A Novel Approach to Chemical Mixture Risk Assessment—Linking Data from Population‐Based Epidemiology and Experimental Animal Tests

Abstract

Humans are continuously exposed to chemicals with suspected or proven endocrine disrupting chemicals (EDCs). Risk management of EDCs presents a major unmet challenge because the available data for adverse health effects are generated by examining one compound at a time, whereas real-life exposures are to mixtures of chemicals. In this work, we integrate epidemiological and experimental evidence toward a whole mixture strategy for risk assessment. To illustrate, we conduct the following four steps in a case study: (1) identification of single EDCs ("bad actors")-measured in prenatal blood/urine in the SELMA studythat are associated with a shorter anogenital distance (AGD) in baby boys; (2) definition and construction of a "typical" mixture consisting of the "bad actors" identified in Step 1; (3) experimentally testing this mixture in an in vivo animal model to estimate a dose-response relationship and determine a point of departure (i.e., reference dose [RfD]) associated with an adverse health outcome; and (4) use a statistical measure of "sufficient similarity" to compare the experimental RfD (from Step 3) to the exposure measured in the human population and generate a "similar mixture risk indicator" (SMRI). The objective of this exercise is to generate a proof of concept for the systematic integration of epidemiological and experimental evidence with mixture risk assessment strategies. Using a whole mixture approach, we could find a higher rate of pregnant women under risk (13%) when comparing with the data from more traditional models of additivity (3%), or a compound-by-compound strategy (1.6%).

The Promises and Challenges of Toxico-Epigenomics: Environmental Chemicals and Their Impacts on the Epigenome

“…An interesting proposal by Bornehag et al (2019) suggests that exposure mixtures should first be identified and reconstructed based on evidence from epidemiological and biomonitoring data (Bornehag et al 2019). These mixtures can then be tested with in vivo experiments to determine a point of departure associated with the studied adverse health outcome, and the final step is to compare the similarity of the experimental data with outcomes measured in the human population (Bornehag et al 2019). In addition to taking into account mixtures in the risk assessment process, this approach could enable the systematic integration of epidemiological and experimental evidence (Bornehag et al 2019).…”

“…These mixtures can then be tested with in vivo experiments to determine a point of departure associated with the studied adverse health outcome, and the final step is to compare the similarity of the experimental data with outcomes measured in the human population (Bornehag et al 2019). In addition to taking into account mixtures in the risk assessment process, this approach could enable the systematic integration of epidemiological and experimental evidence (Bornehag et al 2019). We note that with this proposed notion, the mechanistic effects of combinations of chemicals-whether independent, additive, or synergistic-are not a primary concern; the main concern is that these mixtures are relevant based on epidemiological and biomonitoring data.…”

“…For instance, we envision that assays for global changes in epigenetic or chromatin sates could be used in a manner analogous to the EDSP Tier 1 screening method. This screen may include mixtures of chemicals that have been identified and reconstructed through epidemiological observations or biomonitoring data, as described by Bornehag et al (2019). Hits identified in Tier 1 screens can be further examined with more sensitive epigenome-wide techniques, followed by the identification of phenotypic and molecular perturbations incurred by the exposure.…”

A suggested bisphenol A metabolite (MBP) interfered with reproductive organ development in the chicken embryo while a human-relevant mixture of phthalate monoesters had no such effects

“…At gestational week 10, urine and serum were collected from the women and analyzed for 20 chemicals, including phthalates, phenols, and perfluorinated compounds. Using weighted quantile sum (WQS) regression, levels of 4 phthalate monoesters in the urine of 198 mothers were associated with shorter anogenital distance (AGD) in their baby boys at 21 months of age (Bornehag et al 2019). A mixture (Mixture S) was established for these four phthalates, i.e.…”

“…A mixture (Mixture S) was established for these four phthalates, i.e. monobutyl phthalate, monoisononyl phthalate, monoethylhexyl phthalate, and monobenzyl phthalate, with mixing proportions based on geometric means of estimated serum concentrations in the SELMA mothers (Bornehag et al 2019). Gestational exposure to Mixture S in mice led to reduced AGD and gonadal weight, histological changes in the gonads, and altered mRNA expression of regulators of steroidogenesis in the offspring (Repouskou et al 2019).…”