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Eco Environ Health
Eco Environ Health
Eco-Environment & Health
2772-9850
Elsevier

S2772-9850(24)00027-9
10.1016/j.eehl.2024.03.003
Perspective
The silent threat and countermeasures: Navigating the mixture risk of endocrine-disrupting chemicals on pregnancy loss in China
Xu Yaqian ab
Wang Thanh cd
Yin Jia ab
Hu Ligang abe
Liao Chunyang cyliao@rcees.ac.cn
abe⁎
a School of Environment, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China
b State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
c Department of Physics, Chemistry and Biology (IFM), Linköping University, 581 83 Linköping, Sweden
d Department of Thematic Studies Environmental Change (TemaM), Linköping University, 581 83 Linköping, Sweden
e College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
⁎ Corresponding author. cyliao@rcees.ac.cn
28 3 2024
9 2024
28 3 2024
3 3 266270
4 12 2023
30 1 2024
11 3 2024
© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Currently, many countries and regions worldwide face the challenge of declining population growth due to persistently low rates of female reproduction. Since 2017, China's birth rate has hit historic lows and continued to decline, with the death rate now equaling the birth rate. Concerns have emerged regarding the potential impact of environmental contaminants on reproductive health, including pregnancy loss. Endocrine-disrupting chemicals (EDCs) like phthalate esters (PAEs), bisphenol A (BPA), triclosan (TCS), and perfluoroalkyl substances (PFASs) have raised attention due to their adverse effects on biological systems. While China's 14th Five-Year Plan (2021–2025) for national economic and social development included the treatment of emerging pollutants, including EDCs, there are currently no national appraisal standards or regulatory frameworks for EDCs and their mixtures. Addressing the risk of EDC mixtures is an urgent matter that needs consideration from China's perspective in the near future. In this Perspective, we delve into the link between EDC mixture exposure and pregnancy loss in China. Our focus areas include establishing a comprehensive national plan targeting reproductive-aged women across diverse urban and rural areas, understanding common EDC combinations in women and their surrounding environment, exploring the relationship between EDCs and pregnancy loss via epidemiology, and reconsidering the safety of EDCs, particularly in mixtures and low-dose scenarios. We envision that this study could aid in creating preventive strategies and interventions to alleviate potential risks induced by EDC exposure during pregnancy in China.

Graphical abstract

Image 1

Highlights

• Since 2017, China's birth rate has hit a historic low, now equaling the mortality rate.

• Assessing EDC mixture effects involves recognizing common combinations found in women of reproductive age and the environment.

• People from China and 25 other countries have faced simultaneous exposure to EDCs like PAEs, BPAs, TCS, and PFASs in the past decade.

• In epidemiology, exploring the initial association between EDC mixtures and pregnancy loss is possible.

Keywords

Endocrine-disrupting chemicals
Targeted and nontargeted analysis
Mixture effect
Birth rate
Pregnancy loss
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pmc1 Introduction

The reliance on synthetic chemicals has resulted in unintended consequences for both human health and the environment. Among these concerns, the adverse effects of endocrine-disrupting chemicals (EDCs) have emerged as a significant threat to biological systems worldwide. EDCs encompass a wide range of chemicals, including phthalate esters (PAEs), bisphenol A (BPA), triclosan (TCS), and perfluoroalkyl substances (PFASs) (Table 1). These compounds have been found in environmental matrixes, wildlife, and humans worldwide [1,2]. EDCs might increase the risk of adverse outcomes in pregnant women and children by disrupting hormone-mediated processes that are critical for growth and development during gestation, infancy, and childhood [3]. Given the potential risks posed by EDCs, efforts have been made globally, including initiatives in the Stockholm Convention and the implementation of REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) Regulation, to regulate the use and minimize the exposure to EDCs to protect human health and the ecosystems. However, regulatory frameworks and toxicological testing protocols have primarily been designed to assess the risks associated with a single EDC in isolation. This approach overlooks the complex reality of real-world exposure scenarios, where humans and ecosystems are exposed to mixtures of these chemicals [4]. Recent research revealed an association between early prenatal exposure to a mixture of EDCs (PAEs, BPA, TCS, and PFASs) and language delay in offspring [5]. It is crucial to track complex chemical mixtures in a changing environment [6].Table 1 Selected physicochemical characteristics of the prevalent EDCs.

Table 1EDC	Abbr.	CAS	M.W.	Log KOW	Structure	
Bisphenol A	BPA	80-05-7	228.29	3.32	Image 1	
Perfluorooctane sulfonate	PFOS	1763-23-1	500.13	4.49	Image 2	
Perfluorooctanoic acid	PFOA	335-67-1	414.07	4.81	Image 3	
Perfluorononanoic acid	PFNA	375-95-1	464.08	5.48	Image 4	
Monoethyl phthalate	MEHP	2306-33-4	194.18	1.86	Image 5	
Monobenzyl phthalate	MBzP	2528-16-7	256.25	3.07	Image 6	
Monobutyl phthalate	MBP	131-70-4	222.24	2.84	Image 7	
Mono-carboxy-isooctyl phthalate	MCiOP	898544-09-7	322.4	3.99	Image 8	
Triclosan	TCS	3380-34-5	289.5	4.66	Image 9	

Several countries, including China, are grappling with a persistent issue of declining populations due to decreasing birth rates [7]. Since 2017, China's birth rate has hit historic lows and continued to decline, with the death rate now equaling the birth rate (Fig. 1) [8]. This demographic trend poses one of the most significant challenges for China in the years ahead. In addition to socioeconomic and personal reasons, other factors, such as infertility and pregnancy loss, also contribute to the population decrease. There is growing evidence suggesting that chemical pollutants, particularly EDCs, play a role in pregnancy loss [9]. Recent studies have shown a positive association between EDC mixtures and the risk of early miscarriage and recurrent spontaneous abortion in China, with EDCs being detected in urine samples [10,11]. In 2015, the European Union Commission's Horizon 2020 program funded a four-year project named EDC-MixRisk, which focused on evaluating the effects of EDC mixtures on children and developing risk assessment methods [12]. Although the treatment of emerging pollutants, including EDCs, was included in China's 14th Five-Year Plan (2021–2025) for national economic and social development and long-range objectives through 2035, there are no appraisal standards or regulatory frameworks on EDCs and their mixtures from a national perspective. Addressing the risk of EDC mixtures is thus an urgent matter that needs to be considered from China's perspective in the near future. Several key aspects are discussed below.Fig. 1 Data from https://ourworldindata.org/grapher/births-and-deaths-projected-to-2100?country=∼CHN. Source: United Nations, World Population Prospects (2022) – processed by Our World in Data.

Fig. 1

2 Develop a thorough plan for EDC management with a focus on reproductive-aged women

It is paramount to create a comprehensive strategic plan, evaluation framework, and management system focusing on EDCs from a national perspective, with a special emphasis on women of reproductive age in both rural and urban areas across various regions and demographic groups in China. While some scientific studies have reported on the distribution and levels of EDCs in women, including pregnant women, the size of the investigated population remains limited. To ensure accurate and reliable assessments, it is imperative to expand the sample size to represent a broader population. Furthermore, current pregnancy loss studies lack clear criteria for selecting case and control groups. For instance, in a study investigating the effects of PAE exposure on the risk of early miscarriage, women seeking medical services due to miscarriage were categorized as the case group, while women planning to terminate unintended pregnancies were assigned to the control group [10]. In another case–control study examining the association between PAE metabolites and pregnancy loss, women who experienced clinical pregnancy loss were considered the case group, while healthy pregnant women served as the controls [13]. Therefore, to accurately evaluate the EDC mixture risk on pregnancy loss in China, it is essential to establish explicit and appropriate criteria for selecting both the cases and controls.

3 Optimal EDC mixture design: Integrating targeted and nontargeted analysis as well as statistical techniques

Understanding and assessing the mixture effects of EDCs requires acknowledging the frequent combinations of EDCs found in women of reproductive age and the environment. Tracking complex chemical mixtures in a changing environment is crucial but presents a great challenge [6]. Fig. 2 illustrates that individuals from China and 25 other countries have been simultaneously exposed to multiple types of EDCs, such as PAEs, BPA, TCS, and PFAS, in the past decade. Targeted analysis focuses on identifying and quantifying specific chemicals within a mixture, but it does not fully encompass the broader range of chemical diversity present in the samples. An integrated approach that combines targeted analysis and nontargeted analysis provides a more holistic view of the EDC mixture composition and can uncover novel compounds, transformation products, or chemical combinations that may contribute to the overall mixture effects. Traditional toxicological testing approaches are often inadequate for assessing mixtures due to the high number of possible combinations among the compounds. In this regard, multivariate statistical analysis can be used to detect patterns and correlations within intricate datasets, facilitating the uncovering of combinations of EDCs that commonly co-occur. For instance, Kapraun et al. [14] tackled this issue by introducing frequent itemset mining (FIM), a technique for identifying patterns and correlations within complex datasets, thereby enabling the identification of prevalent combinations of EDCs in humans. By applying FIM to biomonitoring data from the National Health and Nutrition Examination Survey (NHANES), they identified 90 chemical combinations comprising relatively few chemicals and occurring in at least 30% of the US population [14]. Nevertheless, accurately evaluating the EDC mixture risk continues to present significant challenges, primarily due to the fluctuating levels of EDCs in the environment and the body. Continuous efforts are needed to overcome these complexities and ensure effective assessment of EDC mixture risks.Fig. 2 Global distribution of mixtures of PAEs, BPA, TCS, and PFASs detected in humans. Data were from Web of Science ranging June 1st, 2013 to June 1st, 2023 using the keywords of “phthalates” and “human”, “bisphenol A” and “human”, “triclosan” and “human”, and “perfluoroalkyl substance” and “human”, respectively.

Fig. 2

4 Utilize epidemiology to study EDC mixtures and pregnancy loss

From an epidemiological perspective, the association between EDCs and their mixtures and pregnancy loss can be initially explored, which can reduce the need for in vitro or in vivo tests, thus minimizing animal use and resource requirements. A cohort study involving couples attempting pregnancy from the general population demonstrated a positive link between females' preconception concentrations of the polybrominated diphenyl ether 28 and cadmium, components of a mixture of 66 persistent EDCs, and incident human gonadrophin chorionic (hCG) pregnancy loss [15]. Given that pregnancy loss can occur at any stage until childbirth, a comprehensive examination of the link between EDCs and pregnancy loss risk throughout all three trimesters is imperative. To accurately evaluate the risk of pregnancy loss, efforts should be made to minimize residual confounding. Collecting comprehensive data on covariates, such as individual characteristics, behavioral factors, and socioeconomic factors, is essential. The combined impact of multiple EDCs, whether acting simultaneously or sequentially, often manifests at lower doses than experimental effect thresholds for single compounds, resulting in synergistic or additive effects that cannot be predicted based solely on the effects of individual chemicals [16]. Thus, in epidemiological studies focusing on EDC mixtures, the pivotal data analysis strategy involves robust statistical methods that can account for complex interactions and correlations among multiple chemicals, as well as potential confounding factors such as demographics, lifestyle factors, and co-exposures. Advanced techniques like machine learning algorithms and Bayesian approaches are often employed to disentangle the combined effects of EDC mixtures on health outcomes while controlling for various covariates. Additionally, sensitivity analyses and validation techniques are crucial for assessing the robustness and generalizability of findings in such studies. Furthermore, after acknowledging the link between EDC mixtures and pregnancy loss through epidemiological studies, further research should focus on in vitro and in vivo testing of these EDC mixtures to better understand the underlying mechanisms. Drawing from existing research, we have formulated hypotheses regarding the mechanism of EDC-induced pregnancy loss. The fetal thyroid gland remains immature until mid-pregnancy (18–20 weeks), making the placental transfer of maternal thyroid hormones during early pregnancy critical [17]. Previous studies have indicated that pregnant women are exposed to these EDCs before conception, with pollutants such as PFASs exhibiting placental transport characteristics [18]. These pollutants may bind to placental thyroid hormone transporters, competing with thyroid hormones for binding sites, thereby impeding the transport of maternal thyroid hormones to the fetus during early pregnancy. This interference could impact the development of the thyroid–pituitary–hypothalamus axis, potentially leading to pregnancy loss. Further studies are required to identify the underlying mechanisms.

5 Low-dose mixture effects: Non-monotonic dose–response curve

The concept of low-dose effects challenges the prevailing notion that “the dose makes the poison” and highlights the need for reevaluating the safety of EDCs, particularly in mixture scenarios. Traditional toxicological studies have primarily focused on high-dose exposures, assuming that adverse effects follow a linear dose–response relationship. However, mounting evidence suggests that EDCs can exert significant effects at low doses, often below the thresholds established by traditional toxicological testing [19]. The non-monotonic nature of low-dose effects poses a challenge to traditional dose–response modeling [20]. Non-monotonic dose–response curves, known as J shape or inverted U shape, deviate from the traditional linear relationship, showing complex patterns where the response may increase, decrease, or reach a maximum at different dose ranges. This phenomenon is also referred to as hormesis, with stimulation at low doses and inhibition at high doses [21]. These non-linear relationships at environmentally relevant concentrations challenge traditional toxicological paradigms and further emphasize the importance of considering low-dose effects when assessing the mixture toxicity of EDCs.

6 Comparisons with existing plan and the future challenge

In China, specific laws addressing EDC mixture exposure in pregnancy loss are absent. However, the recently unveiled Action Plan for Emerging Pollutants effectively targets environmental and health risks, emphasizing comprehensive environmental risk management and strengthening institutional and technological support. This plan is crucial for alleviating the impact of EDCs on the environment and human health, especially for pregnant women and fetuses. Released by the State Council in September 2021, the “Outline for Women's Development in China (2021–2030)” and the “Outline for Children's Development in China (2021–2030)” provide overarching guidelines. To enhance maternal and child healthcare quality, the National Health Commission has devised the Implementation Plan for the 2021–2030 Outline for Women and Children Development in China. This plan, structured into five sections, emphasizes a people-centered approach and integrates traditional and modern medical practices. It outlines health-related goals, key tasks, and support measures, highlighting the importance of robust leadership and effective monitoring mechanisms in implementation. Overall, our study proposes specific measures aligning with both the Action Plan for the Control of Emerging Pollutants and the Implementation Plan for the 2021–2030 Outline for Women and Children Development in China, focusing on improving maternal and child health outcomes.

We recognize logistical challenges in developing a comprehensive plan for EDC management targeting reproductive-aged women, such as resource allocation and multi-stakeholder cooperation. We plan to address this by engaging relevant government agencies, healthcare providers, and community organizations to ensure comprehensive implementation. Additionally, overcoming difficulties in utilizing epidemiology for studying EDC mixtures and pregnancy loss entails prioritizing adherence to strict ethical guidelines, obtaining informed consent, and ensuring transparency in reporting findings. To protect participants' rights and privacy, specific methods will be implemented: 1) Informed Consent: Obtaining comprehensive informed consent from participants; 2) Confidentiality: Safeguarding personal information with unique identifiers and restricted access; 3) Data Security: Employing robust measures to protect participant data; 4) Ethical Compliance: Adhering to ethical guidelines and obtaining approval from regulatory bodies; and 5) Participant Right Assurance: Providing assurances of participants' rights throughout the study. Through interdisciplinary collaborations and rigorous methodologies, our goal is to advance the understanding of EDC mixture risks related to pregnancy loss while mitigating adverse effects on human health.

CRediT authorship contribution statement

Y.Q.X.: conceptualization, investigation, and writing; T.W., J.Y., and L.G.H.: writing and reviewing; C.Y.L.: conceptualization, reviewing and supervision.

Declaration of competing interests

The authors declare no competing financial interest.

Acknowledgments

This work was jointly supported by the 10.13039/501100012166 National Key Research and Development Program of China (2023YFC3706600 ), the 10.13039/501100001809 National Natural Science Foundation of China (22225605 ), and the K.C. Wong Education Foundation of China (GJTD-2020-03 ).
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References

1 Borrell B. Toxicology: the big test for bisphenol A Nature 464 2010 1122 1124 20414285
2 Evich M.G. Davis M.J.B. McCord J.P. Acrey B. Awkerman J.A. Knappe D.R.U. Per- and polyfluoroalkyl substances in the environment Science 375 6580 2022 eabg9065
3 Braun J.M. Early-life exposure to EDCs: role in childhood obesity and neurodevelopment Nat. Rev. Endocrinol. 13 3 2016 161 173 27857130
4 Dey T. Trasande L. Altman R. Wang Z. Krieger A. Bergmann M. Global plastic treaty should address chemicals Science 378 6622 2022 841 842 36423292
5 Caporale N. Leemans M. Birgersson L. Germain P.L. Cheroni C. Borbély G. From cohorts to molecules: adverse impacts of endocrine disrupting mixtures Science 375 6582 2022 eabe8244
6 Escher B.I. Stapleton H.M. Schymanski E.L. Tracking complex mixtures of chemicals in our changing environment Science 367 6476 2020 388 392 31974244
7 UN, World Population Prospects (2021) – processed by Our World in Data, Children per woman vs. Natural population growth, 2021 https://ourworldindata.org/grapher/children-per-woman-vs-population-growth 2021 (accessed 28 July 2023)
8 UN, World Population Prospects (2022) – processed by Our World in Data, Births and deaths per year, China https://ourworldindata.org/grapher/births-and-deaths-projected-to-2100?country=∼CHN 2022 (accessed 28 July 2023)
9 Jukic A.M. Calafat A.M. McConnaughey D.R. Longnecker M.P. Hoppin J.A. Weinberg C.R. Urinary concentrations of phthalate metabolites and bisphenol A and associations with follicular-phase length, luteal-phase length, fecundability, and early pregnancy loss Environ. Health Perspect. 124 3 2016 321 328 26161573
10 Ji H.L. Wu Z.P. Chen D. Miao M.H. Chen H.X. Shuai W. Individual and joint effects of phthalates exposure on the risk of early miscarriage J. Expo. Sci. Environ. Epidemiol. 34 2024 620 628 36959356
11 Aimuzi R. Huang S. Luo K. Ma S. Huo X. Li G. Levels and health risks of urinary phthalate metabolites and the association between phthalate exposure and unexplained recurrent spontaneous abortion: a large case-control study from China Environ. Res. 212 2022 113393
12 EDC-MixRisk, About EDC-MixRisk: EDC-MixRisk is a four-year project financed through the EU Commission’s programme Horizon 2020, which started in the spring of 2015 https://edcmixrisk.ki.se/aboutedcmixrisk/ 2018 (accessed 28 July 2023)
13 Mu D. Gao F.M. Fan Z.L. Shen H. Peng H. Hu J.Y. Levels of phthalate metabolites in urine of pregnant women and risk of clinical pregnancy loss Environ. Sci. Technol. 49 17 2015 10651 10657 26251123
14 Kapraun D.F. Wambaugh J.F. Ring C.L. Tornero-Velez R. Setzer R.W. A method for identifying prevalent chemical combinations in the US population Environ. Health Perspect. 125 8 2017 087017
15 Smarr M.M. Salehabadi S.M. Barr D.B. Louis G.M.B. Sundaram R. A multi-pollutant assessment of preconception persistent endocrine disrupting chemicals and incident pregnancy loss Environ. Int. 157 2021 106788
16 Kortenkamp A. Ten years of mixing cocktails: a review of combination effects of endocrine-disrupting chemicals Environ. Health Perspect. 115 2007 98 105 18174957
17 Demeneix B.A. Evidence for prenatal exposure to thyroid disruptors and adverse effects on brain development Eur. Thyroid J. 8 6 2019 283 292 31934553
18 Li J. Ma D.H. Qian C.G. Guo B.B. Guan R.N. Liu C. Assessment of fetal exposure and elimination of perfluoroalkyl and polyfluoroalkyl substances: new evidence from paired serum, placenta, and meconium samples Environ. Sci. Technol. 58 5 2024 2260 2270 38252093
19 Vandenberg L.N. Colborn T. Hayes T.B. Heindel J.J. Jacobs D.R. Lee D.H. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses Endocr. Rev. 33 3 2012 378 455 22419778
20 Xu Y.Q. Li K. Wang Z.J. Huang P. Liu S.S. Transfer pattern of hormesis into personal care product mixtures from typical hormesis-inducing compounds Sci. Total Environ. 855 2023 158981
21 Calabrese E.J. Baldwin L.A. Toxicology rethinks its central belief–Hormesis demands a reappraisal of the way risks are assessed Nature 421 6924 2003 691 692 12610596
