Differences in Out-of-Hospital Cardiac Arrest Outcomes Among 5 Racial/Ethnic Groups.

OBJECTIVE: Out-of-hospital cardiac arrest (OHCA) is a major health problem and one of the leading causes of death in adults older than 40. Multiple prior studies have demonstrated survival disparities based on race/ethnicity, but most of these focus on a single racial/ethnic group. This study evaluated OHCA variables and outcomes among on 5 racial/ethnic groups. METHODS: This is a retrospective review of data for adult patients in the Cardiac Arrest Registry to Enhance Survival (CARES) from 3 racially diverse urban counties in the San Francisco Bay Area from May 2009 to October 2021. Stratifying by 5 racial/ethnic groups, we evaluated patient survival outcomes based on patient demographics, emergency medical services response location, cardiac arrest characteristics, and hospital interventions. Adjusted risk ratios were calculated for survival to hospital discharge, controlling for sex, age, response locations, median income of response location, arrest witness, shockable rhythm, and bystander cardiopulmonary resuscitation as well as clustering by census tract. RESULTS: There were 10,757 patient entries analyzed: 42% White, 24% Black, 18% Asian, 9.3% Hispanic, 6.0% Pacific Islander, 0.7% American Indian/Alaska Native, and 0.1% multiple races selected; however, only the first 5 racial/ethnic groups had sufficient numbers for comparison. The adjusted risk ratio for survival to hospital discharge was lower among the 4 racial/ethnic groups compared with the White reference group: Black (0.79, p = 0.003), Asian (0.78 p = 0.004), Hispanic (0.79, p = 0.018), and Pacific Islander (0.78, p = 0.041) groups. The risk difference for positive neurologic outcome was also lower among all 4 racial/ethnic groups compared with the White reference group. CONCLUSIONS: The Black, Asian, Hispanic, and Pacific Islander groups were less likely to survive to hospital discharge from OHCA when compared with the White reference group. No variables were associated with decreased survival across any of these 4 groups.

Implementation of a Leave-behind Naloxone Program in San Francisco: A One-year Experience.

INTRODUCTION: In response to the ongoing opioid overdose crisis, US officials urged the expansion of access to naloxone for opioid overdose reversal. Since then, emergency medical services' (EMS) dispensing of naloxone kits has become an emerging harm reduction strategy. METHODS: We created a naloxone training and low-barrier distribution program in San Francisco: Project FRIEND (First Responder Increased Education and Naloxone Distribution). The team assembled an advisory committee of stakeholders and subject-matter experts, worked with local and state EMS agencies to augment existing protocols, created training curricula, and developed a naloxone-distribution data collection system. Naloxone kits were labeled for registration and data tracking. Emergency medical technicians and paramedics were asked to distribute naloxone kits to any individuals (patient or bystander) they deemed at risk of experiencing or witnessing an opioid overdose, and to voluntarily register those kits. RESULTS: Training modalities included a video module (distributed to over 700 EMS personnel) and voluntary, in-person training sessions, attended by 224 EMS personnel. From September 25, 2019-September 24, 2020, 1,200 naloxone kits were distributed to EMS companies. Of these, 232 kits (19%) were registered by EMS personnel. Among registered kits, 146 (63%) were distributed during encounters for suspected overdose, and 103 (44%) were distributed to patients themselves. Most patients were male (n = 153, 66%) and of White race (n = 124, 53%); median age was 37.5 years (interquartile range 31-47). CONCLUSION: We describe a successful implementation and highlight the feasibility of a low-threshold, leave-behind naloxone program. Collaboration with multiple entities was a key component of the program's success.

A Comparison of Time to Treatment between an Emergency Department Focused Stroke Protocol and Mobile Stroke Units.

BACKGROUND: San Francisco (California USA) is a relatively compact city with a population of 884,000 and nine stroke centers within a 47 square mile area. Emergency Medical Services (EMS) transport distances and times are short and there are currently no Mobile Stroke Units (MSUs). METHODS: This study evaluated EMS activation to computed tomography (CT [EMS-CT]) and EMS activation to thrombolysis (EMS-TPA) times for acute stroke in the first two years after implementation of an emergency department (ED) focused, direct EMS-to-CT protocol entitled "Mission Protocol" (MP) at a safety net hospital in San Francisco and compared performance to published reports from MSUs. The EMS times were abstracted from ambulance records. Geometric means were calculated for MP data and pooled means were similarly calculated from published MSU data. RESULTS: From July 2017 through June 2019, a total of 423 patients with suspected stroke were evaluated under the MP, and 166 of these patients were either ultimately diagnosed with ischemic stroke or were treated as a stroke but later diagnosed as a stroke mimic. The EMS and treatment time data were available for 134 of these patients with 61 patients (45.5%) receiving thrombolysis, with mean EMS-CT and EMS-TPA times of 41 minutes (95% CI, 39-43) and 63 minutes (95% CI, 57-70), respectively. The pooled estimates for MSUs suggested a mean EMS-CT time of 35 minutes (95% CI, 27-45) and a mean EMS-TPA time of 48 minutes (95% CI, 39-60). The MSUs achieved faster EMS-CT and EMS-TPA times (P <.0001 for each). CONCLUSIONS: In a moderate-sized, urban setting with high population density, MP was able to achieve EMS activation to treatment times for stroke thrombolysis that were approximately 15 minutes slower than the published performance of MSUs.

Adult Patients with Respiratory Distress: Current Evidence-based Recommendations for Prehospital Care.

INTRODUCTION: We developed evidence-based recommendations for prehospital evaluation and treatment of adult patients with respiratory distress. These recommendations are compared with current protocols used by the 33 local emergency medical services agencies (LEMSA) in California. METHODS: We performed a review of the evidence in the prehospital treatment of adult patients with respiratory distress. The quality of evidence was rated and used to form guidelines. We then compared the respiratory distress protocols of each of the 33 LEMSAs for consistency with these recommendations. RESULTS: PICO (population/problem, intervention, control group, outcome) questions investigated were treatment with oxygen, albuterol, ipratropium, steroids, nitroglycerin, furosemide, and non-invasive ventilation. Literature review revealed that oxygen titration to no more than 94-96% for most acutely ill medical patients and to 88-92% in patients with acute chronic obstructive pulmonary disease (COPD) exacerbation is associated with decreased mortality. In patients with bronchospastic disease, the data shows improved symptoms and peak flow rates after the administration of albuterol. There is limited data regarding prehospital use of ipratropium, and the benefit is less clear. The literature supports the use of systemic steroids in those with asthma and COPD to improve symptoms and decrease hospital admissions. There is weak evidence to support the use of nitrates in critically ill, hypertensive patients with acute pulmonary edema (APE) and moderate evidence that furosemide may be harmful if administered prehospital to patients with suspected APE. Non-invasive positive pressure ventilation (NIPPV) is shown in the literature to be safe and effective in the treatment of respiratory distress due to acute pulmonary edema, bronchospasm, and other conditions. It decreases both mortality and the need for intubation. Albuterol, nitroglycerin, and NIPPV were found in the protocols of every LEMSA. Ipratropium, furosemide, and oxygen titration were found in a proportion of the protocols, and steroids were not prescribed in any LEMSA protocol. CONCLUSION: Prehospital treatment of adult patients with respiratory distress varies widely across California. We present evidence-based recommendations for the prehospital treatment of undifferentiated adult patients with respiratory distress that will assist with standardizing management and may be useful for EMS medical directors when creating and revising protocols.

Altered Mental Status: Current Evidence-based Recommendations for Prehospital Care.

INTRODUCTION: In the United States emergency medical services (EMS) protocols vary widely across jurisdictions. We sought to develop evidence-based recommendations for the prehospital evaluation and treatment of a patient with an acute change in mental status and to compare these recommendations against the current protocols used by the 33 EMS agencies in the State of California. METHODS: We performed a literature review of the current evidence in the prehospital treatment of a patient with altered mental status (AMS) and augmented this review with guidelines from various national and international societies to create our evidence-based recommendations. We then compared the AMS protocols of each of the 33 EMS agencies for consistency with these recommendations. The specific protocol components that we analyzed were patient assessment, point-of-care tests, supplemental oxygen, use of standardized scoring, evaluating for causes of AMS, blood glucose evaluation, toxicological treatment, and pediatric evaluation and management. RESULTS: Protocols across 33 EMS agencies in California varied widely. All protocols call for a blood glucose check, 21 (64%) suggest treating adults at <60mg/dL, and half allow for the use of dextrose 10%. All the protocols recommend naloxone for signs of opioid overdose, but only 13 (39%) give specific parameters. Half the agencies (52%) recommend considering other toxicological causes of AMS, often by using the mnemonic AEIOU TIPS. Eight (24%) recommend a 12-lead electrocardiogram; others simply suggest cardiac monitoring. Fourteen (42%) advise supplemental oxygen as needed; only seven (21%) give specific parameters. In terms of considering various etiologies of AMS, 25 (76%) give instructions to consider trauma, 20 (61%) to consider stroke, and 18 (55%) to consider seizure. Twenty-three (70%) of the agencies have separate pediatric AMS protocols; others include pediatric considerations within the adult protocol. CONCLUSION: Protocols for patients with AMS vary widely across the State of California. The evidence-based recommendations that we present for the prehospital diagnosis and treatment of this condition may be useful for EMS medical directors tasked with creating and revising these protocols.

Erratum: This Article Corrects: "Trends in Regionalization of Care for ST-Segment Elevation Myocardial Infarction".

[This corrects the article on p. 1010 in vol. 18, PMID: 29085531.].

Trends in Regionalization of Care for ST-Segment Elevation Myocardial Infarction.

INTRODUCTION: California has led successful regionalized efforts for several time-critical medical conditions, including ST-segment elevation myocardial infarction (STEMI), but no specific mandated protocols exist to define regionalization of care. We aimed to study the trends in regionalization of care for STEMI patients in the state of California and to examine the differences in patient demographic, hospital, and county trends. METHODS: Using survey responses collected from all California emergency medical services (EMS) agencies, we developed four categories - no, partial, substantial, and complete regionalization - to capture prehospital and inter-hospital components of regionalization in each EMS agency's jurisdiction between 2005-2014. We linked the survey responses to 2006 California non-public hospital discharge data to study the patient distribution at baseline. RESULTS: STEMI regionalization-of-care networks steadily developed across California. Only 14% of counties were regionalized in 2006, accounting for 42% of California's STEMI patient population, but over half of these counties, representing 86% of California's STEMI patient population, reached complete regionalization in 2014. We did not find any dramatic differences in underlying patient characteristics based on regionalization status; however, differences in hospital characteristics were relatively substantial. CONCLUSION: Potential barriers to achieving regionalization included competition, hospital ownership, population density, and financial challenges. Minimal differences in patient characteristics can establish that patient differences unlikely played any role in influencing earlier or later regionalization and can provide a framework for future analyses evaluating the impact of regionalization on patient outcomes.

Prehospital Care for the Adult and Pediatric Seizure Patient: Current Evidence-based Recommendations.

INTRODUCTION: We sought to develop evidence-based recommendations for the prehospital evaluation and treatment of adult and pediatric patients with a seizure and to compare these recommendations against the current protocol used by the 33 emergency medical services (EMS) agencies in California. METHODS: We performed a review of the evidence in the prehospital treatment of patients with a seizure, and then compared the seizure protocols of each of the 33 EMS agencies for consistency with these recommendations. We analyzed the type and route of medication administered, number of additional rescue doses permitted, and requirements for glucose testing prior to medication. The treatment for eclampsia and seizures in pediatric patients were analyzed separately. RESULTS: Protocols across EMS Agencies in California varied widely. We identified multiple drugs, dosages, routes of administration, re-dosing instructions, and requirement for blood glucose testing prior to medication delivery. Blood glucose testing prior to benzodiazepine administration is required by 61% (20/33) of agencies for adult patients and 76% (25/33) for pediatric patients. All agencies have protocols for giving intramuscular benzodiazepines and 76% (25/33) have protocols for intranasal benzodiazepines. Intramuscular midazolam dosages ranged from 2 to 10 mg per single adult dose, 2 to 8 mg per single pediatric dose, and 0.1 to 0.2 mg/kg as a weight-based dose. Intranasal midazolam dosages ranged from 2 to 10 mg per single adult or pediatric dose, and 0.1 to 0.2 mg/kg as a weight-based dose. Intravenous/intrasosseous midazolam dosages ranged from 1 to 6 mg per single adult dose, 1 to 5 mg per single pediatric dose, and 0.05 to 0.1 mg/kg as a weight-based dose. Eclampsia is specifically addressed by 85% (28/33) of agencies. Forty-two percent (14/33) have a protocol for administering magnesium sulfate, with intravenous dosages ranging from 2 to 6 mg, and 58% (19/33) allow benzodiazepines to be administered. CONCLUSION: Protocols for a patient with a seizure, including eclampsia and febrile seizures, vary widely across California. These recommendations for the prehospital diagnosis and treatment of seizures may be useful for EMS medical directors tasked with creating and revising these protocols.

Acute Stroke: Current Evidence-based Recommendations for Prehospital Care.

INTRODUCTION: In the United States, emergency medical services (EMS) protocols vary widely across jurisdictions. We sought to develop evidence-based recommendations for the prehospital evaluation and treatment of a patient with a suspected stroke and to compare these recommendations against the current protocols used by the 33 EMS agencies in the state of California. METHODS: We performed a literature review of the current evidence in the prehospital treatment of a patient with a suspected stroke and augmented this review with guidelines from various national and international societies to create our evidence-based recommendations. We then compared the stroke protocols of each of the 33 EMS agencies for consistency with these recommendations. The specific protocol components that we analyzed were the use of a stroke scale, blood glucose evaluation, use of supplemental oxygen, patient positioning, 12-lead electrocardiogram (ECG) and cardiac monitoring, fluid assessment and intravenous access, and stroke regionalization. RESULTS: Protocols across EMS agencies in California varied widely. Most used some sort of stroke scale with the majority using the Cincinnati Prehospital Stroke Scale (CPSS). All recommended the evaluation of blood glucose with the level for action ranging from 60 to 80 mg/dL. Cardiac monitoring was recommended in 58% and 33% recommended an ECG. More than half required the direct transport to a primary stroke center and 88% recommended hospital notification. CONCLUSION: Protocols for a patient with a suspected stroke vary widely across the state of California. The evidence-based recommendations that we present for the prehospital diagnosis and treatment of this condition may be useful for EMS medical directors tasked with creating and revising these protocols.

EMS-STARS: Emergency Medical Services "Superuser" Transport Associations: An Adult Retrospective Study.

Abstract Objective. Emergency medical services (EMS) "superusers" -those who use EMS services at extremely high rates -have not been well characterized. Recent interest in the small group of individuals who account for a disproportionate share of health-care expenditures has led to research on frequent users of emergency departments and other health services, but little research has been done regarding those who use EMS services. To inform policy and intervention implementation, we undertook a descriptive analysis of EMS superusers in a large urban community. In this paper we compare EMS superusers to low, moderate, and high users to characterize factors contributing to EMS use. We also estimate the financial impact of EMS superusers. Methods. We conducted a retrospective cross-sectional study based on 1 year of data from an urban EMS system. Data for all EMS encounters with patients age ≥18 years were extracted from electronic records generated on scene by paramedics. We identified demographic and clinical variables associated with levels of EMS use. EMS users were characterized by the annual number of EMS encounters: low (1), moderate (2-4), high (5-14), and superusers (≥15). In addition, we performed a financial analysis using San Francisco Fire Department (SFFD) 2009 charge and reimbursement data. Results. A total of 31,462 adults generated 43,559 EMS ambulance encounters, which resulted in 39,107 transports (a 90% transport rate). Encounters for general medical reasons were common among moderate and high users and less frequent among superusers and low users, while alcohol use was exponentially correlated with encounter frequency. Superusers were significantly younger than moderate EMS users, and more likely to be male. The superuser group created a significantly higher financial burden/person than any other group, comprising 0.3% of the study population, but over 6% of annual EMS charges and reimbursements. Conclusions. In this retrospective study, adult EMS "superusers" emerged as a distinct, predominantly male population and their EMS encounters were associated with alcohol use. Continued analysis of this unique, high-cost, and frequently transported population will likely illuminate specific intervention strategies.

Chest Pain of Suspected Cardiac Origin: Current Evidence-based Recommendations for Prehospital Care.

INTRODUCTION: In the United States, emergency medical services (EMS) protocols vary widely across jurisdictions. We sought to develop evidence-based recommendations for the prehospital evaluation and treatment of chest pain of suspected cardiac origin and to compare these recommendations against the current protocols used by the 33 EMS agencies in the state of California. METHODS: We performed a literature review of the current evidence in the prehospital treatment of chest pain and augmented this review with guidelines from various national and international societies to create our evidence-based recommendations. We then compared the chest pain protocols of each of the 33 EMS agencies for consistency with these recommendations. The specific protocol components that we analyzed were use of supplemental oxygen, aspirin, nitrates, opiates, 12-lead electrocardiogram (ECG), ST segment elevation myocardial infarction (STEMI) regionalization systems, prehospital fibrinolysis and ß-blockers. RESULTS: The protocols varied widely in terms of medication and dosing choices, as well as listed contraindications to treatments. Every agency uses oxygen with 54% recommending titrated dosing. All agencies use aspirin (64% recommending 325 mg, 24% recommending 162 mg and 15% recommending either), as well as nitroglycerin and opiates (58% choosing morphine). Prehospital 12-Lead ECGs are used in 97% of agencies, and all but one agency has some form of regionalized care for their STEMI patients. No agency is currently employing prehospital fibrinolysis or ß-blocker use. CONCLUSION: Protocols for chest pain of suspected cardiac origin vary widely across California. The evidence-based recommendations that we present for the prehospital diagnosis and treatment of this condition may be useful for EMS medical directors tasked with creating and revising these protocols.

Which emergency medical dispatch codes predict high prehospital nontransport rates in an urban community?

BACKGROUND: The Medical Priority Dispatch System (MPDS) is a commonly used computer-based emergency medical dispatch (EMD) system that is widely used to prioritize 9-1-1 calls and optimize resource allocation. There are five major priority classes used to dispatch 9-1-1 calls in the San Francisco System; Alpha codes are the lowest priority (lowest expected acuity) and Echo are the highest priority. OBJECTIVE: We sought to determine which MPDS dispatch codes are associated with high prehospital nontransport rates (NTRs). METHODS: All unique MPDS call categories from 2009 in a highly urbanized, two-tier advanced life support (ALS) system were sorted according to highest NTRs. There are many reasons for nontransport, such as "gone on arrival," and "patient denied transport." Those categories with greater than 100 annual calls were further evaluated. MPDS groups that included multiple categories with NTRs exceeding 25% were then identified and each category was analyzed. Results. EMS responded to a total of 81,437 calls in 2009, of which 18,851 were not transported by EMS. The majority of the NTRs were found among "cardiac/ respiratory arrest/death," "assault/sexual assaults," "unknown problem/man down," "traffic/transportation accidents," and "unconscious/fainting." "Cardiac or respiratory arrest/death -obvious death" (9B1) had the highest overall nontransport rate, 99.25% (1/134), most likely due to declaration of death. "Unknown problem -man down -medical alert notification" had the second highest NTR, 67.22% (138/421). However, Echo priority codes had the highest overall nontransport rates (45.45%) and Charlie had the lowest (13.84%). CONCLUSIONS: The nontransport rates of individual MPDS categories vary considerably and should be considered in any system design. We identified 52 unique call categories to have a 25% or greater NTR, 18 of which exceeded 40%. The majority of NTRs occurred among the "cardiac/respiratory arrest/death," "assault/sexual assaults," "unknown problem/man down," "traffic/transportation accidents," and "unconscious/fainting" categories. The higher the priority code within each subset (AB vs. CDE), the less likely the patient was to be transported. Charlie priority codes had a lower NTR than Delta, and Delta was lower than Echo. Charlie codes were therefore the strongest predictors of hospital transport, while Echo codes (highest priority) were those with the highest nontransport rates and were the worst predictors of hospital transport in the emergent subset.

Ambulance need at mass gatherings.

INTRODUCTION: Scant evidence exists to guide policy-making around public health needs during mass gatherings. In 2006, the City and County of San Francisco began requiring standby ambulances at all mass gatherings with attendance of >15,500 people. The objectives were to evaluate needs for ambulances at mass gatherings, and to make evidence-based recommendations for public health policy-makers. The hypothesis was that the needs for ambulances at mass gatherings can be estimated using community baseline data. METHODS: Emergency medical services plans were reviewed for all public events with an anticipated attendance of >1,000 people in San Francisco County during the 12-month period 01 August 2006 through 31 July 2007. Ambulance transport data were confirmed by event coordinators and ambulance company records, and the rate was calculated by dividing ambulance transports by event attendance. Baseline ambulance transport rate was calculated by dividing the annual ambulance transports in the county's computer-aided dispatch system by the census population estimate. The risk ratio was calculated using the risk of transport from a mass gathering compared with the baseline risk of ambulance transport for the local community. Significance testing and confidence intervals were calculated. RESULTS: Descriptive information was available for 100% of events and ambulance transport data available for 97% of events. The majority of the mass gatherings (47 unique events; 59 event days) were outdoor, weekend festivals, parades, or concerts, though a large proportion were athletic events. The ambulance transport rate from mass gatherings was 1 per 59,000 people every six hours. Baseline ambulance transport rate in San Francisco was 1 per 20,000 people every six hours. The transport rate from mass gatherings was significantly lower than the community baseline (risk ratio [RR]=0.15, 95% CI=0.10-0.22, p<0.001). At events reserving a standby ambulance, 46% of ambulances were unused. DISCUSSION: San Francisco mass gatherings appear to present a lower risk of ambulance transports compared to the community baseline, suggesting that the community baseline sets an appropriate standard for requiring standby ambulances at mass gatherings. The initial ambulance requirement policy in San Francisco may have been overly conservative. CONCLUSIONS: Local baseline data is a recommended starting point when setting policy for public health needs at mass gatherings.

Frequent use of emergency medical services by the elderly: a case-control study using paramedic records.

OBJECTIVE: To identify the factors that lead to increased use of emergency medical services (EMS) by patients 65 years of age and older in an urban EMS system. METHODS: Retrospective, case-control study of frequent EMS use among elderly patients transported during one year in an urban EMS system. Three distinct groups were examined for transports that took place in 1999: (1) 1-3 transports per year (low use); (2) 4-9 times per year (high use); and (3) those transported 10+ times (very high use). This frequency-use indicator variable is the primary outcome measurement. Predictors included age, gender, preexisting medical diseases, ethnicity, number of medications, number of medical problems, primary physician, psychiatric diagnosis, and homelessness. Analysis of predictors was done using ordinal logistic regression model, and a global test of interaction terms. RESULTS: Male gender, black ethnicity, homelessness, and a variety of types of medical problems were associated with increased use of EMS resources. The strongest single predictor of case status remained homelessness, which was nearly eight times as commonly associated with frequent EMS use than for the controls. The number of medical problems and medications also were significantly associated with EMS use in this patient population. There was a lack of association of alcohol, substance abuse, and psychiatric disorders with EMS use. Patients with asthma who did not have a primary care physician were more likely to use EMS services than were those who had a physician. CONCLUSIONS: This analysis highlights homelessness as being strongly associated with frequent EMS use among the elderly and downplays other associated factors, such as psychiatric disease and substance use. Medical illness severity, particularly asthma when no primary care physician is available, also appears to drive frequent EMS use. Both findings have implications in terms of targeting of public resources; providing housing to medically ill elderly and primary care to asthmatics in particular, may provide dividends not only in terms of social welfare and medical care, but in preventing frequent EMS use by the elderly.

Polychlorinated biphenyls modulated tumorigenesis in Sprague Dawley rats: correlation with mixed function oxidase activities and superoxide (O2* ) formation potentials and implied mode of action.

Parallel, chronic (24 months) multidose bioassays of the PCB (polychlorinated biphenyls) Aroclors 1016, 1242, 1254, and 1260 in male and female Sprague-Dawley rats showed sex/Aroclor-dependent increases in hepatic tumors and decreases in extrahepatic tumors. To elucidate the PCB mode of action (MOA) involved, levels of a number of hypothesized mediators were measured in liver specimens collected at 3, 6, 12, 18, and 24 months and screened for correlation with late life hepatotumorigenesis (HT; mostly adenomas). Consistently correlated with HT were (1) tissue accumulations of SigmaPCBs (correlated in both sexes) and of dioxin equivalents (toxic equivalency [TEQ]; correlated in females only); (2) net activities of six groups of mixed function oxidases (MFOs), some PCB-induced, some PCB-repressed, as determined by differential metabolism of PCB congeners; (3) activities of deproteinated, reoxidized hepatic cytosols as catalysts for superoxide (O(2)(*-)) production, such activity having the chemical characteristics of redox-cycling quinones (RCQs), e.g., those derived from the glutathionylated estrogen catechols that were identified in the female rat livers; and (4) increased expression of the indicator of cell proliferation, proliferating cell nuclear antigen. The new findings, along with other recently reported relationships, were indicative of a MOA consisting of (1) SigmaPCB/TEQ accumulation in rat tissues; (2) SigmaPCB/TEQ repression of constitutive MFOs; (3) SigmaPCB/TEQ induction of other MFOs; (4) MFO-mediated formation of RCQs; (5) RCQ-mediated formation of O(2)(*-); (6) O(2)(*-) dismutation to H(2)O(2); and (7) H(2)O(2)-mediated mitotic signaling, resulting in the proliferation of spontaneously or otherwise initiated cells to form hepatic tumors, as in tumor promotion.