Review
A rapid review and meta-regression analyses of the toxicological impacts of microplastic exposure in human cells

https://doi.org/10.1016/j.jhazmat.2021.127861Get rights and content

Highlights

  • Cytotoxicity, immune, barrier and oxidative stress endpoints are affected by MPs.

  • A meta-regression of microplastic (MP) toxicity characteristics has been conducted.

  • Irregular shape was the only MP characteristic predicting cell death.

  • Thresholds of MP-induced toxic effects are at environmentally-relevant levels.

Abstract

Humans are exposed to microplastics (MPs) daily via ingestion and inhalation. It is not known whether this results in adverse health effects and, if so, at what levels of exposure. Without epidemiological studies, human cell in vitro MP toxicological studies provide an alternative approach to this question. This review systematically synthesised all evidence and estimated thresholds of dose–response relationships. MEDLINE and Web of Science were searched from inception to March 2021 and study quality was rated using a novel risk of bias assessment tool. Seventeen studies were included in the rapid review and eight in the meta-regression. Four biological endpoints displayed MP-associated effects: cytotoxicity, immune response, oxidative stress, barrier attributes, and one did not (genotoxicity). Irregular shape was found to be the only MP characteristic predicting cell death, along with the duration of exposure and MP concentration (μg/mL). Cells showed varying cytotoxic sensitivity to MPs, with Caco-2 cells (human adenocarcinoma cell line) being the most susceptible. Minimum, environmentally-relevant, concentrations of 10 μg/mL (5–200 µm), had an adverse effect on cell viability, and 20 μg/mL (0.4 µm) on cytokine release. This work is the first to quantify thresholds of MPs effects on human cells in the context of risk assessment.

Introduction

The prevalence of microplastics (MPs) is ubiquitous, found in almost every compartment of the environment; in the air (Wright et al., 2020), food (Teng et al., 2019) and drinking water (Zhang et al., 2020). MP contamination will continue to rise as plastic production and use around the world increases (Lebreton and Andrady, 2019). If plastic waste mismanagement continues as it is or increases, it is predicted that within a century, MP ecological risks will be widespread in ecosystems across the world (SAM, 2019, SAPEA, 2019). Two environmental routes of exposure are proposed for humans: ingestion (dietary and non-dietary) and inhalation, as established by numerous studies and reviews and reported widely (EFSA, 2016, Gallo et al., 2018, GESAMP, 2016, Karbalaei et al., 2018, Lusher et al., 2017, Prata, 2018). Τhe presence of MPs has been verified in human colectomy samples (Ibrahim et al., 2021), human placenta (Ragusa et al., 2021) and in human lung tissue (Amato-Lourenço et al., 2021, Pauly et al., 1998). Furthermore, when human stool samples were collected from eight volunteers, as part of a prospective case series study, all of them were found positive for MP contamination (Schwabl et al., 2019). A third environmental exposure route has also been proposed via dermal absorption but currently there is no evidence to support it (BfR, 2014). Another recognized exposure route (not environmental) for MPs is via the degradation of medical prosthetics that are entirely made of or contain plastic and present an entirely different paradigm for MP human exposures and effects (Doorn et al., 1996, Minoda et al., 2003, Urban et al., 2000, Willert et al., 1996).

A wide range of MP whole-organism (apical) and mechanistic toxic effects have been discovered in a range of biota, most of which come from the marine ecosystem. The toxic effects concern multiple life stages, including developmental, behavioural, genotoxic and metabolic as well as increased mortality, immune responses and intestinal barrier dysfunction (Chang et al., 2020, Hale et al., 2020, Huang et al., 2021, Prüst et al., 2020).

Risk assessment (RA) is the first and key part of an integrated risk analysis and its outcomes are a qualitative or quantitative expression of the likelihood of a hazard, in this case MPs, to cause harm (FAO and WHO, 2009). The aims of a human health RA are to estimate the risk to a specific population (general or sub-population) that has been exposed to an agent, taking into consideration the characteristics of both the agent and the population (IPCS, 2004). Human risk assessments usually include epidemiological studies but in the case of MPs, the only currently available scientific toxicological data come from in vitro studies (animal and human cells) and in vivo animal studies, most of which focus on marine organisms and to a lesser extent, on rodents (e.g. Devriese et al., 2017; Li et al., 2020; Santana et al., 2018). There are four interconnected processes in a RA: hazard identification, hazard characterisation/ dose-response, exposure assessment and risk characterization (WHO and IPCS, 2010). The toxicity biological endpoints considered in a risk assessment can include early mechanistic responses, but also extend to apical biological endpoints (IPCS, 2009) which are beyond the focus of this review.

The aim of this rapid review and meta-regression was to identify all currently available scientific data on MP toxicity on human cells, assess their quality and collate data to define thresholds of dose–response relationships, in order to inform a human RA. Such thresholds are health-based guidance values based on available toxicological evidence which provide an estimate of the safe levels of human exposure for different biological endpoints and health outcomes (EPA, 2014). A further objective was to detect whether there was an association between specific characteristics of the experimental conditions and the resulting toxicity in human cell lines. In the absence of epidemiological evidence, human cell lines are one of the currently available sources of scientific evidence for human health effects, the other being animal in vivo and in vitro studies, which are beyond the scope of this review.

Section snippets

Methods

The methodology used for the rapid review (Garritty et al., 2020, Hamel et al., 2021) was based on a simplified version of the systematic review guidelines (Higgins et al., 2021), and used a protocol based on the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols (PRISMA-P) (Moher et al., 2015, Shamseer et al., 2015). The eligibility criteria stated that only experimental study designs were eligible for inclusion. No publication date limits were

Study selection

Database searches identified 166 publications, and a further two were identified from searching the reference lists of relevant reviews. During the first level screening 144 studies were excluded based on their title and abstract. The full text of 24 studies was then assessed and 17 met the eligibility criteria set for this rapid review. Eight of those studies were included in a quantitative meta-regression (Fig. 1). The reasons for the exclusion of the studies in the second-level screening are

Discussion

This is the first rapid review, to our knowledge, focusing on MP toxicity on human cells and attempting a meta-regression approach to determine whether MPs are toxic to humans. A large number of recent reviews have examined the topic of MP toxicity with a broader scope, including animal in vitro and in vivo studies (Chang et al., 2020, Jacob et al., 2020, Jeong and Choi, 2019, Kogel et al., 2020, Rubio et al., 2020, Shi et al., 2021). Nevertheless, the scope of this review and meta-regression

Conclusions

MP contamination is on the verge of being established as MP pollution. A risk analysis is essential in understanding the extend of the issue in terms of adverse effects posed to humans. In the absence of epidemiological data, in vitro toxicology studies can be used to delineate the molecular initiating event and the consecutive key events that lead to adverse effects in an adverse outcome pathways framework. This first rapid review has synthesised and appraised currently available data using a

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by a Ph.D. scholarship within the “Health inequalities and emerging environmental contaminants – Places and People” cluster funded by the University of Hull, UK.

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