A review of outbreaks of foodborne disease associated with passenger ships: evidence for risk management

OBJECTIVE: Foodborne disease outbreaks on ships are of concern because of their potentially serious health consequences for passengers and crew and high costs to the industry. The authors conducted a review of outbreaks of foodborne diseases associated with passenger ships in the framework of a World Health Organization project on setting guidelines for ship sanitation. METHODS: The authors reviewed data on 50 outbreaks of foodborne disease associated with passenger ships. For each outbreak, data on pathogens/toxins, type of ship, factors contributing to outbreaks, mortality and morbidity, and food vehicles were collected. RESULTS: The findings of this review show that the majority of reported outbreaks were associated with cruise ships and that almost 10,000 people were affected. Salmonella spp were most frequently associated with outbreaks. Foodborne outbreaks due to enterotoxigenic E. coli spp, Shigella spp, noroviruses (formally called Norwalk-like viruses), Vibrio spp, Staphylococcus aureus, Clostridium perfringens, Cyclospora sp, and Trichinella sp also occurred on ships. Factors associated with the outbreaks reviewed include inadequate temperature control, infected food handlers, contaminated raw ingredients, cross-contamination, inadequate heat treatment, and onshore excursions. Seafood was the most common food vehicle implicated in outbreaks. CONCLUSIONS: Many ship-associated outbreaks could have been prevented if measures had been taken to ensure adequate temperature control, avoidance of cross-contamination, reliable food sources, adequate heat treatment, and exclusion of infected food handlers from work.     

Application of benzo(a)pyrene and coal tar tumor dose-response data to a modified benchmark dose method of guideline development

Assessment of cancer risk from exposure to polycyclic aromatic hydrocarbons (PAHs) has been traditionally conducted by applying the conservative linearized multistage (LMS) model to animal tumor data for benzo(a)pyrene (BaP), considered the most potent carcinogen in PAH mixtures. Because it has been argued that LMS use of 95% lower confidence limits on dose is unnecessarily conservative, that assumptions of low-dose linearity to zero in the dose response imply clear mechanistic understanding, and that "acceptable" cancer risk rests on a policy decision, an alternative cancer risk assessment approach has been developed. Based in part on the emerging benchmark dose (BMD) method, the modified BMD method we used involves applying a suite of conventional mathematical models to tumor dose-response data. This permits derivation of the average dose corresponding to 5% extra tumor incidence (BMD0.05) to which a number of modifying factors are applied to achieve a guideline dose, that is, a daily dose considered safe for human lifetime exposure. Application of the modified BMD method to recent forestomach tumor data from BaP ingestion studies in mice suggests a guideline dose of 0.08 microg/kg/day. Based on this and an understanding of dietary BaP, and considering that BaP is a common contaminant in soil and therefore poses human health risk via soil ingestion, we propose a BaP soil guideline value of 5 ppm (milligrams per kilogram). Mouse tumor data from ingestion of coal tar mixtures containing PAHs and BaP show that lung and not forestomach tumors are most prevalent and that BaP content cannot explain the lung tumors. This calls into question the common use of toxicity equivalence factors based on BaP for assessing risk from complex PAH mixtures. Emerging data point to another PAH compound--H-benzo(c)fluorene--as the possible lung tumorigen.     

A framework for assessing risks to children from exposure to environmental agents

In recent years there has been an increasing focus in environmental risk assessment on children as a potentially susceptible population. There also has been growing recognition of the need for a systematic approach for organizing, evaluating, and incorporating the available data on children's susceptibilities in risk assessments. In this article we present a conceptual framework for assessing risks to children from environmental exposures. The proposed framework builds on the problem formulation-->analysis-->risk characterization paradigm, identifying at each phase the questions and issues of particular importance for characterizing risks to the developing organism (from conception through organ maturation). The framework is presented and discussed from the complementary perspectives of toxicokinetics and toxicodynamics.     

Childhood asthma hospitalizations and ambient air sulfur dioxide concentrations in Bronx County, New York

The association between asthma hospitalizations and ambient sulfur dioxide (SO2) concentrations was examined in a case-control study in Bronx County, New York. Cases comprised 2629 children aged 0-14 yr who were admitted to hospitals for asthma. There were 2236 controls who were admitted for reasons other than asthma. Daily ambient SO2 concentrations were categorized into quartiles of both average and maximum levels and various exposure windows (i.e., day of admission and 1-, 2-, and 3-d lags). Cases were exposed to higher daily average concentrations of SO2 than controls. The authors compared the highest exposure quartile with the lowest, and the odds ratios were 1.66, 1.90, 2.05, and 2.21 (all p < 0.01 for same-day, 1-, 2-, and 3-d lags, respectively), with a similar finding for daily SO2 maximum exposure. The results suggest a consistent positive association between SO2 exposure and hospitalizations for childhood asthma.     

Ethanol-induced increases in neuroactive steroids in the rat brain and plasma are absent in adrenalectomized and gonadectomized rats

Peripheral administration of alcohol has been demonstrated to cause significant increases in neurosteroid levels in the brain and periphery. These findings have led to several theories suggesting a role for neurosteroids in the actions of alcohol. However, the anatomical sources of these steroids (e.g., brain or periphery) are as yet unknown. This study utilized gas chromatography/mass spectrometry (GC/MS) to assess the levels of several neuroactive steroids in plasma and brain frontal cortex 30-360 min following acute administration of alcohol (2 g/kg, i.p.). Concentrations of pregnenolone, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), and allotetrahydrodeoxycorticosterone (3alpha,21-dihydroxy-5alpha-pregnan-20-one) were all measured. In order to determine the contribution of peripheral endocrine organs to neurosteroid responses, neuroactive steroid levels were measured in both intact and adrenalectomized/gonadectomized male Wistar rats 30 min after acute administration of alcohol. Intact animals exhibited a maximal increase of pregnenolone in plasma and frontal cortex 30 min after acute administration of alcohol. In addition, allopregnanolone levels increased, with a maximal effect observed at 60 min in plasma. However, in the adrenalectomized/gonadectomized groups treated with alcohol, no significant increases of pregnenolone, allopregnanolone, or allotetrahydrodeoxycorticosterone were found after 30 min. Thus, the alcohol-induced response was associated first with a relatively rapid increase in the first and rate-limiting step in the conversion of cholesterol to steroids, leading to increases in pregnenolone levels. This response was followed by the further secretion of the anxiolytic neuroactive steroids allopregnanolone and allotetrahydrodeoxycorticosterone, both of which appeared to be of adrenal and gonadal origin.     

Design, synthesis, and biological evaluation of thio-containing compounds with serum HDL-cholesterol-elevating properties

A novel series of substituted sulfanyldihydroimidazolones (1) that modulates high-density lipoprotein cholesterol (HDL-C) has been reported to have HDL-elevating properties in several animal models. Concerns about the chemical and metabolic stability of 1 directed us to explore the structure-activity relationship (SAR) of a related series of substituted thiohydantoins (2). Expansion of the scope of the thiohydantoin series led to exploration of compounds in related thio-containing ring systems 3-7 and the N-cyanoguanidine derivative 8. Compounds were tested sequentially in three animal models to assess their HDL-C elevating efficacy and safety profiles. Further evaluation of selected compounds in a dose-response paradigm culminated in the identification of compound 2.39 as a candidate compound for advanced preclinical studies.     

Discovery of novel phenolic antioxidants as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases

Vascular cell adhesion molecule-1 (VCAM-1) mediates recruitment of leukocytes to endothelial cells and is implicated in many inflammatory conditions. Since part of the signal transduction pathway that regulates the activation of VCAM-1 expression is redox-sensitive, compounds with antioxidant properties may have inhibitory effects on VCAM-1 expression. Novel phenolic compounds have been designed and synthesized starting from probucol (1). Many of these compounds demonstrated potent inhibitory effects on cytokine-induced VCAM-1 expression and displayed potent antioxidant effects in vitro. Some of these derivatives (4o, 4p, 4w, and 4x) inhibited lipopolysaccharide (LPS)-induced secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 from human peripheral blood mononuclear cells (hPBMCs) in a concentration-dependent manner in vitro and showed antiinflammatory effects in an animal model. Compounds 4ad and 4ae are currently in clinical trials for the treatment of rheumatoid arthritis (RA) and prevention of chronic organ transplant rejection, respectively.     

The pharmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers

Nanocrystal budesonide (nanobudesonide) is a suspension for nebulization in patients with steroid-responsive pulmonary diseases such as asthma. The pharmacokinetics and safety of the product were compared to those of Pulmicort Respules. Sixteen healthy volunteers were administered nanobudesonide 0.5 and 1.0 mg, Pulmicort Respules 0.5 mg, and placebo in a four-way, randomized crossover design. All nebulized formulations were well tolerated, with no evidence of bronchospasm. Nebulization times were significantly shorter for nanobudesonide compared to Pulmicort Respules. Because of a low oral bioavailability, plasma concentration of budesonide is a good marker of lung-delivered dose. The pharmacokinetics of nanobudesonide 0.5 and 1.0 mg were approximately dose proportional with respect to Cmax, AUC(0-t), and AUC(0-infinity). Nanobudesonide 0.5 mg and Pulmicort Respules 0.5 mg exhibited similar AUCs, suggesting a similar extent of pulmonary absorption. A higher Cmax was noted with nanobudesonide 0.5 mg, and the tmax was significantly different, suggesting a more rapid rate of drug delivery of nanobudesonide 0.5 mg than Pulmicort Respules. In conclusion, nebulized nanobudesonide 0.5 mg was safe in healthy volunteers, with a similar extent of absorption as Pulmicort Respules.