臺灣成年族群內分泌活性化學物質風險評估： 以細胞毒性試驗探討混合暴露之效應

Abstract

內分泌干擾物 (Endocrine-Disrupting Chemicals, EDCs) ，如雙酚A (Bisphenol A, BPA) 、個人護理產品成分 (personal care products, PCPs)、防腐劑及殺蟲劑等，因其可能干擾人體荷爾蒙平衡，已成為重要的公共衛生議題。雖然人類會透過攝食、吸入及皮膚接觸等多種途徑，同時暴露於多種內分泌干擾物，但現行風險評估大多以單一化學物質為對象，對混合暴露所造成的累積效應仍缺乏充分了解。 本研究以臺灣成年族群為對象，探討內分泌干擾物混合物的健康風險，並以細胞實驗探討潛在交互作用。研究整合環境與食品中的殘留濃度資料及相關暴露參數，利用蒙地卡羅模擬（10,000次模擬抽樣）估算臺灣成年人終生平均每日暴露劑量；並結合HepG2細胞混合物毒性試驗結果，探討化學物質間交互作用對累積健康風險評估之影響。 結果顯示，飲食攝取是臺灣成年人接觸內分泌干擾物的主要途徑，約占總暴露量的98%。在各類食品中，罐頭食品因含有較高濃度的BPA，導致飲食暴露量顯著增加 (男性最高達9.04 × 10⁻⁵ mg/kg bw/day)；而穀物與穀類製品則是多種污染物共同暴露的重要來源。就其他暴露途徑而言，BPA的吸入暴露風險高於飲用水暴露。機率式風險評估結果亦顯示性別差異：男性在吸入、飲用水及總飲食攝取量方面高於女性，而女性則具有較高的皮膚接觸暴露量。然而，在高暴露族群中，男性的累積風險高於女性；但女性在蔬菜及罐裝蔬菜的攝取暴露量仍高於男性。 細胞體外試驗的結果顯示，HepG2細胞毒性試驗中的內分泌干擾物混合物呈現拮抗作用 (Model Deviation Ratio, MDR < 0.5)，表示實際混合毒性低於理論加成模型的預測值。此外，由於採用歐洲食品安全局 (European Food Safety Authority , EFSA) 更新後的BPA每日可耐受攝取量 (TDI = 0.2 ng/kg bw/day) 作為評估標準，BPA的危害商數 (Hazard Quotients, HQ) 及累積危害指數 (Hazard Indices, HI) 皆明顯超過1，顯示可能存在非致癌健康風險。 綜合而言，本研究建立了一套涵蓋多暴露途徑與多污染物的整合性風險評估架構。研究結果顯示，雖然混合物於細胞試驗中呈現拮抗交互作用，但基於目前對複雜混合暴露效應之不確定性，採用濃度加成模型進行累積風險評估仍可提供較保守且具保護性之健康風險估算。本研究成果可作為臺灣制定內分泌干擾物監管政策及公共衛生管理策略的重要科學依據。

Endocrine-disrupting chemicals (EDCs), such as Bisphenol A (BPA), personal care products (PCPs), preservatives, and Insect repellents, have emerged as a critical public health concern due to their ability to interfere with hormonal homeostasis. Although humans are concurrently exposed to multiple EDCs through various pathways—including ingestion, inhalation, and dermal contact—current risk assessments primarily focus on single substances, leaving the cumulative effects of mixtures poorly understood. This study aimed to evaluate the health risks associated with EDC mixture exposure among the Taiwanese adult population and investigate potential toxicological interactions through in vitro cellular assays. By integrating environmental and dietary residue concentrations with corresponding exposure parameters, Monte Carlo simulations (10,000 iterations) were employed to estimate the Average Daily Dose (ADD) for Taiwanese adults. The results of HepG2 cell-based mixture toxicity assays were further incorporated to evaluate the influence of chemical interactions on cumulative health risk assessment. The results indicate that dietary ingestion is the predominant exposure pathway for Taiwanese adults, contributing approximately 98% of the total burden. Among food categories, canned foods exhibit high concentrations of BPA, leading to a significantly elevated dietary intake (peaking in males at 9.04×10-5 mg/kg bw/day), while grains and cereals emerge as a primary vehicle for concurrent exposures to multiple contaminants at substantial levels. Comparing other exposure pathways, inhalation exposure to BPA yields a higher risk proportion than the drinking water route. Probabilistic risk characterization reveals distinct sex-specific variations across specific pathways: males exhibit higher inhalation, drinking water, and total dietary intake doses than females, whereas females present higher dermal exposure levels. However, within the high-exposure cohort (upper percentiles), male cumulative risks surpass those of females, though females maintain higher intake levels specifically from vegetables and canned vegetables. Regarding toxicological validation, HepG2 cytotoxicity screenings demonstrate that the EDC mixtures manifest an antagonistic interaction (Model Deviation Ratio, MDR < 0.5), indicating that the combined cytotoxicity is lower than estimated by theoretical additive models. Furthermore, when the updated tolerable daily intake (TDI = 0.2 ng/kg bw/day) for BPA established by the European Food Safety Authority (EFSA) was applied as the health-based reference value, both the hazard quotient (HQ) for BPA and the cumulative hazard index (HI) exceeded 1, indicating a potential non-carcinogenic health hazard. In conclusion, this study establishes a comprehensive multi-pathway and multi-contaminant risk assessment framework. The findings demonstrated that, although the mixture exhibited an antagonistic interaction in the in vitro cellular assay, applying the concentration addition (CA) model for cumulative risk assessment can provide a more conservative and health-protective risk estimation due to the current uncertainties associated with complex mixture effects. The results of this study provide scientific support for the risk assessment of EDC mixtures and the development of public health management strategies in Taiwan.