Hazard characterization of Alternaria toxins to identify data gaps and improve risk assessment for human health.

Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a large range of substrates. A spectrum of structurally diverse secondary metabolites with toxic potential has been identified, but occurrence and relative proportion of the different metabolites in complex mixtures depend on strain, substrate, and growth conditions. This review compiles the available knowledge on hazard identification and characterization of Alternaria toxins. Alternariol (AOH), its monomethylether AME and the perylene quinones altertoxin I (ATX-I), ATX-II, ATX-III, alterperylenol (ALP), and stemphyltoxin III (STTX-III) showed in vitro genotoxic and mutagenic properties. Of all identified Alternaria toxins, the epoxide-bearing analogs ATX-II, ATX-III, and STTX-III show the highest cytotoxic, genotoxic, and mutagenic potential in vitro. Under hormone-sensitive conditions, AOH and AME act as moderate xenoestrogens, but in silico modeling predicts further Alternaria toxins as potential estrogenic factors. Recent studies indicate also an immunosuppressive role of AOH and ATX-II; however, no data are available for the majority of Alternaria toxins. Overall, hazard characterization of Alternaria toxins focused, so far, primarily on the commercially available dibenzo-α-pyrones AOH and AME and tenuazonic acid (TeA). Limited data sets are available for altersetin (ALS), altenuene (ALT), and tentoxin (TEN). The occurrence and toxicological relevance of perylene quinone-based Alternaria toxins still remain to be fully elucidated. We identified data gaps on hazard identification and characterization crucial to improve risk assessment of Alternaria mycotoxins for consumers and occupationally exposed workers.

Impact of climate change on foodborne infections and intoxications.

Background: Temperature, precipitation, and humidity are important factors that can influence the spread, reproduction, and survival of pathogens. Climate change affects these factors, resulting in higher air and water temperatures, increased precipitation, or water scarcity. Climate change may thus have an increasing impact on many infectious diseases. Methods: The present review considers those foodborne pathogens and toxins in animal and plant foods that are most relevant in Germany, on the basis of a selective literature review: the bacterial pathogens of the genera Salmonella, Campylobacter and Vibrio, parasites of the genera Cryptosporidium and Giardia, and marine biotoxins. Results: As climate change continues to progress, all infections and intoxications discussed here can be expected to increase in Germany. Conclusions: The expected increase in foodborne infections and intoxications presents a growing public health risk in Germany.

[The One Health approach in the context of global commodity chains, crises, and food and feed safety]. / Das One-Health-Konzept im Kontext globaler Warenketten, Krisen und der Sicherheit von Lebens- und Futtermitteln.

The holistic view of food and feed safety, including animal health and environmental conditions, is an important pillar of the One Health approach. The terminology thus clearly goes beyond the prevention of spreading microbiological diseases, in which context it is often understood, and highlights that humans, animals, and the environment as well as their interaction should be considered in a transdisciplinary context.In terms of One Health, this discussion paper focuses less on microbiological risks, but rather on the connection to chemical risks in the food chain. This is illustrated by concrete examples of chemical contaminants (metals, persistent organic contaminants, natural toxins). The mechanisms of input and transfer along the food chain are presented.Minimizing the presence of contaminants and thus exposure requires international and interdisciplinary cooperation in the spirit of the One Health approach. Climate change, pandemics, shortages of raw materials, energy deficiencies, political crises, and environmental disasters can affect the entire food chain from primary production of plant and animal foods to further processing and provision of products to consumers. In addition to changing availability, this can also have an impact on the composition, quality, and safety of food and feed. Based on the effect on global commodity chains, vulnerable and resilient areas along the food chain become visible. In terms of the One Health approach, the aim is to increase safety and resilience along the food chain and to minimize its vulnerability.

Results of the BfR MEAL Study: In Germany, mercury is mostly contained in fish and seafood while cadmium, lead, and nickel are present in a broad spectrum of foods.

The BfR MEAL Study provides representative levels of substances in foods consumed in Germany. Mercury, cadmium, lead, and nickel are contaminants present in foods introduced by environmental and industrial processes. Levels of these elements were investigated in 356 foods. Foods were purchased representatively, prepared as consumed and pooled with similar foods before analysis. Highest mean levels of mercury were determined in fish and seafood, while high levels of cadmium, lead, and nickel were present in cocoa products and legumes, nuts, oilseeds, and spices. The sampling by region, season, and production type showed minor differences in element levels for specific foods, however no tendency over all foods or for some food groups was apparent. The data on mercury, cadmium, lead, and nickel provide a comprehensive basis for chronic dietary exposure assessment of the population in Germany. All levels found were below regulated maximum levels.

Comparison of long-term versus short-term effects of okadaic acid on the apoptotic status of human HepaRG cells.

The biotoxin okadaic acid (OA) is a lipophilic secondary metabolite of marine microalgae. Therefore, OA accumulates in the fatty tissue of various shellfish and may thus enter the food chain. The ingestion of OA via contaminated marine species can lead to the diarrhetic shellfish poisoning syndrome characterized by the occurrence of a series of acute gastrointestinal symptoms in humans. In addition, genotoxicity and tumor-promoting properties of OA might constitute a long-term threat to human health. In order to deepen our understanding of the molecular effects of OA, we compared long-term (14 d) and short-term (24 h and 48 h) apoptotic effects of the compound on human HepaRG hepatocarcinoma cells. Cells were treated either with single doses for 24 and 48 h, respectively, or seven times over a period of 14 d, so that the cumulated quantities of OA in the long-term approach were equal to the single doses upon short-term treatment. Both short-term treatment scenarios led to the induction of apoptosis. Specific caspase activation assays and transcriptional analysis of mRNAs encoding proteins involved in the regulation of apoptosis suggest that OA-induced apoptosis occurs presumably by activation of the intrinsic apoptotic pathway. In contrast, effects were much less pronounced in case of long-term treatment. This is possibly linked to cellular protective mechanisms against low amounts of toxins, e.g. transporter-mediated efflux. In conclusion, our results show a clear concentration- and time-dependency of OA-mediated apoptotic effects in HepaRG cells and contribute to the elucidation of molecular effects of OA.

Okadaic acid activates Wnt/ß-catenin-signaling in human HepaRG cells.

The lipophilic phycotoxin okadaic acid (OA) occurs in the fatty tissue and hepatopancreas of filter-feeding shellfish. The compound provokes the diarrhetic shellfish poisoning (DSP) syndrome after intake of seafood contaminated with high levels of the DSP toxin. In animal experiments, long-term exposure to OA is associated with an elevated risk for tumor formation in different organs including the liver. Although OA is a known inhibitor of the serine/threonine protein phosphatase 2A, the mechanisms behind OA-induced carcinogenesis are not fully understood. Here, we investigated the influence of OA on the ß-catenin-dependent Wnt-signaling pathway, addressing a major oncogenic pathway relevant for tumor development. We analyzed OA-mediated effects on ß-catenin and its biological function, cellular localization, post-translational modifications, and target gene expression in human HepaRG hepatocarcinoma cells treated with non-cytotoxic concentrations up to 50 nM. We detected concentration- and time-dependent effects of OA on the phosphorylation state, cellular redistribution as well as on the amount of transcriptionally active ß-catenin. These findings were confirmed by quantitative live-cell imaging of U2OS cells stably expressing a green fluorescent chromobody which specifically recognize hypophosphorylated ß-catenin. Finally, we demonstrated that nuclear translocation of ß-catenin mediated by non-cytotoxic OA concentrations results in an upregulation of Wnt-target genes. In conclusion, our results show a significant induction of the canonical Wnt/ß-catenin-signaling pathway by OA in human liver cells. Our data contribute to a better understanding of the molecular mechanisms underlying OA-induced carcinogenesis.

The marine biotoxin okadaic acid affects intestinal tight junction proteins in human intestinal cells.

Okadaic acid (OA) is a lipophilic phycotoxin that accumulates in the hepatopancreas and fatty tissue of shellfish. Consumption of highly OA-contaminated seafood leads to diarrhetic shellfish poisoning which provokes severe gastrointestinal symptoms associated with a disruption of the intestinal epithelium. Since the molecular mechanisms leading to intestinal barrier disruption are not fully elucidated, we investigated the influence of OA on intestinal tight junction proteins (TJPs) in differentiated Caco-2 cells. We found a concentration- and time-dependent deregulation of genes encoding for intestinal TJPs of the claudin family, occludin, as well as zonula occludens (ZO) 1 and 2. Immunofluorescence staining showed concentration-dependent effects on the structural organization of TJPs already after treatment with a subtoxic but human-relevant concentration of OA. In addition, changes in the structural organization of cytoskeletal F-actin as well as its associated protein ZO-1 were observed. In summary, we demonstrated effects of OA on TJPs in intestinal Caco-2 cells. TJP expressions were affected after treatment with food-relevant OA concentrations. These results might explain the high potential of OA to disrupt the intestinal barrier in vivo as its first target. Thereby the present data contribute to a better understanding of the OA-dependent induction of molecular effects within the intestinal epithelium.

Palliative care consultation teams cut hospital costs for Medicaid beneficiaries.

Patients facing serious or life-threatening illnesses account for a disproportionately large share of Medicaid spending. We examined 2004-07 data to determine the effect on hospital costs of palliative care team consultations for patients enrolled in Medicaid at four New York State hospitals. On average, patients who received palliative care incurred $6,900 less in hospital costs during a given admission than a matched group of patients who received usual care. These reductions included $4,098 in hospital costs per admission for patients discharged alive, and $7,563 for patients who died in the hospital. Consistent with the goals of a majority of patients and their families, palliative care recipients spent less time in intensive care, were less likely to die in intensive care units, and were more likely to receive hospice referrals than the matched usual care patients. We estimate that the reductions in Medicaid hospital spending in New York State could eventually range from $84 million to $252 million annually (assuming that 2 percent and 6 percent of Medicaid patients discharged from the hospital received palliative care, respectively), if every hospital with 150 or more beds had a fully operational palliative care consultation team.

Variability in access to hospital palliative care in the United States.

BACKGROUND: Hospital palliative care programs provide high-quality, comprehensive care for seriously ill patients and their families. OBJECTIVE: To examine geographic variation in patient and medical trainee access to hospital palliative care and to examine predictors of these programs. METHODS: Primary and secondary analyses of national survey and census data. Hospital data including hospital palliative care programs were obtained from the American Hospital Association (AHA) Annual Survey Databasetrade mark for fiscal year 2006 supplemented by mailed surveys. Medical school-affiliated hospitals were obtained from the American Association of Medical Colleges, Web-site review, and telephone survey. Health care utilization data were obtained from the Dartmouth Atlas of Health Care 2008. Multivariate logistic regression was used to identify characteristics significantly associated with the presence of hospital palliative care. RESULTS: A total of 52.8% of hospitals with 50 or more total facility beds reported hospital palliative care with considerable variation by state; 40.9% (144/352) of public hospitals, 20.3% (84/413) of for-profit hospitals, and 28.8% (160/554) of Medicare sole community providers reported hospital palliative care. A total of 84.5% of medical schools were associated with at least one hospital palliative care program. Factors significantly associated (p < 0.05) with hospital palliative care included geographic location, owning a hospice program, having an American College of Surgery approved cancer program, percent of persons in the county with a university education, and medical school affiliation. For-profit and public hospitals were significantly less likely to have hospital palliative care when compared with nonprofit institutions. States with higher hospital palliative care penetration rates were observed to have fewer Medicare hospital deaths, fewer intensive care unit/cardiac care unit (ICU/CCU) days and admissions during the last 6 months of life, fewer ICU/CCU admission during terminal hospitalizations, and lower overall Medicare spending/enrollee. DISCUSSION: This study represents the most recent estimate to date of the prevalence of hospital palliative care in the United States. There is wide geographic variation in access to palliative care services although factors predicting hospital palliative care have not changed since 2005. Overall, medical students have high rates of access to hospital palliative care although complete penetration into academic settings has not occurred. The association between hospital palliative care penetration and lower Medicare costs is intriguing and deserving of further study.

Lifetime prevalence of mental disorders and suicide attempts in diverse lesbian, gay, and bisexual populations.

Past studies have reported little about variability in mental disorders among lesbians, gay men, and bisexual individuals. We assessed the prevalence of psychiatric disorders in 388 lesbian, gay, and bisexual Black, Latino, and White individuals. Black lesbians, gay men, and bisexual individuals had lower prevalence of all disorders than did Latino and White individuals; younger cohorts had fewer mood disorders than did older cohorts; bisexual persons had more substance use disorders than did gay men and lesbians; and Latino respondents attempted suicide more often than did White respondents.

Prenatal insecticide exposures and birth weight and length among an urban minority cohort.

We reported previously that insecticide exposures were widespread among minority women in New York City during pregnancy and that levels of the organophosphate chlorpyrifos in umbilical cord plasma were inversely associated with birth weight and length. Here we expand analyses to include additional insecticides (the organophosphate diazinon and the carbamate propoxur), a larger sample size (n = 314 mother-newborn pairs), and insecticide measurements in maternal personal air during pregnancy as well as in umbilical cord plasma at delivery. Controlling for potential confounders, we found no association between maternal personal air insecticide levels and birth weight, length, or head circumference. For each log unit increase in cord plasma chlorpyrifos levels, birth weight decreased by 42.6 g [95% confidence interval (CI), -81.8 to -3.8, p = 0.03] and birth length decreased by 0.24 cm (95% CI, -0.47 to -0.01, p = 0.04). Combined measures of (ln)cord plasma chlorpyrifos and diazinon (adjusted for relative potency) were also inversely associated with birth weight and length (p < 0.05). Birth weight averaged 186.3 g less (95% CI, -375.2 to -45.5) among newborns with the highest compared with lowest 26% of exposure levels (p = 0.01). Further, the associations between birth weight and length and cord plasma chlorpyrifos and diazinon were highly significant (p < or = 0.007) among newborns born before the 2000-2001 U.S. Environmental Protection Agency's regulatory actions to phase out residential use of these insecticides. Among newborns born after January 2001, exposure levels were substantially lower, and no association with fetal growth was apparent (p > 0.8). The propoxur metabolite 2-isopropoxyphenol in cord plasma was inversely associated with birth length, a finding of borderline significance (p = 0.05) after controlling for chlorpyrifos and diazinon. Results indicate that prenatal chlorpyrifos exposures have impaired fetal growth among this minority cohort and that diazinon exposures may have contributed to the effects. Findings support recent regulatory action to phase out residential uses of the insecticides.

Effects of transplacental exposure to environmental pollutants on birth outcomes in a multiethnic population.

Inner-city, minority populations are high-risk groups for adverse birth outcomes and also are more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), polycyclic aromatic hydrocarbons (PAHs), and pesticides. In a sample of 263 nonsmoking African-American and Dominican women, we evaluated the effects on birth outcomes of prenatal exposure to airborne PAHs monitored during pregnancy by personal air sampling, along with ETS estimated by plasma cotinine, and an organophosphate pesticide (OP) estimated by plasma chlorpyrifos (CPF). Plasma CPF was used as a covariate because it was the most often detected in plasma and was highly correlated with other pesticides frequently detected in plasma. Among African Americans, high prenatal exposure to PAHs was associated with lower birth weight (p = 0.003) and smaller head circumference (p = 0.01) after adjusting for potential confounders. CPF was associated with decreased birth weight and birth length overall (p = 0.01 and p = 0.003, respectively) and with lower birth weight among African Americans (p = 0.04) and reduced birth length in Dominicans (p < 0.001), and was therefore included as a covariate in the model with PAH. After controlling for CPF, relationships between PAHs and birth outcomes were essentially unchanged. In this analysis, PAHs and CPF appear to be significant independent determinants of birth outcomes. Further analyses of pesticides will be carried out. Possible explanations of the failure to find a significant effect of PAHs in the Hispanic subsample are discussed. This study provides evidence that environmental pollutants at levels currently encountered in New York City adversely affect fetal development.

Residential pesticide use during pregnancy among a cohort of urban minority women.

Residential pesticide use is widespread in the United States. However, data are limited specific to use among minority populations. Nor are data available on the extent of pesticide exposure resulting from residential use during pregnancy. We have gathered questionnaire data on pesticide use in the home during pregnancy from 316 African-American and Dominican women residing in northern Manhattan and the South Bronx. Additionally, 72 women underwent personal air monitoring for 48 hr during their third trimester of pregnancy to determine exposure levels to 21 pesticides (19 insecticides and 2 fungicides). Of the women questioned, 266 of 314 (85%) reported that pest control measures were used in the home during pregnancy; 111 of 314 (35%) reported that their homes were sprayed by an exterminator, and of those, 45% said the spraying was done more than once per month. Most (>or= 90%) of the pesticide was used for cockroach control. Use of pest control measures increased significantly with the level of housing disrepair reported. Of the women monitored, all (100%) had detectable levels of three insecticides: the organophosphates diazinon (range, 2.0-6,010 ng/m3) and chlorpyrifos (range, 0.7-193 ng/m3) and the carbamate propoxur (range, 3.8-1,380 ng/m3), as well as the fungicide o-phenylphenol (range, 5.7-743 ng/m3). We also frequently detected the following four insecticides (47-83% of samples) but at lower concentrations: the pyrethroid trans-permethrin, piperonyl butoxide (an indicator of exposure to pyrethrins), and the organochlorines 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane and chlordane. Thirty percent of the women had detectable levels of all eight pesticides. Exposures were generally higher among African Americans than among Dominicans. We detected other pesticides in