Figure 9. Example risk assessment/risk management workflow integrating traditional and probabilistic dose–response approaches with tiered uncertainty reduction.

Note: LOAEL, Lowest Observed Adverse Effect Level; NOAEL, No Observed Adverse Effect Level; BMD, Benchmark Dose; HQ, Hazard Quotient; RfD, Reference Dose; I, Population Incidence.

- Figure 9 (217 KB)

### Supplemental Materials

#### Supplemental Material

- Supplemental Material (618 KB)