A plea for urgent action: Addressing the critical shortage of cardiothoracic surgical workforce in the COSECSA region.

BACKGROUND: The College of Surgeons of East, Central, and Southern Africa (COSECSA) comprises 14 countries, many of which currently grapple with an increasing burden of cardiothoracic surgical (CTS) diseases. Health and economic implications of unaddressed CTS conditions are profound and require a robust regional response. This study aimed to define the status of CTS specialist training in the region (including the density of specialists, facilities, and active training posts), examine implications, and proffer recommendations. METHODS: A desk review of COSECSA secretariat documents and program accreditation records triangulated with information from surgical societies was performed in May 2022 and September 2023 as part of education quality improvement. A modified nominal group process involving contextual experts was used to develop a relevant action framework. RESULTS: Only 6 of 14 (43%) of COSECSA countries offered active training programs with annual intake of only 18 trainees. Significant training gaps existed in Burundi, Botswana, Malawi, Rwanda, South Sudan, Zambia, and Zimbabwe. Country specialist density ranged from 1 per 400,000 (Namibia) to 1 per 8,000,000 (Ethiopia). Overall, the region had 0.2 CTS specialists per million population as compared with 7.15 surgeons per million in High-Income Countries. Surgical education experts proposed an action framework to address the training crisis including increasing investments in CTS education, establishing regional centers of excellence, retention incentives and opportunities for women, and leveraging international partnerships. CONCLUSION: Proactive investments in infrastructure, human resources, training, and collaborative efforts by national governments, regional intergovernmental organizations, and international partners are critical to expanding regional CTS training.

Operative Case Volumes and Variation for General Surgery Training in East, Central, and Southern Africa.

BACKGROUND: Operative experience is a necessary part of surgical training. The College of Surgeons of East, Central, and Southern Africa (COSECSA), which oversees general surgery training programs in the region, has implemented guidelines for the minimum necessary case volumes upon completion of two (Membership) and five (Fellowship) years of surgical training. We aimed to review trainee experience to determine whether guidelines are being met and examine the variation of cases between countries. METHODS: Operative procedures were categorized from a cohort of COSECSA general surgery trainees and compared to the guideline minimum case volumes for Membership and Fellowship levels. The primary and secondary outcomes were total observed case volumes and cases within defined categories. Variations by country and development indices were explored. RESULTS: One hundred ninety-four trainees performed 69,283 unique procedures related to general surgery training. The review included 70 accredited hospitals and sixteen countries within Africa. Eighty percent of MCS trainees met the guideline minimum of 200 overall cases; however, numerous trainees did not meet the guideline minimum for each procedure. All FCS trainees met the volume target for total cases and orthopedics; however, many did not meet the guideline minimums for other categories, especially breast, head and neck, urology, and vascular surgery. The operative experience of trainees varied significantly by location and national income level. CONCLUSIONS: Surgical trainees in East, Central, and Southern Africa have diverse operative training experience. Most trainees fulfill the overall case volume requirements; however, further exploration of how to meet the demands of specific categories and procedures is necessary.

Treatment outcomes of esophageal cancer in Eastern Africa: protocol of a multi-center, prospective, observational, open cohort study.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer morbidity and mortality in Eastern Africa. The majority of patients with ESCC in Eastern Africa present with advanced disease at the time of diagnosis. Several palliative interventions for ESCC are currently in use within the region, including chemotherapy, radiation therapy with and without chemotherapy, and esophageal stenting with self-expandable metallic stents; however, the comparative effectiveness of these interventions in a low resource setting has yet to be examined. METHODS: This prospective, observational, multi-center, open cohort study aims to describe the therapeutic landscape of ESCC in Eastern Africa and investigate the outcomes of different treatment strategies within the region. The 4.5-year study will recruit at a total of six sites in Kenya, Malawi and Tanzania (Ocean Road Cancer Institute and Muhimbili National Hospital in Dar es Salaam, Tanzania; Kilimanjaro Christian Medical Center in Moshi, Tanzania; Tenwek Hospital in Bomet, Kenya; Moi Teaching and Referral Hospital in Eldoret, Kenya; and Kamuzu Central Hospital in Lilongwe, Malawi). Treatment outcomes that will be evaluated include overall survival, quality of life (QOL) and safety. All patients (≥18 years old) who present to participating sites with a histopathologically-confirmed or presumptive clinical diagnosis of ESCC based on endoscopy or barium swallow will be recruited to participate. Key clinical and treatment-related data including standardized QOL metrics will be collected at study enrollment, 1 month following treatment, 3 months following treatment, and thereafter at 3-month intervals until death. Vital status and QOL data will be collected through mobile phone outreach. DISCUSSION: This study will be the first study to prospectively compare ESCC treatment strategies in Eastern Africa, and the first to investigate QOL benefits associated with different treatments in sub-Saharan Africa. Findings from this study will help define optimal management strategies for ESCC in Eastern Africa and other resource-limited settings and will serve as a benchmark for future research. TRIAL REGISTRATION: This study was retrospectively registered with the ClinicalTrials.gov database on December 15, 2021,  NCT05177393 .

The impact of COSECSA in developing the surgical workforce in East Central and Southern Africa.

BACKGROUND: The Association of Surgeons of East Africa (ASEA) was formed in 1952. In 1996 a Steering Committee was formed to transform ASEA into a surgical college. The College of Surgeons of East Central and Southern Africa was officially launched in December 1999 in Nairobi, Kenya. Today the College consists of 14 constituent member countries but trains in 20 countries in Sub-Saharan Africa. PROGRAMMES: COSECSA runs a 5 year training programme in all the surgical specialties. In the first 2 years trainees do the Membership (MCS) programme. This is followed by 3 years of the Fellowship (FCS) programme. More recently the College has started a 2 year sub-specialty Fellowship in paediatric orthopaedics. GRADUATES: The main aim of the College was to expand and improve surgical training in the COSECSA region. This goal was partially realised in December 2020 when the total number of surgeons produced by the College from inception reached 557. RETENTION: Another key success story of COSECSA is that the majority of graduates have remained in the region leading to a high retention rate of 88.3%. WOMEN IN SURGERY AFRICA (WISA): Since the formation of WISA in 2015 the College has witnessed an increase in the number of female trainees. Currently only 9% of surgeons in the region are women. CONCLUSION: In its current Strategic Plan (2021-2025) COSECSA aims not only to increase the surgical workforce in the region but also to modernise its training programmes and strengthen its governance structures.

Optimal management of esophageal cancer in Africa: A systemic review of treatment strategies.

Esophageal cancer (EC) is a leading cause of cancer morbidity and mortality in Africa. Despite the high burden of disease, optimal management strategies for EC in resource-constrained settings have yet to be established. This systematic review evaluates the literature on treatments for EC throughout Africa and compares the efficacy and safety of varying treatment strategies in this context (PROSPERO CRD42017071546). PubMed, Embase and African Index Medicus were searched for studies published on treatment strategies for EC in Africa from 1980 to 2020. Searches were supplemented by examining bibliographies of included studies and relevant conference proceedings. Methodological quality/risk of bias was assessed using the Cochrane Risk-of-Bias tool and the Newcastle-Ottawa Scale. Forty-six studies were included. Case series constituted the majority of studies: 13 were case series reporting on outcomes of esophagectomies, 17 on palliative luminal or surgical interventions, four on radiotherapy and three on concurrent chemoradiation. Nine randomized controlled trials were identified, of which four prospectively compared different treatment modalities (one investigating radiotherapy vs chemoradiation, three evaluating rigid plastic stents vs other treatments). This review summarizes the research on EC treatments in Africa published over the last four decades and outlines critical gaps in knowledge related to management in this context. Areas in need of further research include (a) evaluation of the safety and efficacy of neoadjuvant therapy in patients with locally advanced disease; (b) strategies to improve long-term survival in patients treated with definitive chemoradiation; and (c) the comparative effectiveness of modern palliative interventions, focusing on quality of life and survival as outcome measures.

Operative Self-Confidence, Hesitation, and Ability Assessment of Surgical Trainees in Rural Kenya.

BACKGROUND: The education of surgical trainees is ideally designed to produce surgeons with both confidence and competence. This involves the development of autonomy in the operating room. Factors associated with autonomy and entrustment have been studied in high-resource settings. In a resource-limited context, where autonomy is solely at the discretion of faculty, and there are fewer external constraints to restrict it, we hypothesized that assessment of a trainee's performance would be dependent upon reported confidence levels of both faculty and trainees in those trainees' abilities. MATERIALS AND METHODS: At a teaching hospital in rural Kenya, operative experience surveys were administered to eleven general surgery trainees (PGY1-5) and six faculty paired dyads immediately following operative procedures in May 2016 to elicit self-reported assessments of confidence, hesitation, and ability as measured by the Zwisch Scale. We examined factors related to learning and used dyadic structural equation models to understand factors related to the assessment of ability. RESULTS: There were 107 paired surveys among 136 trainees and 130 faculty evaluations. Faculty scrubbed into 76 (72%) cases. In comparison to trainees, faculty were more likely to give a higher average score for confidence (4.08 versus 3.90; P value: 0.005), a lower score for hesitation (2.67 versus 2.84; P value: 0.001), and a lower score for the ability to perform the operation independently (2.73 versus 3.02; P value: 0.01). Faculty and trainee perceptions of hesitation influenced their ability scores. Trainee hesitation (OR 12.1; 1.2-127.6, P = 0.04) predicted whether trainees reported experiencing learning. CONCLUSIONS: Between trainees and faculty at a teaching program in rural Kenya, assessment scores of confidence, hesitation, and ability differ in value but remain fairly correlated. Hesitation is predictive of ability assessment, as well as self-reported learning opportunities. Focus upon identifying when trainees hesitate to proceed with a case may yield important educational opportunities.

Assessing Post-operative Pain with Self-reports via the Jerrycan Pain Scale in Rural Kenya.

BACKGROUND: Perioperative pain management is an essential component to improving patient outcomes. Measurement and description of pain are challenging and vary in different contexts. The objective of this study was to assess the utility of self-reporting via visual analogue scales using the Jerrycan visual analogue scale in the assessment of post-operative pain and to validate the use of this novel scale compared to standard pain scales. MATERIALS AND METHODS: Two hundred and forty-one inpatients who underwent surgical procedures were prospectively assessed for post-operative pain over a 12-month period from February 2016 to January 2017. Participants included patients who underwent general surgery, orthopedic and obstetrics/gynecology procedures. On post-operative day one, four scales were assessed: Verbal scale, Hands scale, Faces scale and Jerrycan scale, each ranging from 0-5. Scores for each scale were recorded, and agreements between scales were calculated using kappa values and Spearman's rank coefficients. RESULTS: The mean age was 34.8 years and more female subjects were evaluated (68%). The majority received spinal anesthesia (61%). The mean pain score was 2.5 for all scales. The Jerrycan (0.50) and Faces scales (0.43) had moderate agreements with the Verbal scale. Participants preferred the Jerrycan Pain Scale. CONCLUSION: The Jerrycan pain scale had comparable scores and reasonable agreement with 3 other pain scales among a cohort of post-operative patients. Patient preference and ease of use of the Jerrycan scale may impact assessment and management of pain in a rural African setting. This scale may be adapted for use in similar resource settings for post-operative pain management.

Operative Case Volume Minimums Necessary for Surgical Training Throughout Rural Africa.

BACKGROUND: Resident operative case volumes are an important aspect of surgical education, and minimums are required in Accreditation Council for Graduate Medical Education (ACGME) programs. Minimum operative case volumes for training do not exist in rural Africa. Our objective was to determine the optimal minimum operative case volume necessary for general surgery training in rural Africa. METHODS: A cross-sectional census electronic survey was conducted among faculty (N = 24) and graduates (N = 56) of Pan-African Academy of Christian Surgeons training programs. Three equally weighted exposures (median minimum case volume suggested by participants, operative experience of prior graduates, and comparisons with ACGME minimums), adjusted from responses to targeted questions, were utilized to construct an optimal minimum operative case volume for training. RESULTS: Sixty-four surgeons were contacted and 40 (13 faculty, 24 graduates, and 3 graduates who became faculty) participated. All participants thought operative case minimums were necessary, and the majority (98%) felt current training adequately prepared surgeons for their setting. Constructed optimal case volumes included 1000 major cases with fewer required cases than ACGME in abdomen, breast, thoracic, vascular, endoscopy, and laparoscopy and more required cases than ACGME for alimentary tract, endocrine, operative trauma, skin and soft tissue, pediatric, and plastic surgery. Other categories (gynecology, orthopedics, and urology) were deemed necessary for surgical training, with regional differences. Prior graduates satisfied the overall, but not category-specific, proposed minimums. CONCLUSIONS: The surveyed surgeons highlighted the need for diverse surgical training with minimum exposures. They described increased need for cases reflecting regional variations with a desire for more experience in categories less common at their institutions.

Curative Surgery Improves Survival for Colorectal Cancer in Rural Kenya.

BACKGROUND/AIMS: Colorectal cancer (CRC) is increasing in low- and middle-income countries. Surgical care is essential for the treatment. Many patients do not have access to curative surgery for colorectal cancer in rural Kenya. To better understand the impact of surgical care on colorectal cancer in a resource-limited setting, we compared the experience of patients undergoing operations to those who did not. METHODS: All patients with histologically confirmed CRC at Tenwek Hospital from January 1, 1999, to December 31, 2017, were reviewed. Demographic and clinical data were extracted from records when available. The exposure was either curative operation, palliative operation, or no operation. The primary outcome was survival at 5 years, assessed with Cox proportional hazard analysis after propensity-score matching for age, sex, tumor site, time period, and stage. RESULTS: One hundred and sixty-five patients were identified on chart review. Survival information was available for 150 patients with a median follow-up of 319 days. Fifty-two percent had colon cancer and 48% had rectal cancer. At diagnosis, the mean age was 55.4 years (SD: 16.7) and the male to female ratio was 1.1:1. Thirty-nine percent underwent curative operations, 25% palliative operations, and 36% no operations. One-year survival was estimated to be 98% for curative surgery, 73% for palliative surgery, and 83% for no surgery (p = 0.0005). On crude analysis, 5-year survival improved with curative operation in comparison to no operation with a hazard ratio of 0.30 (CI: 0.14-0.64) (p = 0.002). After propensity matching, the hazard ratio for curative operation versus no operation remained significant, 0.34 (CI: 0.14-0.80) (p = 0.01). CONCLUSIONS: Curative surgery improves survival in our resource-limited environment. Although various factors contribute to the use of surgical treatment, the survival advantage persists after adjusted analysis. Barriers exist for access to prompt surgical evaluation and treatment. Surgical care should be a priority to address the increasing burden of CRC in resource-limited settings.

Cross sectional study of serum selenium concentration and esophageal squamous dysplasia in western Kenya.

BACKGROUND: Low serum selenium status has been associated with increased risk of esophageal squamous cell carcinoma (ESCC). East Africa is a region of high ESCC incidence and is known to have low soil selenium levels, but this association has not previously been evaluated. In this study we assessed the association of serum selenium concentration and the prevalence of esophageal squamous dysplasia (ESD), the precursor lesion of ESCC, in a cross-sectional study of subjects from Bomet, Kenya. METHODS: 294 asymptomatic adult residents of Bomet, Kenya completed questionnaires and underwent endoscopy with Lugol's iodine staining and biopsy for detection of ESD. Serum selenium concentrations were measured by instrumental neutron activation analysis. Odds ratios (OR) and confidence intervals (95% CI) for associations between serum selenium and ESD were calculated using unconditional logistic regression. RESULTS: The mean serum selenium concentration was 85.5 (±28.3) µg/L. Forty-two ESD cases were identified (14% of those screened), including 5 (12%) in selenium quartile 1 (Q1), 5 (12%) in Q2, 15 (36%) in Q3, and 17 (40%) in Q4. Higher serum selenium was associated with prevalence of ESD (Q4 vs Q1: OR: 3.03; 95% CI: 1.05-8.74) and this association remained after adjusting for potential confounders (Q4 vs Q1: OR: 3.87; 95% CI: 1.06-14.19). CONCLUSION: This is the first study to evaluate the association of serum selenium concentration and esophageal squamous dysplasia in an African population at high risk for ESCC. We found a positive association between higher serum selenium concentration and prevalence of ESD, an association contrary to our original hypothesis. Further work is needed to better understand the role of selenium in the etiology of ESCC in this region, and to develop effective ESCC prevention and control strategies.

Esophageal Squamous Dysplasia is Common in Asymptomatic Kenyans: A Prospective, Community-Based, Cross-Sectional Study.

OBJECTIVES: Esophageal squamous cell carcinoma (ESCC) is endemic in east Africa and is a leading cause of cancer death among Kenyans. The asymptomatic precursor lesion of ESCC is esophageal squamous dysplasia (ESD). We aimed to determine the prevalence of ESD in asymptomatic adult residents of southwestern Kenya. METHODS: In this prospective, community-based, cross-sectional study, 305 asymptomatic adult residents completed questionnaires and underwent video endoscopy with Lugol's iodine chromoendoscopy and mucosal biopsy for detection of ESD. RESULTS: Study procedures were well tolerated, and there were no adverse events. The overall prevalence of ESD was 14.4% (95% confidence interval (CI): 10-19%), including 11.5% with low-grade dysplasia and 2.9% with high-grade dysplasia. The prevalence of ESD was >20% among men aged >50 years and women aged >60 years. Residence location was significantly associated with ESD (Zone A adjusted odds ratio (OR) 2.37, 95% CI: 1.06-5.30 and Zone B adjusted OR 2.72, 95% CI: 1.12-6.57, compared with Zone C). Iodine chromoendoscopy with biopsy of unstained lesions was more sensitive than white-light endoscopy or random mucosal biopsy for detection of ESD and had 67% sensitivity and 70% specificity. CONCLUSIONS: ESD is common among asymptomatic residents of southwestern Kenya and is especially prevalent in persons aged >50 years and those living in particular local regions. Lugol's iodine chromoendoscopy is necessary for detection of most ESD but has only moderate sensitivity and specificity in this setting. Screening for ESD is warranted in this high-risk population, and endoscopic screening of Kenyans is feasible, safe, and acceptable, but more accurate and less invasive screening tests are needed.

Randomized Trial of Small-diameter Versus Large-diameter Esophageal Stents for Palliation of Malignant Esophageal Obstruction.

GOALS: To assess the effect of esophageal stent diameter on outcomes of patients with malignant esophageal obstruction. BACKGROUND: Esophageal self-expandable metal stents (SEMS) effectively palliate dysphagia due to malignancy, but the best stent diameter is unknown. STUDY: A prospective randomized trial was conducted at a regional referral hospital. One hundred persons with unresectable esophageal cancer were enrolled, randomized to receive a SEMS of either 18 or 23 mm shaft diameter but identical design, and followed until death. Outcome measurements were dysphagia score, adverse events, endoscopic reintervention, and survival. RESULTS: The study arms were evenly matched. Dysphagia resolved after stent placement in 95% in both groups. After 6 months the cumulative incidence of recurrent dysphagia was 38% (95% CI 18%-53%) versus 47% (26%-63%) in the small-diameter versus large-diameter groups, respectively (P=0.23). The cumulative incidence of adverse events was 57% in both groups at 6 months, with trends toward more frequent gastrointestinal bleeding and esophago-respiratory fistula in the large-diameter group, and more frequent stent migration, stent occlusion, and endoscopic reintervention in the small-diameter group. There was a trend toward longer survival in the small-diameter group (median survival, 5.9 vs. 3 mo; P=0.10). Higher initial performance status score and female gender were associated with improved survival. Limitations include enrollment of only 100 (of a planned 200) persons and incomplete follow-up of some participants. CONCLUSIONS: Small-diameter and large-diameter esophageal SEMS provided similar palliation of dysphagia due to esophageal cancer. The overall incidence of adverse events was not affected by stent diameter, but there was a trend toward longer survival with small-diameter stents (Clinical trial registration number: NCT01894763).

Health assessment of gasoline and fuel oxygenate vapors: neurotoxicity evaluation.

Sprague-Dawley rats were exposed via inhalation to vapor condensates of either gasoline or gasoline combined with various fuel oxygenates to assess potential neurotoxicity of evaporative emissions. Test articles included vapor condensates prepared from "baseline gasoline" (BGVC), or gasoline combined with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA). Target concentrations were 0, 2000, 10,000 or 20,000mg/mg(3) and exposures were for 6h/day, 5days/week for 13weeks. The functional observation battery (FOB) with the addition of motor activity (MA) testing, hematoxylin and eosin staining of brain tissue sections, and brain regional analysis of glial fibrillary acidic protein (GFAP) were used to assess behavioral changes, traditional neuropathology and astrogliosis, respectively. FOB and MA data for all agents, except G/TBA, were negative. G/TBA behavioral effects resolved during recovery. Neuropathology was negative for all groups. Analyses of GFAP revealed increases in multiplebrain regions largely limited to males of the G/EtOH group, findings indicative of minor gliosis, most significantly in the cerebellum. Small changes (both increases and decreases) in GFAP were observed for other test agents but effects were not consistent across sex, brain region or exposure concentration.

Health assessment of gasoline and fuel oxygenate vapors: generation and characterization of test materials.

In compliance with the Clean Air Act regulations for fuel and fuel additive registration, the petroleum industry, additive manufacturers, and oxygenate manufacturers have conducted comparative toxicology testing on evaporative emissions of gasoline alone and gasoline containing fuel oxygenates. To mimic real world exposures, a generation method was developed that produced test material similar in composition to the re-fueling vapor from an automotive fuel tank at near maximum in-use temperatures. Gasoline vapor was generated by a single-step distillation from a 1000-gallon glass-lined kettle wherein approximately 15-23% of the starting material was slowly vaporized, separated, condensed and recovered as test article. This fraction was termed vapor condensate (VC) and was prepared for each of the seven test materials, namely: baseline gasoline alone (BGVC), or gasoline plus an ether (G/MTBE, G/ETBE, G/TAME, or G/DIPE), or gasoline plus an alcohol (G/EtOH or G/TBA). The VC test articles were used for the inhalation toxicology studies described in the accompanying series of papers in this journal. These studies included evaluations of subchronic toxicity, neurotoxicity, immunotoxicity, genotoxicity, reproductive and developmental toxicity. Results of these studies will be used for comparative risk assessments of gasoline and gasoline/oxygenate blends by the US Environmental Protection Agency.

The mammalian toxicological hazards of petroleum-derived substances: an overview of the petroleum industry response to the high production volume challenge program.

Petroleum-derived substances are complex and composed of aliphatic (normal-, iso-, and cycloparaffins), olefinic, and/or aromatic constituents. Approximately 400 of these complex substances were evaluated as part of the US Environmental Protection Agency voluntary High Production Volume (HPV) Challenge program. The substances were separated into 13 groups (categories), and all available data were assessed. Toxicology testing was conducted as necessary to fully address the end points encompassed by the HPV initiative. In a broad sense, volatile hydrocarbons may cause acute central nervous system effects, and those that are liquids at room temperature pose aspiration hazards if taken into the lungs as liquids and may also cause skin irritation. Higher boiling substances may contain polycyclic aromatic constituents (PACs) that can be mutagenic and carcinogenic and may also cause developmental effects. Substances containing PACs can also cause target organ and developmental effects. The effects of aliphatic constituents include liver enlargement and/or renal effects in male rats via an α-2u-globulin-mediated process and, in some cases, small but statistically significant reductions in hematological parameters. Crude oils may contain other constituents, particularly sulfur- and nitrogen-containing compounds, which are removed during refining. Aside from these more generic considerations, some specific petroleum substances may contain unusually toxic constituents including benzene, 1,3-butadiene, and/or n-hexane, which should also be taken into account if present at toxicologically relevant levels.

Use of a statistical model to predict the potential for repeated dose and developmental toxicity of dermally administered crude oil and relation to reproductive toxicity.

Petroleum (commonly called crude oil) is a complex substance primarily composed of hydrocarbon constituents. Based on the results of previous toxicological studies as well as occupational experience, the principal acute toxicological hazards are those associated with exposure by inhalation to volatile hydrocarbon constituents and hydrogen sulfide, and chronic hazards are associated with inhalation exposure to benzene and dermal exposure to polycyclic aromatic compounds. The current assessment was an attempt to characterize the potential for repeated dose and/or developmental effects of crude oils following dermal exposures and to generalize the conclusions across a broad range of crude oils from different sources. Statistical models were used to predict the potential for repeated dose and developmental toxicity from compositional information. The model predictions indicated that the empirical data from previously tested crude oils approximated a "worst case" situation, and that the data from previously tested crude oils could be used as a reasonable basis for characterizing the repeated dose and developmental toxicological hazards of crude oils in general.

Subchronic and developmental toxicity of aromatic extracts.

Aromatic extracts (AEs; distillate AEs [DAEs] and residual AEs [RAEs]) are complex, highly viscous liquid petroleum streams with variable compositions derived by extraction of aromatic compounds from distillate and residual petroleum fractions from a vacuum distillation tower, respectively. The DAEs generally contain significant amounts of polycyclic aromatic compounds (PACs) and are carcinogenic. The RAEs typically contain lower concentrations of biologically active PACs. The PACs in refinery streams can cause effects in repeated-dose and developmental toxicity studies. In a 13-week dermal study, light paraffinic DAE had several dose-related effects involving multiple organs; no-observed-effect level was <5 mg/kg/d, with no overt toxicity. Predicted dose-responses at 10% (PDR10s), modeled doses causing a 10% effect on sensitive end points based on PAC content, ranged from 25 to 78 mg/kg/d for untested paraffinic DAEs. The no observed adverse effect level (NOAEL) for developmental toxicity for light paraffinic DAE was 5 mg/kg/d. Statistically significant developmental effects at higher doses were associated with maternal effects. The PDR10s for developmental toxicity of paraffinic DAEs ranged from 7 to >2000 mg/kg/d, reflecting differences due to variation in PACs. The NOAELs for RAEs were 500 mg/kg for 90-day studies and 2000 mg/kg for developmental toxicity. Reproductive toxicity is not considered to be a sensitive end point for AEs based on the toxicity tests with DAEs, RAEs, and other PAC-containing petroleum substances. In vivo micronucleus tests on heavy paraffinic DAE, RAEs, and a range of other petroleum substances have been negative. The exception to this general trend was a marginally positive response with light paraffinic DAE. Most DAEs are considered unlikely to produce chromosomal effects in vivo.

Acute, subchronic, and developmental toxicological properties of lubricating oil base stocks.

Lubricating oil base stocks (LOBs) are substances used in the manufacture of finished lubricants and greases. They are produced from residue remaining after atmospheric distillation of crude oil that is subsequently fractionated by vacuum distillation and additional refining steps. Initial LOB streams that have been produced by vacuum distillation but not further refined may contain polycyclic aromatic compounds (PACs) and may present carcinogenic hazards. In modern refineries, LOBs are further refined by multistep processes including solvent extraction and/or hydrogen treatment to reduce the levels of PACs and other undesirable constituents. Thus, mildly (insufficiently) refined LOBs are potentially more hazardous than more severely (sufficiently) refined LOBs. This article discusses the evaluation of LOBs using statistical models based on content of PACs; these models indicate that insufficiently refined LOBs (potentially carcinogenic LOBs) can also produce systemic and developmental effects with repeated dermal exposure. Experimental data were also obtained in ten 13-week dermal studies in rats, eight 4-week dermal studies in rabbits, and seven dermal developmental toxicity studies with sufficiently refined LOBs (noncarcinogenic and commonly marketed) in which no observed adverse effect levels for systemic toxicity and developmental toxicity were 1000 to 2000 mg/kg/d with dermal exposures, typically the highest dose tested. Results in both oral and inhalation developmental toxicity studies were similar. This absence of toxicologically relevant findings was consistent with lower PAC content of sufficiently refined LOBs. Based on data on reproductive organs with repeated dosing and parameters in developmental toxicity studies, sufficiently refined LOBs are likely to have little, if any, effect on reproductive parameters.