Genetic Toxicity of Complex Mixtures of Polycyclic Aromatic Hydrocarbons: Evaluating Dose-Additivity in a Transgenic Mouse Model

Abstract

This study evaluates the risk assessment approach currently employed for polycyclic aromatic hydrocarbon (PAH)-contaminated media, wherein carcinogenic hazards are evaluated using a dose-addition model that employs potency equivalency factors (PEFs) for targeted carcinogenic PAHs. Here, MutaMouse mice were subchronically exposed to PAH mixtures (p.o.), and mutagenic potency (MP) values were determined for five tissues. Predicted dose-additive mixture MPs were generated by summing the products of the concentrations and MPs of the individual targeted PAHs; values were compared to the experimental MPs of the mixtures to evaluate dose-additivity. Additionally, the PEF-determined BaP-equivalent concentrations were compared to those determined using a bioassay-derived method (BDM) (i.e., an additivity-independent approach). In bone marrow, mixture mutagenicity was less than dose-additive and the PEF-method provided higher estimates of BaP-equivalents than the BDM. Conversely, mixture mutagenicity in site-of-contact tissues (e.g., small intestine) was generally more than dose-additive and the PEF-method provided lower estimates of BaP-equivalents than the BDM. Overall, this study demonstrates that dose-additive predictions of mixture mutagenic potency based on the concentrations and potencies of a small number of targeted PAHs results in values that are surprisingly close to those determined experimentally, providing support for the dose-additive assumption employed for human health risk assessment of PAH mixtures.

Molecular Simulation of Naphthalene, Phenanthrene, and Pyrene Adsorption on MCM-41

“…Polycyclic aromatic hydrocarbons (PAHs) generally refer to hydrocarbons that have two or more benzene rings [1,2]. PAHs, commonly known as carcinogens, mutagens, teratogens, and bioaccumulators, can cause great damage in humans and the environment [3,4,5,6,7,8]. They are also a part of the atmospheric particulate pollutant PM 2.5 [9].…”

The Long Goodbye: Finally Moving on from the Relative Potency Approach to a Mixtures Approach for Polycyclic Aromatic Hydrocarbons (PAHs)

“…The CCME [ 11 ] noted the PEF approach tended to underestimate the potency of coal tar and creosote mixtures typically found at contaminated sites. They therefore adopted a three-fold safety factor when using a relative potency approach to calculate the toxicity of creosote or coal tar mixtures; however, few other jurisdictions have applied a similar safety factor for PAH mixtures, and at least one recent study [ 18 ] found only modest deviations from additivity of priority PAHs when assessing the toxicity of two coal tars and one coal-tar-based pavement sealant.…”

“…Potency only provided for comparative purposes. 6 Long et al, 2017 [ 18 ]. Table S2 : A literature review was conducted to identify the lowest and highest published PEFs for each compound.…”

Genotoxicity assessment: opportunities, challenges and perspectives for quantitative evaluations of dose–response data

“…For instance, combined genotoxic effects have been demonstrated in vitro for the alkylating agents methyl methanesulfonate and ethyl methanesulfonate (Kojima et al 1992 ) and also for a polycyclic aromatic hydrocarbon (benzo [a] pyrene) and a heterocyclic amine (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) (Jamin et al 2013 ). Moreover, in vitro and in vivo mutagenicity studies on mixtures of polycyclic aromatic hydrocarbons supported the assumption of dose additivity (Lemieux et al 2015 ; Long et al 2017 ).…”