Cytisinicline for Vaping Cessation in Adults Using Nicotine E-Cigarettes: The ORCA-V1 Randomized Clinical Trial.

Importance: The prevalence of e-cigarette use among US adults, especially young adults, is rising. Many would like to quit vaping nicotine but are unable to do so. Cytisinicline, a plant-based alkaloid, targets nicotinic acetylcholine receptors, reduces nicotine dependence, and helps adults to stop smoking cigarettes. Cytisinicline may also help e-cigarette users to quit vaping. Objective: To determine the efficacy and safety of cytisinicline vs placebo to produce abstinence from e-cigarette use in adults seeking to quit vaping nicotine. Design, Setting, and Participants: This double-blind placebo-controlled randomized clinical trial compared 12 weeks of treatment with cytisinicline vs placebo, with follow-up to 16 weeks. It was conducted from July 2022 to February 2023 across 5 US clinical trial sites. A total of 160 adults who vaped nicotine daily, sought to quit, and did not currently smoke cigarettes were enrolled, and 131 (81.9%) completed the trial. Intervention: Participants were randomized (2:1) to cytisinicline, 3 mg, taken 3 times daily (n = 107) or placebo (n = 53) for 12 weeks. All participants received weekly behavioral support. Main Outcomes and Measures: Biochemically verified continuous e-cigarette abstinence during the last 4 weeks of treatment (weeks 9-12; primary outcome) and through 4 weeks posttreatment (weeks 9-16; secondary outcome). Missing outcomes were counted as nonabstinence. Results: Of 160 randomized participants (mean [SD] age, 33.6 [11.1] years; 83 [51.9%] female), 115 (71.9%) formerly smoked (≥100 lifetime cigarettes). Continuous e-cigarette abstinence in cytisinicline and placebo groups occurred in 34 of 107 participants (31.8%) vs 8 of 53 participants (15.1%) (odds ratio, 2.64; 95% CI, 1.06-7.10; P = .04) at end of treatment (weeks 9-12) and in 25 of 107 participants (23.4%) vs 7 of 53 participants (13.2%) during weeks 9 to 16 (odds ratio, 2.00; 95% CI, 0.82-5.32; P = .15). There was no evidence, based on nonsignificant interactions, that cytisinicline efficacy differed in subgroups defined by demographic characteristics, vaping pattern, e-cigarette dependence, or smoking history. Cytisinicline was well tolerated, with 4 participants (3.8%) discontinuing cytisinicline due to an adverse event. Conclusions and Relevance: In this randomized clinical trial, cytisinicline for 12 weeks, with behavioral support, demonstrated efficacy for cessation of e-cigarette use at end of treatment and was well tolerated by adults, offering a potential pharmacotherapy option for treating nicotine e-cigarette use in adults who seek to quit vaping. These results need confirmation in a larger trial with longer follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT05431387.

Insulinoma in Patient With Nonalcoholic Steatohepatitis.

An insulinoma is a rare neuroendocrine tumor characterized by inappropriate secretion of insulin with resultant hypoglycemia and concomitant symptoms. Symptoms include diaphoresis, tremor, palpitations, tachycardia, visual disturbances, weakness, confusion, syncope, seizures, and even coma. Enteropancreatic neoplasms are rare in general but among them, insulinomas are among the more common neuroendocrine tumors though they still have a very low incidence. They can be benign or malignant, however, the latter is exceptionally rare. In the case of malignancy, such spread usually includes metastasis to the liver and surrounding nodes. They can also be sporadic or occur in association with other inherited conditions. Herein, we present a case of insulinoma in a 51-year-old female.

Primary Hepatic Angiosarcoma Presenting As Cryptogenic Cirrhosis.

Primary hepatic angiosarcoma (PHA) is an exceedingly rare and aggressive neoplasm of mesenchymal origin. PHA makes a very small portion of primary liver tumors and conveys a poor prognosis. Symptomatology can be vague and often mimics primary hepatocellular carcinoma upon presentation. Diagnosis requires careful immunohistopathologic confirmation. We present a case of PHA in a patient with abdominal pain and suspected underlying cryptogenic cirrhosis.

Cytisinicline for Smoking Cessation: A Randomized Clinical Trial.

Importance: Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4ß2 nicotinic acetylcholine receptors, which mediate nicotine dependence. Although not licensed in the US, cytisinicline is used in some European countries to aid smoking cessation, but its traditional dosing regimen and treatment duration may not be optimal. Objective: To evaluate the efficacy and tolerability of cytisinicline for smoking cessation when administered in a novel pharmacokinetically based dosing regimen for 6 or 12 weeks vs placebo. Design, Setting, and Participants: A 3-group, double-blind, placebo-controlled, randomized trial (ORCA-2) compared 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily and wanted to quit. It was conducted at 17 US sites from October 2020 to December 2021. Interventions: Participants were randomized (1:1:1) to cytisinicline, 3 mg, 3 times daily for 12 weeks (n = 270); cytisinicline, 3 mg, 3 times daily for 6 weeks then placebo 3 times daily for 6 weeks (n = 269); or placebo 3 times daily for 12 weeks (n = 271). All participants received behavioral support. Main Outcomes and Measures: Biochemically verified continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo (primary) and from end of treatment to 24 weeks (secondary). Results: Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred. Conclusions and Relevance: Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04576949.

Lobular Breast Carcinoma Mimicking a Primary Gastric Malignancy.

Invasive lobular carcinoma (ILC) is the second most common subclass of breast cancer and adds to the breast malignancy burden in women. Studies focused on metastatic patterns of ILC have reported bone, gynecologic organs, the peritoneum, and the gastrointestinal tract as potential sites of metastasis. Metastatic spread to the stomach has been reported, but generally remains an infrequent finding. Due to vague symptomatology and the visual limitations of endoscopic examination, metastatic lesions can often mimic a primary gastric malignancy. Metastasis in the stomach can be challenging to diagnose and requires a multimodal, thorough endoscopic and immunohistochemical evaluation. It is important to distinguish the primary origin of malignant lesions as treatment can range from systemic chemotherapy to surgical resection based on the diagnosis. We present a case of an underlying ILC metastatic lesion mimicking a primary gastric adenocarcinoma.

Aquatic insect accumulation of uranium at spring outflows in the Grand Canyon region as influenced by aqueous and sediment geochemistry and biological factors: implications for monitoring.

Potential adverse ecological effects of expanded uranium (U) mining within the Grand Canyon region motivated studies to better understand U exposure and risk to endemic species. This study documents U exposures and analyzes geochemical and biological factors affecting U bioaccumulation at spring-fed systems within the Grand Canyon region. The principal objective was to determine if aqueous U was broadly indicative of U accumulated by insect larvae, a dominate fauna. Analyses focused on three widely distributed taxa: Argia sp. (a predatory damselfly), Culicidae (suspension feeding mosquitos), and Limnephilus sp. (a detritivorous caddisfly). The study showed that U accumulated by aquatic insects (and periphyton) generally correlated positively with total dissolved U, although correlations were strongest when based on modeled concentrations of the U-dicarbonato complex, UO2(CO3)2-2, and UO2(OH)2. Sediment metal concentration was a redundant indicator of U bioaccumulation. Neither insect size or U in the gut content of Limnephilus sp. substantially affected correlations between aqueous U and whole-body U concentrations. However, in Limnephilus sp., the gut and its content contained large quantities of U. Estimates of the sediment burden in the gut indicated that sediment was a minor source of U mass but contributed substantially to the total insect weight. As a result, whole-body U concentration would tend to vary inversely with the sediment burden of the gut. The correlations between aqueous U and bioaccumulated U provide an initial relational baseline against which newly acquired data could be evaluated for changes in U exposure during and after mining operations.

Peculiar Presentation of Gastrointestinal Stromal Tumor in a Patient With Early Satiety.

Gastrointestinal stromal tumors (GISTs) are one of the most common, potentially malignant, subepithelial lesions identified in the gastrointestinal tract. Hypothesized to derive from the interstitial cells of Cajal (ICC), GISTs commonly demonstrate gain of function mutations in proto-oncogenic receptor tyrosine kinase CD117 (KIT). Depending on mitotic activity and tumor size characteristics, GISTs may transform from benign to malignant neoplasms. Increasing evidence suggests that early identification of a GIST is paramount for optimal prognostic outcomes. We present a rare case of a GIST located in the uncinate pancreas identified via endoscopic ultrasound (EUS) and diagnosed with an EUS-guided fine needle aspiration (EUS-FNA) biopsy.

Multiorgan Failure and Omicron: A Suspected Case of Post-COVID-19 Cholangiopathy.

Since the declaration of a global pandemic by the World Health Organization on March 11, 2020, coronavirus disease 2019 (COVID-19) has impacted millions worldwide. This complex disease process has been primarily associated with respiratory illness. As we continue to learn about COVID-19, there appears to be a growing spectrum of non-pulmonary manifestations. A major topic of interest is hepatic dysfunction related to COVID-19, specifically the growing number of cases involving acute liver failure in the setting of COVID-19. Here, we present a rare case of a patient with COVID-19 antibodies, negative inpatient COVID-19 testing, jaundice, and elusive multiorgan dysfunction.

Rectal Tonsil in a Patient With Positive Syphilis Serology.

Rectal tonsils are an abnormal reactive proliferation of lymphoid tissue in the rectum. Typical lymphoid tissue of the colon and rectum can proliferate with an increased number of germinal centers in response to exposure to an antigen in the GI tract. This response, in rare cases, escalates to the proliferation of a lymphoid mass known as a rectal tonsil. Here, we present a case of a 46-year-old woman with iron deficiency anemia who underwent colonoscopy with incidental finding of a rectal tonsil. This report discusses initial clinical workup, colonoscopy findings, pathological analysis, subsequent testing, and surgical removal of the identified mass and this rare finding.

Fractured copper intrauterine device (IUD) retained in the uterine wall leading to hysterectomy: A case report.

Several types of contraception methods exist, and among these are hormonal and non-hormonal intrauterine devices (IUDs). Cases have been reported of fractured IUD pieces and retention of copper fragments upon attempted removal in office. These findings suggest the importance of careful removal of an IUD by providers. A 38-year-old Caucasian woman, gravida 2, para 2, presented for a colposcopy and endometrial biopsy (EMB). She had had a copper IUD (ParaGard) placed 10 years prior. She now requested to have it removed. After completion of the colposcopy and EMB, the provider located the IUD strings for removal. During careful removal of the IUD, a piece was broken off and remained in the uterine cavity. Upon visual inspection of the removed IUD, the right wing was missing and presumed to be still in the patient. Transabdominal and transvaginal ultrasound (TVUS) confirmed presence of a portion of the IUD in the uterine wall near the cervix. The patient was scheduled for surgical removal of the IUD by robot-assisted total laparoscopic hysterectomy with bilateral salpingectomy. This case highlights the importance of thorough evaluation of an IUD upon removal. Practitioners who work with IUD insertion and removal should remain informed about this rare complication. Risk of fracture during IUD removal should be better communicated between physicians and patients. This case study underlines the importance of careful IUD planning, from insertion to removal. Further research considering improved stepwise removal should be considered.

Uranium Bioaccumulation Dynamics in the Mayfly Neocloeon triangulifer and Application to Site-Specific Prediction.

Little is known about the underlying mechanisms governing the bioaccumulation of uranium (U) in aquatic insects. We experimentally parameterized conditional rate constants for aqueous U uptake, dietary U uptake, and U elimination for the aquatic baetid mayfly Neocloeon triangulifer. Results showed that this species accumulates U from both the surrounding water and diet, with waterborne uptake prevailing. Elevated dietary U concentrations decreased feeding rates, presumably by altering food palatability or impairing the mayfly's digestive processes, or both. Nearly 90% of the accumulated U was eliminated within 24 h after the waterborne exposure ceased, reflecting the desorption of weakly bound U from the insect's integument. To examine whether the experimentally derived rate constants for N. triangulifer could be generalized to baetid mayflies, mayfly U concentrations were predicted using the water chemistry and U measured in periphyton from springs in Grand Canyon (United States) and were compared to U concentrations in spring-dwelling mayflies. Predicted and observed mayfly U concentrations were in good agreement. Under the modeled site-specific conditions, waterborne U uptake accounted for 52-93% of the bioaccumulated U. U accumulation was limited in these wild populations due to a combination of factors including low concentrations of bioavailable dissolved U species, slow U uptake rates from food, and fast U elimination.

Serum Free Methylated Glutathione S-transferase 1 DNA Levels, Survival, and Response to Docetaxel in Metastatic, Castration-resistant Prostate Cancer: Post Hoc Analyses of Data from a Phase 3 Trial.

BACKGROUND: Glutathione S-transferase 1 (GSTP1) expression is inactivated in >90% of all prostate cancers in association with aberrant DNA methylation. Detection of serum free methylated GSTP1 (mGSTP1) DNA is associated with overall survival (OS) and response to docetaxel in metastatic castration-resistant prostate cancer (mCRPC) in test and internal validation cohorts. OBJECTIVE: To assess the relationship between serum free mGSTP1 and treatment outcomes in SYNERGY, a phase 3 multicentre randomised trial testing the addition of custirsen to first-line chemotherapy with docetaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Serum free mGSTP1 DNA was measured by a sensitive methylation-specific polymerase chain reaction assay in paired samples (baseline and after two cycles of docetaxel) from 600 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between serum free mGSTP1 at baseline, change in mGSTP1 after docetaxel, OS, and time to prostate-specific antigen (PSA) progression were examined using Cox proportional hazards models and Kaplan-Meier methods. RESULTS AND LIMITATIONS: Serum free mGSTP1 was detectable at baseline in 458 (81%) patients. Of those with detectable mGSTP1 at baseline, mGSTP1 became undetectable after two cycles in 243 (53%). Undetectable mGSTP1 at baseline was associated with longer OS (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.29-0.55; p<0.00001). The event of mGSTP1 becoming undetectable after two cycles of chemotherapy was associated with longer OS (HR 0.36, 95% CI 0.29-0.46; p<0.00001) and longer time to PSA progression (HR 0.44, 95% CI 0.35-0.56; p<0.00001). Associations between mGSTP1 and clinical outcomes were independent of other established prognostic variables. Analysis was limited by the lack of radiographic progression-free survival data. CONCLUSIONS: This is the first study to externally validate the prognostic role of a circulating epigenetic biomarker in mCRPC. Further studies are needed to validate serum free mGSTP1 as a surrogate endpoint for clinical trials and as a potential clinical decision tool. PATIENT SUMMARY: In this study, we confirmed that a blood marker predicted outcomes after chemotherapy for metastatic prostate cancer. This marker may accelerate future clinical trials of new therapies and be useful in the clinic to guide treatment decisions.

Analysis of workers' compensation disabling claims in Oregon's seafood preparation and packaging industry, 2007-2013.

BACKGROUND: Few occupational health and safety studies have focused on the US seafood preparation and packaging industry, and none on Oregon's seafood industry. METHODS: Oregon workers' compensation (WC) disabling claims data were analyzed. Oregon Employment Department and US Census Bureau data were used as denominators for rates. RESULTS: During 2007-2013, there were 188 accepted disabling claims, with an average annual rate of 24 claims per 1000 workers. Men experienced a significantly higher rate (27.6 per 1000) than women. The most frequent incident characteristics and circumstances were: by nature-traumatic injuries to muscles, tendons, ligaments, joints (42%); by body part-upper extremities (44%); and by event-overexertion and bodily reaction (48%), and contact with objects and equipment (31%). CONCLUSION: Analyzing WC disabling claims data provides important preliminary information for understanding workplace hazards to develop control strategies. Reducing traumatic and cumulative injury risk among seafood workers is paramount.

Assessing the Dietary Bioavailability of Metals Associated with Natural Particles: Extending the Use of the Reverse Labeling Approach to Zinc.

We extend the use of a novel tracing technique to quantify the bioavailability of zinc (Zn) associated with natural particles using snails enriched with a less common Zn stable isotope. Lymnaea stagnalis is a model species that has relatively fast Zn uptake rates from the dissolved phase, enabling their rapid enrichment in 67Zn during the initial phase of labeling. Isotopically enriched snails were subsequently exposed to algae mixed with increasing amounts of metal-rich particles collected from two acid mine drainage impacted rivers. Zinc bioavailability from the natural particles was inferred from calculations of 66Zn assimilation into the snail's soft tissues. Zinc assimilation efficiency (AE) varied from 28% for the Animas River particles to 45% for the Snake River particles, indicating that particle-bound, or sorbed Zn, was bioavailable from acid mine drainage wastes. The relative binding strength of Zn sorption to the natural particles was inversely related to Zn bioavailability; a finding that would not have been possible without using the reverse labeling approach. Differences in the chemical composition of the particles suggest that their geochemical properties may influence the extent of Zn bioavailability.

Biogeochemical Controls of Uranium Bioavailability from the Dissolved Phase in Natural Freshwaters.

To gain insights into the risks associated with uranium (U) mining and processing, we investigated the biogeochemical controls of U bioavailability in the model freshwater species Lymnaea stagnalis (Gastropoda). Bioavailability of dissolved U(VI) was characterized in controlled laboratory experiments over a range of water hardness, pH, and in the presence of complexing ligands in the form of dissolved natural organic matter (DOM). Results show that dissolved U is bioavailable under all the geochemical conditions tested. Uranium uptake rates follow first order kinetics over a range encompassing most environmental concentrations. Uranium uptake rates in L. stagnalis ultimately demonstrate saturation uptake kinetics when exposure concentrations exceed 100 nM, suggesting uptake via a finite number of carriers or ion channels. The lack of a relationship between U uptake rate constants and Ca uptake rates suggest that U does not exclusively use Ca membrane transporters. In general, U bioavailability decreases with increasing pH, increasing Ca and Mg concentrations, and when DOM is present. Competing ions did not affect U uptake rates. Speciation modeling that includes formation constants for U ternary complexes reveals that the aqueous concentration of dicarbonato U species (UO2(CO3)2(-2)) best predicts U bioavailability to L. stagnalis, challenging the free-ion activity model postulate.

Dietary Uptake of Cu Sorbed to Hydrous Iron Oxide is Linked to Cellular Toxicity and Feeding Inhibition in a Benthic Grazer.

Whereas feeding inhibition caused by exposure to contaminants has been extensively documented, the underlying mechanism(s) are less well understood. For this study, the behavior of several key feeding processes, including ingestion rate and assimilation efficiency, that affect the dietary uptake of Cu were evaluated in the benthic grazer Lymnaea stagnalis following 4-5 h exposures to Cu adsorbed to synthetic hydrous ferric oxide (Cu-HFO). The particles were mixed with a cultured alga to create algal mats with Cu exposures spanning nearly 3 orders of magnitude at variable or constant Fe concentrations, thereby allowing first order and interactive effects of Cu and Fe to be evaluated. Results showed that Cu influx rates and ingestion rates decreased as Cu exposures of the algal mat mixture exceeded 10(4) nmol/g. Ingestion rate appeared to exert primary control on the Cu influx rate. Lysosomal destabilization rates increased directly with Cu influx rates. At the highest Cu exposure where the incidence of lysosomal membrane damage was greatest (51%), the ingestion rate was suppressed 80%. The findings suggested that feeding inhibition was a stress response emanating from excessive uptake of dietary Cu and cellular toxicity.

Novel and nontraditional use of stable isotope tracers to study metal bioavailability from natural particles.

We devised a novel tracing approach that involves enriching test organisms with a stable metal isotope of low natural abundance prior to characterizing metal bioavailability from natural inorganic particles. In addition to circumventing uncertainties associated with labeling natural particles and distinguishing background metals, the proposed "reverse labeling" technique overcomes many drawbacks inherent to using radioisotope tracers. Specifically, we chronically exposed freshwater snails ( Lymnaea stagnalis ) to synthetic water spiked with Cu that was 99.4% (65)Cu to increase the relative abundance of (65)Cu in the snail's tissues from ~32% to >80%. The isotopically enriched snails were then exposed to benthic algae mixed with Cu-bearing Fe-Al particles collected from the Animas River (Colorado), an acid mine drainage impacted river. We used (63)Cu to trace Cu uptake from the natural particles and inferred their bioavailability from calculation of Cu assimilation into tissues. Cu assimilation from these particles was 44%, indicating that 44% of the particulate Cu was absorbed by the invertebrate. This demonstrates that inorganic particulate Cu can be bioavailable. The reverse labeling approach shows great potential in various scientific areas such as environmental contamination and nutrition for addressing questions involving uptake of an element that naturally has multiple isotopes.

Dietary bioavailability of Cu adsorbed to colloidal hydrous ferric oxide.

The dietary bioavailability of copper (Cu) adsorbed to synthetic colloidal hydrous ferric oxide (HFO) was evaluated from the assimilation of (65)Cu by two benthic grazers, a gastropod and a larval mayfly. HFO was synthesized, labeled with (65)Cu to achieve a Cu/Fe ratio comparable to that determined in naturally formed HFO, and then aged. The labeled colloids were mixed with a food source (the diatom Nitzschia palea) to yield dietary (65)Cu concentrations ranging from 211 to 2204 nmol/g (dry weight). Animals were pulse fed the contaminated diet and assimilation of (65)Cu from HFO was determined following 1-3 days of depuration. Mass transfer of (65)Cu from HFO to the diatom was less than 1%, indicating that HFO was the source of (65)Cu to the grazers. Estimates of assimilation efficiency indicated that the majority of Cu ingested as HFO was assimilated (values >70%), implying that colloidal HFO potentially represents a source of dietary Cu to benthic grazers, especially where there is active formation and infiltration of these particles into benthic substrates.

Elevated occupational transportation fatalities among older workers in Oregon: an empirical investigation.

Older workers have an elevated risk of being killed on the job, and transportation incidents involving vehicles or mobile machinery are especially deadly for this group. The present study was designed to address the research gap in understanding contributing factors to these incidents and recommend evidence-based guidelines for interventions. We gathered and analyzed data from several sources, including the Oregon Fatality Assessment and Control Evaluation program, the Oregon Workers' Compensation system, the Census of Fatal Occupational Injuries, the Bureau of Labor Statistics, and peer reviewed research literatures. Rates and rate ratios (RR) were used to evaluate excess risk among groups. The results of this study show that older workers in Oregon have an elevated risk of fatality both in all events (RR=3.0, 95% CI 2.2-4.0) and transportation events (RR=3.6, 95% CI 2.4-5.4). Additional analyses and extant literature supports our hypotheses that multiple risk factors contribute to the phenomenon, including (a) hazard exposure, (b) organization of work, (c) physical fragility, and (d) normative cognitive, sensory, and psychomotor changes that occur with age. The evidence-based framework proposed may provide valuable guidance for developing safety interventions that protect older workers.

Bioaccumulation dynamics and exposure routes of Cd and Cu among species of aquatic mayflies.

Consumption of periphyton is a potentially important route of metal exposure to benthic invertebrate grazers. The present study examined the bioaccumulation kinetics of dissolved and dietary Cd and Cu in five species of mayflies (class Insecta). Artificial stream water and benthic diatoms were separately labeled with enriched stable metal isotopes to determine physiological rate constants used by a biokinetic bioaccumulation model. The model was employed to simulate the effects of metal partitioning between water and food, expressed as the bioconcentration factor (BCF), as well as ingestion rate (IR) and metal assimilation efficiency of food (AE), on the relative importance of water and food to metal bioaccumulation. For all test species, the contribution of dietary uptake of Cd and Cu increased with BCF. For a given BCF, the contribution of food to the body burden increased with k(uf) , the metal uptake rate constant from food that combined variation in IR and AE. To explore the relative importance of water and diet exposure routes under field conditions, we used estimated site-specific aqueous free-ion concentrations to model Cd and Cu accumulation from aqueous exposure, exclusively. The predicted concentrations accounted for less than 5% of the observed concentrations, implying that most bioaccumulated metal was acquired from food. At least for the taxa considered in this study, we conclude that consumption of metal-contaminated periphyton can result in elevated metal body burdens and potentially increase the risk of metal toxicity.