The establishment of a molecular diagnostic platform for mitochondrial diseases: from conventional to next-generation sequencing.

BACKGROUND: The aim of this study was to create a molecular diagnostic platform and establish a diagnostic pipeline for patients highly suspected of mitochondrial disorders. The effectiveness of three methods, namely, traditional restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR), Sanger sequencing for hotspot detection and whole mitochondrial DNA (mtDNA), and third-generation (Nanopore) whole mtDNA sequencing, will be compared in diagnosing patients with suspected primary mitochondrial diseases (PMDs). The strengths and limitations of different methods are also discussed. MATERIAL AND METHODS: A single-center prospective cohort study was conducted to validate the diagnostic pipeline for suspected mitochondrial diseases. In the first stage, a PCR-based method with five sets of primers was used to screen for eight hotspots (m.3243A>G, m.3460G>A, m.8344A>G, m.8993T>G, m.9185T>C, m.11778G>A, m.13513G>A, and m.4977deletion) using either RFLP or direct Sanger sequencing. Sanger sequencing was also used to confirm the RFLP-positive samples. In the second stage, for samples with negative screening results for the eight hotspots, mitochondrial whole-genome sequencing was performed using Sanger sequencing or third-generation nanopore sequencing. RESULTS: Between June 2020 and May 2023, 30 patients from ages 0 to 63 with clinically suspected mitochondrial disease were enrolled. The positive yield for the diagnosis of PMDs was 8/30=26.7%, and the sensitivity of the heteroplasmy level for the RFLP-based method was approximately 5%. The remaining 22 patients who tested negative at the first stage were tested using Sanger sequencing or the third-generation sequencing Nanopore, and all tested negative for pathological mtDNA mutations. Compared to the Sanger sequencing method, the results of RFLP-PCR were compromised by the limitations of incomplete RFLP enzyme digestion. For whole-genome sequencing of mtDNA, Sanger sequencing, instead of nanopore sequencing, is preferred at our institution because of its cost-effectiveness. CONCLUSIONS: In our highly selective cohort, most tested positive in the first stage of the 8 hot spots screen. Sanger sequencing is a conventional and accurate method for mitochondrial disease screening, at least for the most common hot spots in the region. The results revealed that Sanger sequencing is an accurate method with the benefit of being more cost-effective. This integral platform of molecular diagnosis bears the advantages of being relatively low cost and having a shorter reporting time, facilitating crucial identification of patients with clinical evidence of such disorders. This diagnostic flowchart has also been translated into routine clinical use in the tertiary hospital.

Defect-Rich SnO2 Nanofiber as an Oxygen-Defect-Driven Photoenergy Shield against UV Light Cell Damage.

Usually, most studies focus on toxic gas and photosensors by using electrospinning and metal oxide polycrystalline SnO2 nanofibers (PNFs), while fewer studies discuss cell-material interactions and photoelectric effect. In this work, the controllable surface morphology and oxygen defect (VO) structure properties were provided to show the opportunity of metal oxide PNFs to convert photoenergy into bio-energy for bio-material applications. Using the photobiomodulation effect of defect-rich polycrystalline SnO2 nanofibers (PNFs) is the main idea to modulate the cell-material interactions, such as adhesion, growth direction, and reactive oxygen species (ROS) density. The VO structures, including out-of-plane oxygen defects (op-VO), bridge oxygen defects (b-VO), and in-plane oxygen defects (ip-VO), were studied using synchrotron analysis to investigate the electron transfer between the VO structures and conduction bands. These intragrain VO structures can be treated as generation-recombination centers, which can convert various photoenergies (365-520 nm) into different current levels that form distinct surface potential levels; this is referred to as the photoelectric effect. PNF conductivity was enhanced 53.6-fold by enlarging the grain size (410 nm2) by increasing the annealing temperature, which can improve the photoelectric effect. In vitro removal of reactive oxygen species (ROS) can be achieved by using the photoelectric effect of PNFs. Also, the viability and shape of human bone marrow mesenchymal stem cells (hMSCs-BM) were also influenced significantly by the photobiomodulation effect. The cell damage and survival rate can be prevented and enhanced by using PNFs; metal oxide nanofibers are no longer only environmental sensors but can also be a bio-material to convert the photoenergy into bio-energy for biomedical science applications.

Short-term low-intensity Early Start Denver Model program implemented in regional hospitals in Northern Taiwan.

LAY ABSTRACT: The Early Start Denver Model is an evidence-based early intervention program for young and very young children with autism. This interdisciplinary model is used by many types of professionals, such as psychologists, occupational therapists, speech pathologists, early child special educators, and paraprofessionals, as well as by parents. Most previous studies on the Early Start Denver Model were conducted in the West, and there are scarce studies on the topics of generalization in culture and countries outside the Western world. In this study, we evaluated the effect of the Early Start Denver Model with some adaptations, including a lower intensity, shorter duration, and delivery in regional general hospitals in Northern Taiwan. In total, 45 young children with autism, aged 2-4 years, were divided into the Early Start Denver Model and community-based control groups. The children in the Early Start Denver Model group received one-on-one intervention for approximately 8-9 h per week for 6 months. The results revealed that compared with the control group, the Early Start Denver Model group showed greater gains in overall development ability and nonverbal development ability from pre- to post-intervention. However, these differences did not sustain at the 6-month follow-up after the completion of the intervention. Being mindful of some caveats in trial designs, this study provides preliminary evidence to support the effectiveness of the Early Start Denver Model intervention in the regional general hospital settings in the context of Han-Chinese-mainly culture. Our findings can provide helpful information to stakeholders and policymakers of early intervention service systems for children with autism in Taiwan, as well as in Asian countries.

Assessment of Measurement of Salivary Urea by ATR-FTIR Spectroscopy to Screen for CKD.

Stages of CKD are currently defined by eGFR and require measurement of serum creatinine concentrations. Previous studies have shown a good correlation between salivary and serum urea levels and the stage of CKD. However, quantitative salivary urea assays in current clinical use require costly and labor-intensive commercial kits, which restricts the advantage of using saliva and limits wider applicability as a quick and easy means of assessing renal function. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy has been shown to provide a potentially straightforward, reagent-free method for the identification of a range of disease-related biomarkers and is in current clinical use for analyses of the chemical composition of kidney stones. We assessed the feasibility of ATR-FTIR spectroscopy as an alternative method to measure salivary urea in patients with different stages of CKD. The ATR-FTIR spectra of dried saliva samples from six healthy controls and 20 patients with CKD (stages 1-5) were analyzed to provide their urea concentrations. The lower limit of detection of salivary urea by the ATR-FTIR spectroscopy method was 1-2 mM, at the lower end of the clinically relevant range. Statistically significant differences in salivary urea concentrations were demonstrated between healthy subjects (4.1±0.5 mM) and patients with CKD stages 3-5 (CKD stage 3, 6.8±0.7 mM; CKD stage 4, 9.1±1 mM; CKD stage 5, 14.8±1.6 mM). These salivary urea concentrations correlated well with serum urea levels in the same patients measured by an automated analyzer (Spearman rank correlation coefficient of 0.71; P<0.001). The ability of the method to detect and stage CKD was assessed from the sensitivity and specificity parameters of a receiver operating characteristics (ROC) curve analysis. This proof-of-concept study demonstrates that quantitation of salivary urea by ATR-FTIR spectroscopy could provide a viable tool for rapid and cost-effective diagnosis of stages 3-5 CKD.

Are conventional stone analysis techniques reliable for the identification of 2,8-dihydroxyadenine kidney stones? A case series.

We have recently encountered patients incorrectly diagnosed with adenine phosphoribosyltransferase (APRT) deficiency due to misidentification of kidney stones as 2,8-dihydroxyadenine (DHA) stones. The objective of this study was to examine the accuracy of stone analysis for identification of DHA. Medical records of patients referred to the APRT Deficiency Research Program of the Rare Kidney Stone Consortium in 2010-2018 with a diagnosis of APRT deficiency based on kidney stone analysis were reviewed. The diagnosis was verified by measurement of APRT enzyme activity or genetic testing. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectra of pure crystalline DHA and a kidney stone obtained from one of the confirmed APRT deficiency cases were generated. The ATR-FTIR spectrum of the kidney stone matched the crystalline DHA spectrum and was used for comparison with available infrared spectra of stone samples from the patients. Of 17 patients referred, 14 had sufficient data available to be included in the study. In all 14 cases, the stone analysis had been performed by FTIR spectroscopy. The diagnosis of APRT deficiency was confirmed in seven cases and rejected in the remaining seven cases. Comparison of the ATR-FTIR spectrum of the DHA stone with the FTIR spectra from three patients who did not have APRT deficiency showed no indication of DHA as a stone component. Misidentification of DHA as a kidney stone component by clinical laboratories appears common among patients referred to our program. Since current clinical protocols used to interpret infrared spectra for stone analysis cannot be considered reliable for the identification of DHA stones, the diagnosis of APRT deficiency must be confirmed by other methods.

Preliminary clinical outcomes of a short-term low-intensity Early Start Denver Model implemented in the Taiwanese public health system.

LAY ABSTRACT: The Early Start Denver Model is a comprehensive naturalistic developmental behavioral intervention for young children with autism spectrum disorder. Rigorous studies indicate that long-term, high-intensity Early Start Denver Model in home-based settings can help young children with autism spectrum disorder have great progress in language, cognitive development, and adaptive skills and reduce overall symptom severity. In accordance with the current limitations in resourcing for early intervention in Taiwan, this study evaluated the effects of implementing the Early Start Denver Model in the Taiwanese public health system with some adaptations, including lower intensity, shorter duration, and delivery in general hospitals. A total of 16 children with autism spectrum disorder, aged between 25 and 46 months, received approximately 8 h per week one-on-one Early Start Denver Model intervention. After 6 months of intervention, the children showed great improvements in language and overall cognitive functioning and reduced symptom severity in communication and play. This study suggests that directly delivering the Early Start Denver Model in community-based hospitals may be an effective intervention, which can make more young children with autism spectrum disorder in Taiwan access the Early Start Denver Model service.

Characterization of a Novel Thermobifida fusca Bacteriophage P318.

Thermobifida fusca is of biotechnological interest due to its ability to produce an array of plant cell wall hydrolytic enzymes. Nonetheless, only one T. fusca bacteriophage with genome information has been reported to date. This study was aimed at discovering more relevant bacteriophages to expand the existing knowledge of phage diversity for this host species. With this end in view, a thermostable T. fusca bacteriophage P318, which belongs to the Siphoviridae family, was isolated and characterized. P318 has a double-stranded DNA genome of 48,045 base pairs with 3'-extended COS ends, on which 52 putative ORFs are organized into clusters responsible for the order of genome replication, virion morphogenesis, and the regulation of the lytic/lysogenic cycle. In comparison with T. fusca and the previously discovered bacteriophage P1312, P318 has a much lower G+C content in its genome except at the region encompassing ORF42, which produced a protein with unknown function. P1312 and P318 share very few similarities in their genomes except for the regions encompassing ORF42 of P318 and ORF51 of P1312 that are homologous. Thus, acquisition of ORF42 by lateral gene transfer might be an important step in the evolution of P318.

Promotion of Bamboo Mosaic Virus Accumulation in Nicotiana benthamiana by 5'→3' Exonuclease NbXRN4.

Bamboo mosaic virus (BaMV) has a 6.4-kb (+) sense RNA genome with a 5' cap and a 3' poly(A) tail. ORF1 of this potexvirus encodes a 155-kDa replication protein responsible for the viral RNA replication/transcription and 5' cap formation. To learn more about the replication complex of BaMV, a protein preparation enriched in the 155-kDa replication protein was obtained from Nicotiana benthamiana by a protocol involving agroinfiltration and immunoprecipitation. Subsequent analysis by SDS-PAGE and mass spectrometry identified a handful of host proteins that may participate in the viral replication. Among them, the cytoplasmic exoribonuclease NbXRN4 particularly caught our attention. NbXRN4 has been shown to have an antiviral activity against Tomato bushy stunt virus and Tomato mosaic virus. In Arabidopsis, the enzyme could reduce RNAi- and miRNA-mediated RNA decay. This study found that downregulation of NbXRN4 greatly decreased BaMV accumulation, while overexpression of NbXRN4 resulted in an opposite effect. Mutations at the catalytically essential residues abolished the function of NbXRN4 in the increase of BaMV accumulation. Nonetheless, NbXRN4 was still able to promote BaMV accumulation in the presence of the RNA silencing suppressor P19. In summary, the replication efficiency of BaMV may be improved by the exoribonuclease activity of NbXRN4.

Computer-generated surface and tone enhancements to distinguish neoplastic from non-neoplastic colon polyps less than 1 cm in diameter.

BACKGROUND AND STUDY AIMS: Computer-generated enhancements, which can highlight the surface and color of a colonic lesion, may be helpful to predict the histology; however, it remains unclear whether this technology can distinguish neoplastic from non-neoplastic colon polyps when the polyps are <1 cm without magnification. PATIENTS AND METHODS: Images of colorectal polyps less than 1 cm in diameter were obtained from 54 patients who underwent non-magnified colonoscopy with surface enhancement (SE) and tone enhancement (TE). We calculated the sensitivity, specificity, and accuracy in the prediction of histology. Inter- and intra-observer consistency was evaluated by inviting four endoscopists to rate 45 static images. RESULTS: Overall sensitivity, specificity, and accuracy following the sequence of SE, TE colon, and TE pit pattern modes were 87.7% (95% confidence interval 81.3-94.1%), 84.1% (76.9-91.3%), and 86.1% (79.4-92.8%), respectively. For each modality, the results were 75.0% (68.7-81.3%), 82.7% (77.2-88.2%), and 77.2% (71.1-83.3%) for SE; 71.1% (64.5-77.7%), 78.8 (72.8-84.8), and 73.3% (66.8-79.8%) for TE colon mode; and 75.0% (68.7-81.3%), 80.8% (75.0-86.8%), and 76.7% (70.5-82.9%) for TE pit pattern mode. Their inter- and intra-observer agreements were all fair (κ range 0.522-0.568) and good (0.605-0.694), respectively. When the same rater evaluated the same lesion under different modalities, eight of 45 (18%) polyps yielded discordant interpretations, and the possibility of incorrect diagnoses was the highest with the TE colon mode. CONCLUSION: Computer-generated enhancements are satisfactory in predicting the histology of small colon polyps without the need for magnification. This advantage is mostly related to the pit pattern enhancement.

Gearing of molecular swirls: columnar packing of nematogenic hexakis(4-alkoxyphenylethynyl)benzene derivatives.

Through molecular design and straightforward synthesis, incorporating an additional alkoxy chain onto various numbers of peripheral phenyls in nematogenic hexakis(4-alkoxyphenylethynyl)benzene was achieved to generate columnar phases with significantly expanded temperature ranges. For the compound with two decyloxy chains on every peripheral phenyl, scanning tunnelling microscopic studies indicate the molecule adopts a preferred molecular-swirl geometry by restricting the conformational arrangement of the alkoxy side chains. Cooperative packing of the molecular swirls by a lock-in mechanism among columns results in a stable helical column packing evidenced by powder X-ray diffraction.

Early risk stratification with simple clinical parameters for cirrhotic patients with acute upper gastrointestinal bleeding.

OBJECTIVE: This study aimed to identify pre-endoscopic clinical parameters independently associated with 6-week mortality and to develop a prognostic model in cirrhotic patients with acute upper gastrointestinal (UGI) bleeding. METHODS: A total of 542 consecutive admissions of 389 cirrhotic patients with acute UGI bleeding were retrospectively investigated. Pertinent clinical data obtained at the emergency department were analyzed. Multivariate logistic regression analysis was performed to determine risk factors for 6-week mortality and to develop a predictive model. RESULTS: Forty-four patients (8.12%) died within 6 weeks. The 6-week mortality was independently associated with male sex, hepatocellular carcinoma, non-hepatocellular carcinoma malignancy, hypoxemia with peripheral oxygen saturation less than 95%, serum bilirubin, and prothrombin time. A predictive model consisting of these 6 simple parameters was built. The c statistic of our model was 0.84, significantly superior to that (0.71) of the model for end-stage liver disease score (P = .002). CONCLUSIONS: Simple pre-endoscopic clinical parameters are valuable for early risk stratification in cirrhotic patients with acute UGI bleeding. Our prognostic model warrants prospective validation by further studies.

Assessing the arsenic-contaminated rice (Oryza sativa) associated children skin lesions.

The purpose of this study was to assess the potential risk of children skin lesions from arsenic-contaminated rice (Oryza sativa) consumption in West Bengal (India). Published age- and gender-specific skin lesions data in West Bengal were reanalyzed and incorporated into a Weibull dose-response model to predict children skin lesion prevalence. Monomethylarsonous acid (MMA(III)) levels in urine was used as a biomarker that could be predicted from a human physiologically based pharmacokinetic (PBPK) model. This study integrated arsenic contents in irrigation water, bioaccumulation factors of paddy soil, cooking methods, and arsenic bioavailability of cooked rice in gastrointestinal tract into a probabilistic risk model. Results indicated that children aged between 13 and 18 years might pose a relative higher potential risk of skin lesions to arsenic-contaminated cooked rice (odds ratios (ORs)=1.18 (95% CI 1.12-2.15)) than those of 1-6 years children (ORs=0.98 (0.85-1.40)). This study revealed the need to consider the relationships between cooking method and arsenic in cooked rice when assessing the risk associated with children skin lesions from rice consumption. This study suggested that arsenic-associated skin lesions risk from arsenic-contaminated rice consumption would be reduced significantly by adopting traditional rice cooking method (wash until clean; rice:water=1:6; discard excess water) as followed in West Bengal (India) and using water containing lower arsenic (e.g., <10 microg L(-1)) for cooking.

Delayed endoscopy as a risk factor for in-hospital mortality in cirrhotic patients with acute variceal hemorrhage.

BACKGROUND AND AIMS: Risk factors for mortality in acute variceal hemorrhage remain incompletely understood. Whether endoscopy timing is associated with risk of mortality has not been investigated. We aimed to investigate risk factors for in-hospital mortality in cirrhotic patients with acute variceal hemorrhage, with emphasis on endoscopy timing. METHODS: Three hundred and eleven (73% male and 23% female) consecutive cirrhotic patients presenting with acute variceal hemorrhage from July 2004 to July 2007 were investigated. The univariate association of endoscopy timing as the predictor for in-hospital mortality was examined. Independent risk factors for mortality were determined by multivariate logistic regression analysis consisting of clinical, laboratory and endoscopic parameters. RESULTS: Twenty-five (8.04%) patients died within admission. By plotting the receiver operating curve of endoscopy timing for mortality, we selected 15 h as the optimal cut-off point to define delayed endoscopy. Multivariate regression analysis revealed that independent risk factors predictive for in-hospital mortality included delayed endoscopy performed 15 h after admission (adjusted odds ratio [aOR] = 3.67; 95% confidence interval [CI], 1.27-10.39), every point increment of model for end-stage liver disease (MELD) score (aOR = 1.16; 95% CI, 1.07-1.25), failure of the first endoscopy (aOR = 4.36; 95% CI, 1.54-12.30) and hematemesis as the chief complaint (compared with melena, aOR = 8.66; 95% CI, 1.06-70.94). CONCLUSION: Delayed endoscopy for more than 15 h, high MELD score, failure of the first endoscopy and hematemesis are independent risk factors for in-hospital mortality in cirrhotic patients with acute variceal hemorrhage.

Risk assessment of arsenic-induced internal cancer at long-term low dose exposure.

Previous epidemiological studies have indicated that ingested inorganic arsenic is strongly associated with a wide spectrum of internal cancers. Little is conducted, however, to assess health effects at long-term low dose exposures by linking biologically based mechanistic models and arsenic epidemiological data. We present an integrated approach by linking the Weibull dose-response function and a physiologically based pharmacokinetic (PBPK) model to estimate reference arsenic guideline. The proposed epidemiological data are based on an 8 years follow-up study of 10,138 residents in arseniasis-endemic areas in southwestern and northeastern Taiwan. The 0.01% and 1% excess lifetime cancer risk based point-of-departure analysis were adopted to quantify the internal cancer risks from arsenic in drinking water. Positive relationships between arsenic exposures and cumulative incidence ratios of bladder, lung, and urinary-related cancers were found using Weibull dose-response model r(2)=0.58-0.89). The result shows that the reference arsenic guideline is recommended to be 3.4 microg L(-1) based on male bladder cancer with an excess risk of 10(-4) for a 75-year lifetime exposure. The likelihood of reference arsenic guideline and excess lifetime cancer risk estimates range from 1.9-10.2 microg L(-1) and 2.84 x 10(-5) to 1.96 x 10(-4), respectively, based on the drinking water uptake rates of 1.08-6.52 L d(-1). This study implicates that the Weibull model-based arsenic epidemiological and the PBPK framework can provide a scientific basis to quantify internal cancer risks from arsenic in drinking water and to further recommend the reference drinking water arsenic guideline.

Nonverbal communication skills in young children with autism.

OBJECTIVE: The study was to examine nonverbal communication in young children with autism. METHODS: The participants were 23 young children with autism (mean CA = 32.79 months), 23 CA and MA-matched children with developmental delay and 22 18-20-month-old, and 22 13-15-month-old typically developing toddlers and infants. The abbreviated Early Social Communication Scales [Mundy et al. 1996, Early social communication scales (ESCS)] were used to test three types of nonverbal communicative skills, i.e., joint attention, requesting, and social interaction. Both frequency and proportion analyses were done in group comparisons. RESULTS: (1) Two- to three-year-old children with autism displayed deficits in joint attention ability, especially high-level skills. (2) The deficit in terms of frequency of communication was marked even compared with typically developing infants with younger mental age. (3) Young children with autism had different nonverbal communication profile compared with all three comparison groups. CONCLUSION: Early social-communicative difficulties in autism involve early triadic communications involving joint attention and possibly dyadic turn-taking skills, which has implications for both early screening and early intervention.

A Weibull-PBPK model for assessing risk of arsenic-induced skin lesions in children.

Chronic arsenic exposure and skin lesions (keratosis and hyperpigmentation) are inextricably linked. This paper was to quantify the children skin lesions risks and to further recommend safe drinking water arsenic standard based on reported arsenic epidemiological data. We linked the Weibull dose-response function and a physiologically based pharmacokinetic (PBPK) model to estimate safe drinking water arsenic concentrations and to perform the risk characterization. We calculated odds ratios (ORs) to assess the relative magnitude of the effect of the arsenic exposure on the likelihood of the prevalence of children skin lesions by calculating proposed Weibull-based prevalence ratios of exposed to control groups associated with the age group-specific PBPK model predicted dimethylarsinite (MMA(III)) levels in urine. Positive relationships between arsenic exposures and cumulative prevalence ratios of skin lesions were found using Weibull dose-response model (r2=0.91-0.96). We reported that the safe drinking water arsenic standards were recommended to be 2.2 and 1 microg/L for male and 6 and 2.8 microg/L for female in 0-6 and 7-18 years age groups, respectively, based on hyperpigmentation with an excess risk of 10(-3) for a 75 years lifetime exposure. Risk predictions indicate that estimated ORs have 95% confidence intervals of 1.33-5.12, 1.74-19.15, and 2.81-19.27 based on mean drinking water arsenic contents of 283.19, 282.65, and 468.81 microg/L, respectively, in West Bengal, India, Bangladesh, and southwestern Taiwan. Our findings also suggest that increasing urinary monomethylarsonic acid (MMA) levels are associated with an increase in risks of arsenic-induced children skin lesions.

Arsenic cancer risk posed to human health from tilapia consumption in Taiwan.

Ingested inorganic arsenic is strongly associated with a wide spectrum of adverse health outcomes. We propose a bioaccumulation and the Weibull model-based epidemiological framework to accurately estimate the reference arsenic intake guideline for tilapia consumption and tilapia-cultured water arsenic concentration based on bioaccumulations of tilapia and gender/age/cancer-specific epidemiological data from the arseniasis-endemic area in Taiwan. Our results show a positive relationship between arsenic exposure and age/gender- and cancer-specific cumulative incidence ratio using Weibull dose-response model. Based on male bladder cancer with an excess lifetime cancer risk of 10(-4), we estimate the reference tilapia inorganic arsenic guideline value to be 0.084 microg g(-1) dry wt based on the suggested daily consumption rate of 120 gd(-1). Our findings show that consumption of tilapia in a blackfoot disease (BFD)-endemic area poses no significant cancer risk (excess cancer risks ranging from 3.4 x 10(-5) to 9.3 x 10(-5)), implying that people in BFD-endemic areas are not readily associated with higher fatalities for bladder cancer exposed from tilapia consumption. We are confident that our model can be easily adapted for other aquaculture species, and encourage risk managers to use the model to evaluate the potential population-level long-term low-dose cancer risks. We conclude that, by integrating the bioaccumulation concept and epidemiological investigation of humans exposed to arsenic, we can provide a scientific basis for risk analysis to enhance risk management strategies.