A generalized physiologically-based toxicokinetic modeling system for chemical mixtures containing metals

Abstract

BackgroundHumans are routinely and concurrently exposed to multiple toxic chemicals, including various metals and organics, often at levels that can cause adverse and potentially synergistic effects. However, toxicokinetic modeling studies of exposures to these chemicals are typically performed on a single chemical basis. Furthermore, the attributes of available models for individual chemicals are commonly estimated specifically for the compound studied. As a result, the available models usually have parameters and even structures that are not consistent or compatible across the range of chemicals of concern. This fact precludes the systematic consideration of synergistic effects, and may also lead to inconsistencies in calculations of co-occurring exposures and corresponding risks. There is a need, therefore, for a consistent modeling framework that would allow the systematic study of cumulative risks from complex mixtures of contaminants.MethodsA Generalized Toxicokinetic Modeling system for Mixtures (GTMM) was developed and evaluated with case studies. The GTMM is physiologically-based and uses a consistent, chemical-independent physiological description for integrating widely varying toxicokinetic models. It is modular and can be directly "mapped" to individual toxicokinetic models, while maintaining physiological consistency across different chemicals. Interaction effects of complex mixtures can be directly incorporated into the GTMM.ConclusionsThe application of GTMM to different individual metals and metal compounds showed that it explains available observational data as well as replicates the results from models that have been optimized for individual chemicals. The GTMM also made it feasible to model toxicokinetics of complex, interacting mixtures of multiple metals and nonmetals in humans, based on available literature information. The GTMM provides a central component in the development of a "source-to-dose-to-effect" framework for modeling population health risks from environmental contaminants. As new data become available on interactions of multiple chemicals, the GTMM can be iteratively parameterized to improve mechanistic understanding of human health risks from exposures to complex mixtures of chemicals.

Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: A general review of metal mixture mechanism in brain

“…The current literature of metal induced neuronal damage is primarily confined to single metal exposure (Zhu et al, 2014) and no published literature was found on quaternary mixture of Pb, Cd, As and MeHg evoked toxicity. Metal mixture exposure and their mode of action relation evaluating either independent or addition and synergistic effects are not well developed (Rodríguez et al 1998;Sasso et al 2010). However, the evidence for these kind of interactions continue to grow (Stackelberg, 2013).…”

Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures

“…Further considerations include early life exposures such as in utero (Beaudouin et al 2010), through lactation (Verner et al 2008) and during infancy (Edginton and Ritter 2009). PBTK models are capable of capturing multiple chemical interactions at the level of metabolism; however, the lack of sufficient experimental data to describe the interaction terms has resulted in a limited number of applications so far, such as in the case of volatile organic compounds (VOCs) (Sarigiannis and Gotti 2008) and metals (Sasso et al 2010). PBTK models can also be used to reconstruct external exposure from HBM data.…”

Estimation of the Personal Deposited Dose of Particulate Matter and Particle-Bound Metals Using Data from Selected European Cities

“…Figure 7 indicates that after 1-day exposure Cd was primarily accumulated in lungs (2.3 × 10 −4 µg) and in intestines (4.2 × 10 −5 µg) whereas after 35 days from initial intake accumulation was higher in other tissues (7.2 × 10 −5 µg), in kidney (5.3 × 10 −5 µg) and in liver (4.4 × 10 −5 µg). Several studies [98,109,110] found that Cd accumulates in kidney and liver. In addition, the WHO [110] suggests that the half-life of Cd in kidney is about 10-20 years with kidney damage being a primary health concern [109] because it is considered a critical target organ [32].…”