Dose-Related Severity Sequence, and Risk-Based Integration, of Chemically Induced Health Effects

Abstract

Risk assessment of chemical hazards is typically based on single critical health effects. This work aims to expand the current approach by characterizing the dose-related sequence of the development of multiple (lower- to higher-order) toxicological health effects caused by a chemical. To this end a “reference point profile” is defined as the relation between benchmark doses for considered health effects, and a standardized severity score determined for these effects. For a given dose of a chemical or mixture the probability for exceeding the reference point profile, thereby provoking lower- to higher-order effects, can be assessed. The overall impact at the same dose can also be derived by integrating contributions across all health effects following severity-weighting. In its generalized form the new impact metric relates to the probability of response for the most severe health effects. Reference points (points of departure) corresponding to defined levels of response can also be estimated. The proposed concept, which is evaluated for dioxin-like chemicals, provides an alternative for characterizing the low-dose region below the reference point for a severe effect like cancer. The shape and variability of the reference point profile add new dimensions to risk assessment, which for example extends the characterization of chemical potency, and the concept of acceptable effect sizes for individual health effects. Based on the present data the method shows high stability at low doses/responses, and is also robust to differences in severity categorization of effects. In conclusion, the novel method proposed enables risk-based integration of multiple dose-related health effects. It provides a first step towards a more comprehensive characterization of chemical toxicity, and suggests a potential for improved low-dose risk assessment.

A common approach for ranking of microbiological and chemical hazards in foods based on risk assessment - useful but is it possible?

“…campylobacter dose-response (Teunis, Nagelkerke and Haas 1999). Sand et al (2018) presents a method relating to this issue for chemicals. The method is based on a model (denoted "reference point profile") that describes the relation between the BMD for various effects (non-case-based as well as case-based effects), and the severity of toxicity determined for these effects.…”

“…the endpoint is not a case of illness. For example a change in body or organ weights in experimental animals, which historically have been common critical effects (Sand et al 2018). Such data on continuous effects do not reflect a discrete case of illness and is therefore difficult to translate into measures of disease burden.…”

A novel method for combining outcomes with different severities or gene-level classifications

“…The RP is based on the critical health effect and is, whenever possible, recommended to be derived by the benchmark dose (BMD) approach (Crump, 1984;Dourson et al, 1985;EFSA, 2005EFSA, , 2009EFSA, , 2017Haber et al, 2018;US EPA, 2005, 2012. Sand et al (2018) proposed to expand the current approach by characterizing the dose-related sequence of RPs (e.g., BMDs) associated with lower-to higher-order health effects, representing low to high severities, instead of only using a single RP, for the critical health effect, as a basis for risk characterization. Modeling of data describing different severities has previously been performed by regression methods designed to handle categories (discrete data).…”

“…Many of the methods discussed above may be used to compute the probability for a given severity category at a given dose. Sand et al (2018) provides this type of output simultaneously across all categories. In addition, a new response metric that integrates probability and severity across the entire severity domain is calculated, and dose equivalents for specified levels of this response can also be derived.…”

“…The new response metric is a comprehensive quantitative measure of chemical toxicity that is expressed in terms of the most severe health effects. Integration across different severities requires weighting, and the developed system in Sand et al (2018) with nine severity categories, C1 through C9, is therefore mapped to a quantitative severity scale, S = 0 to S = 1, and this mapping may be modified systematically by a mathematical function.…”