Ornamental plants as vectors of pesticide exposure and potential threat to biodiversity and human health.

The production of conventional ornamental plants is pesticide-intensive. We investigated whether pesticide active ingredients (AIs) are still present in ornamentals at the time of purchase and assessed their potential ecotoxicity to non-target organisms. We purchased 1000 pot plants and 237 cut flowers of different species from garden centers in Austria and Germany between 2011 and 2021 and analyzed them for up to 646 AIs. Ecotoxicological risks of AIs were assessed by calculating toxic loads for honeybees (Apis mellifera), earthworms (Eisenia fetida), birds (Passer domesticus), and mammals (Rattus norvegicus) based on the LD50 values of the detected AIs. Human health risks of AIs were assessed on the basis of the hazard statements of the Globally Harmonized System. Over the years, a total of 202 AIs were detected in pot plants and 128 AIs in cut flowers. Pesticide residues were found in 94% of pot plants and 97% of cut flowers, with cut flowers containing about twice as many AIs (11.0 ± 6.2 AIs) as pot plants (5.8 ± 4.0 AIs). Fungicides and insecticides were found most frequently. The ecotoxicity assessment showed that 47% of the AIs in pot plants and 63% of the AIs in cut flowers were moderately toxic to the considered non-target organisms. AIs found were mainly toxic to honeybees; their toxicity to earthworms, birds, and mammals was about 105 times lower. Remarkably, 39% of the plants labeled as "bee-friendly" contained AIs that were toxic to bees. More than 40% of pot plants and 72% of cut flowers contained AIs classified as harmful to human health. These results suggest that ornamental plants are vectors for potential pesticide exposure of consumers and non-target organisms in home gardens.

Biomarkers of Innate Immunity and Immunological Susceptibility to Viral Infection in Patients with Alcoholic Cirrhosis.

BACKGROUND: The harmful effect of alcohol on the immune system may be due to both a direct action of the alcohol or its metabolites on immune cells as an indirect action modifying the different mechanisms of intercellular interaction. The interplay between stimulatory (aKIR) and inhibitory (iKIR) natural killer (NK) cell receptors and their corresponding human leukocyte antigen (HLA) ligands influences the outcome of virus infection. The aim was to analyze the influence of the KIR/HLA pair genetic profile in male alcoholic cirrhosis (AC) patients with and without viral infections to find susceptibility biomarkers that can help establish the risks and prevent viral infections. METHODS: A total of 281 male AC patients were analyzed. The sociodemographic characteristics, viral hepatitis C (HCV), hepatitis B (HBV), and cytomegalovirus (CMV) infections were analyzed. Genomic DNA was extracted, and genetic the KIR/HLA profiles were investigated. A total of 6 KIR genes and their corresponding ligands (HLA-C) were analyzed. Patients were grouped into two groups: with and without associated viral infection. RESULTS: A statistically significant increase in the combination of KIR2DL2+/C1C1 was observed in male AC patients with viral infection compared to those without viral infection (45.9% vs. 24.5%, p = 0.021). The analysis of KIR2DL3+/C1+ showed a high frequency comparing healthy controls and male AC patients without virus infection (85% vs. 76.4%; p = 0.026). The analysis of KIR2DL3+/C2C2 frequency showed a statistically significant increase comparing male AC patients without viral infection and healthy controls (23.6% vs. 15%; p = 0.026). CONCLUSIONS: The genetic KIR2DL2+/C2C2 profiles may play a significant role in determining the vulnerability of male AC patients to viral infections, providing valuable insights for future research and potential therapeutic interventions.

Evaluating the trophic transfer of PCBs from fish to humans: Insights from a synergism of environmental monitoring and physiologically-based pharmacokinetic modeling.

Accumulation of polychlorinated biphenyls (PCBs) within fish tissues has prompted many states to issue consumption advisories. In Pennsylvania such advisories suggest one meal per month for most game species harvested from Lake Erie; however, these advisories do not account for the emergent properties of regional PCB mixtures, and the downstream accumulation of PCB congeners into human tissues is poorly documented. This study aimed to demonstrate the utility of pairing environmental monitoring with pharmacokinetic modeling for the purpose of estimating dietary PCB exposure in humans. We qualified and quantified the PCB congeners present in the filets of five Lake Erie fish species and used these data to estimate exposure under consumption scenarios that matched or exceeded the advisories. Physiologically-based pharmacokinetic (PBPK) modeling was then employed to predict PCB accumulation within seven tissue compartments of a hypothetical man and woman over 10 years. Twenty-one congeners were detected between the five fish species at concentrations ranging from 56.0 to 411.7 ng/g. Predicted accumulation in human tissues varied based on tissue type, the species consumed, biological sex, and fish-consumption rate. Notably, steady-state concentrations were higher in fatty tissue compartments ("Fat" and "Liver") and across all tissues in women compared to men. This study serves as a preliminary blueprint for generating predictions of site-specific and tissue-specific exposure through the integration of environmental monitoring and pharmacokinetic modeling. Although the details may vary across applications, this simple approach could complement traditional exposure assessments for vulnerable communities in the Great Lakes region that continue to suffer from legacy contamination.

Unexpected air pollutants with potential human health hazards: Nitrification inhibitors, biocides, and persistent organic substances.

To better understand the influence of land use and meteorological parameters on air pollutants, we deployed passive air samplers in 15 regions with different land use in eastern Austria. The samplers consisted of polyurethane PUF and polyester PEF filter matrices, which were analyzed for 566 substances by gas-chromatography/mass-spectrometry. In a previous article, we highlighted a widespread contamination of ambient air with pesticides that depends on the surrounding land use and meteorological parameters. Here we report that, in addition to agricultural pesticides, eight other substances were frequently detected in ambient air: Nitrapyrin, a nitrification inhibitor used to increase nitrogen use efficiency of fertilizers and banned in Austria since 1993; biocides against insects (DEET and transfluthrin) used mainly outside agriculture; piperonyl butoxide (PBO), a synergist mixed into pesticide formulations; and four industrially used polychlorinated biphenyls (PCBs), long banned worldwide. Concentrations of the detected substances were positively related to air temperature, but only slightly related to agricultural land use in the sampler's vicinity. The city center showed the highest concentrations of biocides, PCBs and PBO, but also medium concentrations of nitrapyrin. Four sites had no air contamination with these substances; including two national parks dominated by grassland or forest, but also two sites with mixed land use. The potential human toxicity of the detected substances based on globally harmonized hazard classifications was high: seven substances had specific organ toxicity, six were cancerogenic, and two were acutely toxic; however, several substances had incomplete information of hazard profiles. Moreover, all substances were acutely and chronically toxic to aquatic life. We recommend that substances of different origins be included in the air pollution monitoring portfolio to comprehensively assess the potential hazards to humans and the environment.

Pesticide drift mitigation measures appear to reduce contamination of non-agricultural areas, but hazards to humans and the environment remain.

Pesticide drift onto non-agricultural land is a common problem in intensively farmed regions, and national action plans have been established across Europe to prevent it. Here, we analyzed official data on pesticide residues in grass samples collected over six years to determine whether implemented measures to reduce pesticide drift were effective. We used 306 samples collected between 2014 and 2020 on non-agricultural land in one of the most intensively managed apple and wine growing regions in Europe, the Autonomous Province of Bolzano-South Tyrol, Italy. Samples were analyzed for up to 314 substances by gas chromatography and mass spectrometry. Percentage of sites with multiple pesticides and number of pesticides decreased between 2014 and 2020. Fungicides were most often detected, with fluazinam found on 74 % and captan on 60 % of the contaminated sites (53 sites out of a total of 88 sites were contaminated). The most frequently found insecticide, phosmet, was detected in 49 % of the contaminated sites. Only one herbicide, oxadiazon, was detected in <1 % of the sites; glyphosate was not analyzed. The percentage of residues with human hazard properties increased significantly across years regarding reproductive toxicity (from 21 % of the detected substances in 2014 to 88 % in 2020) and specific target organ toxicity (0 % in 2014 to 21 % in 2020). Percentages of substances associated with endocrine-disruption (89 % of substances across years) or carcinogenic properties (45 % of substances across years) remained constant. The percentage of sites where concentrations in grass samples exceeded the surrogate maximum residue levels (MRLs) for lettuce also remained constant. Potential ecotoxicological hazards of detected residues regarding acute contact toxicity to honeybees remained high over the study years, while the acute and chronic toxicity to earthworms decreased. Our results suggest that while drift mitigation measures contributed some reduction in pesticide contamination, they were not sufficient to eliminate substantial risks to human health and the environment in nontarget areas.

Pesticides in ambient air, influenced by surrounding land use and weather, pose a potential threat to biodiversity and humans.

Little is known about (i) how numbers and concentrations of airborne pesticide residues are influenced by land use, interactions with meteorological parameters, or by substance-specific chemo-physical properties, and (ii) what potential toxicological hazards this could pose to non-target organisms including humans. We installed passive air samplers (polyurethane PUF and polyester PEF filter matrices) in 15 regions with different land uses in eastern Austria for up to 8 months. Samples were analyzed for 566 substances by gas-chromatography/mass-spectrometry. We analyzed relationships between frequency and concentrations of pesticides, land use, meteorological parameters, substance properties, and season. We found totally 67 pesticide active ingredients (24 herbicides, 30 fungicides, 13 insecticides) with 10-53 pesticides per site. Herbicides metolachlor, pendimethalin, prosulfocarb, terbuthylazine, and the fungicide HCB were found in all PUF samplers, and glyphosate in all PEF samplers; chlorpyrifos-ethyl was the most abundant insecticide found in 93% of the samplers. Highest concentrations showed the herbicide prosulfocarb (725 ± 1218 ng sample-1), the fungicide folpet (412 ± 465 ng sample-1), and the insecticide chlorpyrifos-ethyl (110 ± 98 ng sample-1). Pesticide numbers and concentrations increased with increasing proportions of arable land in the surroundings. However, pesticides were also found in two National Parks (10 and 33 pesticides) or a city center (17 pesticides). Pesticide numbers and concentrations changed between seasons and correlated with land use, temperature, radiation, and wind, but were unaffected by substance volatility. Potential ecotoxicological exposure of mammals, birds, earthworms, fish, and honeybees increased with increasing pesticide numbers and concentrations. Human toxicity potential of detected pesticides was high, with averaged 54% being acutely toxic, 39% reproduction toxic, 24% cancerogenic, and 10% endocrine disrupting. This widespread pesticide air pollution indicates that current environmental risk assessments, field application techniques, protective measures, and regulations are inadequate to protect the environment and humans from potentially harmful exposure.

From properties to toxicity: Comparing microplastics to other airborne microparticles.

Microplastic (MP) debris is considered as a potentially hazardous material. It is omnipresent in our environment, and evidence that MP is also abundant in the atmosphere is increasing. Consequently, the inhalation of these particles is a significant exposure route to humans. Concerns about potential effects of airborne MP on human health are rising. However, currently, there are not enough studies on the putative toxicity of airborne MP to adequately assess its impact on human health. Therefore, we examined potential drivers of airborne MP toxicity. Physicochemical properties like size, shape, ζ-potential, adsorbed molecules and pathogens, and the MP's bio-persistence have been proposed as possible drivers of MP toxicity. Since their role in MP toxicity is largely unknown, we reviewed the literature on toxicologically well-studied non-plastic airborne microparticles (asbestos, silica, soot, wood, cotton, hay). We aimed to link the observed health effects and toxicology of these microparticles to the abovementioned properties. By comparing this information with studies on the effects of airborne MP, we analyzed possible mechanisms of airborne MP toxicity. Thus, we provide a basis for a mechanistic understanding of airborne MP toxicity. This may enable the assessment of risks associated with airborne MP pollution, facilitating effective policymaking and product design.

Marine Neurotoxins' Effects on Environmental and Human Health: An OMICS Overview.

Harmful algal blooms (HAB), and the consequent release of toxic metabolites, can be responsible for seafood poisoning outbreaks. Marine wildlife can accumulate these toxins throughout the food chain, which presents a threat to consumers' health. Some of these toxins, such as saxitoxin (STX), domoic acid (DA), ciguatoxin (CTX), brevetoxin (BTX), tetrodotoxin (TTX), and ß-N-methylamino-L-alanine (BMAA), cause severe neurological symptoms in humans. Considerable information is missing, however, notably the consequences of toxin exposures on changes in gene expression, protein profile, and metabolic pathways. This information could lead to understanding the consequence of marine neurotoxin exposure in aquatic organisms and humans. Nevertheless, recent contributions to the knowledge of neurotoxins arise from OMICS-based research, such as genomics, transcriptomics, proteomics, and metabolomics. This review presents a comprehensive overview of the most recent research and of the available solutions to explore OMICS datasets in order to identify new features in terms of ecotoxicology, food safety, and human health. In addition, future perspectives in OMICS studies are discussed.

Toxicological evaluation of ergocalciferol, cholecalciferol, and their metabolites by a category approach.

Predictive toxicology plays an integral role in determining the toxicological profiles of chemicals for safety assessment. Vitamin D is an essential vitamin for the regulation of calcium absorption and homeostasis, as well as the treatment and prevention of several diseases such as rickets and osteomalacia. According to European Medicines Agency (EMA) Guideline on setting health-based exposure limits for use in risk identification in the manufacturing of different medicinal products in shared facilities, permitted daily exposure (PDE) calculation for active pharmaceutical ingredients (APIs) should be done by the medicinal product producers. PDE calculation is mainly based on critical toxicological endpoints such as repeated dose toxicity, genotoxicity, carcinogenicity, developmental and reproductive toxicity, and hypersensitivity potential. During this procedure, critical toxicological endpoints data of an API can be used to predict the PDE of another API that has a similar chemical structure. In the present paper, human toxicological endpoints of vitamin D2, D3, and their metabolites were evaluated and afterwards the data gaps in the toxicological endpoints were filled by forming a category. The read-across was justified by the structural and metabolic similarities. Molecular similarity and mechanistic relevance were found to be substantial, resulting in low uncertainty. The untested vitamin D analogs within the category can be read across with confidence to complete the data gaps related to the human health endpoints.

Poisonings in Poland reported to the Polish National Health Fund in the years 2009-2011.

BACKGROUND: Poisonings constitute a significant medical, social and economic problem worldwide. In Poland there is no nationwide registry of poisonings, which results in a lack of accurate epidemiological data. Few publications dealing with the problem are based on data obtained from toxicology units and therefore do not include information about cases treated at emergency departments and other non-toxicology units. METHODS: We analyzed all admissions due to poisonings reported to the Polish National Health Fund by all hospital units in Poland in the 2009-2011 period. Diagnoses were encoded according to the ICD-10 classification. RESULTS: A total of 254,425 admissions were reported, 85,398 in 2009, 85,230 in 2010 and 83,797 in 2011. The male to female ratios were 1.88, 1.75 and 1.80 respectively. The most frequent causes of admissions were poisonings with ethanol (n = 121,874; 47.9%), carbon monoxide (n = 17,179; 6.8%) and benzodiazepines (n = 10,340; 4.1%). Alcohols were the reason for 104,680 admissions in men (63.2%) and 22,612 admissions in women (25.5%; p < 0.01). Poisonings with pharmaceuticals and other drugs were reported in 34,616 men (20.9%) and 45,238 women (51%; p < 0.01). There were 1680 cases of fatal poisonings in the analyzed period. The hospital mortality due to poisonings increased from 1.1% in 2009 to 1.5% in 2011 (p < 0.01). The mortality in general Intensive Care Units increased from 14.4% in 2009 to 22.3% in 2011 (p < 0.01). The etiology of fatal poisonings was highly dependent on the type of hospital unit. CONCLUSIONS: The overall number of admissions due to poisonings decreased slightly during the study period, but they remained a significant cause of morbidity and mortality. Alcohols were the main cause of admissions in the analyzed period. Alcohol intoxications were more frequent in men while poisonings with pharmaceuticals were more frequent in women. Carbon monoxide exposures were a significant cause of morbidity and mortality in the studied period in Poland. A national poison information and toxicovigilance system should be created in Poland, ideally allowing for near real-time monitoring of cases of poisonings.

Intracoronary Thrombus Formation Following Carbon Monoxide Poisoning.

Thromboembolic events in the context of carbon monoxide (CO) exposure have been well described in the literature. Six cases of clinically significant coronary thrombosis following CO exposure were previously reported. However, factors affecting the development of coronary thrombus in CO exposure are poorly understood, and the significance of this finding in a forensic context is not clear. This article discusses a case of coronary thrombosis found at autopsy following a death in which CO poisoning was suspected. A 67-year-old man was found dead in his garage with four vehicles with their ignition in the "on" position and their tanks empty. At autopsy, severe coronary atherosclerosis and an acute nonocclusive coronary thrombus were found. Given the dissimilarities among cases and the presence of CO exposure, it was suggested that the coronary artery thrombosis is likely due to the inherent prothrombotic mechanism of CO, the only common denominator in all the cases.

Endosulfan poisoning: An overview.

Endosulfan, an organochlorine (OC) insecticide, is a widely used agricultural pesticide, despite its life threatening toxic effects. In this review, the pharmacokinetics of endosulfan, mechanism of endosulfan toxicity, clinical presentations and management, histopathological findings, and toxicological analysis are described, in addition to its environmental toxicity. The toxic effects of endosulfan can affect many organs and systems presenting in a wide array of signs and symptoms. Although termed a restricted OC-classed pesticide, it continues to be used, especially in the developing world, owing to its beneficial effects on agriculture. Several cases of endosulfan poisoning have been reported from different regions of the world. Whether accidental or intentional, endosulfan ingestion proves to be fatal unless immediate, aggressive treatment is initiated. Management is mainly supportive as no antidote exists for endosulfan poisoning as yet. The use of endosulfan needs to be strictly regulated and eventually banned worldwide altogether to lower the current morbidity and mortality resulting from this pesticide. Additionally, monitoring biological samples, using non-invasive techniques such as breast milk sampling, can provide an effective method of observing the elimination of this environmentally persistent organic pollutant from the general population.

Dietary supplementation of coenzyme Q10 plus multivitamins to hamper the ROS mediated cisplatin ototoxicity in humans: A pilot study.

Oxidative stress exerts major role in the pathogenesis of side effects of many antineoplastic drugs, including ototoxicity of cisplatin. In particular, increased levels of reactive oxygen species (ROS) represent one of the molecular mechanisms underlying the apoptosis of different types of hearing cells. Antioxidants and ROS scavengers may thus represent potential therapeutic options to prevent platinum-associated ototoxicity. The aim of this preliminary case-control study was to explore the efficacy of a dietary antioxidant supplement, in order to hamper the occurrences of ototoxicity in patients undergoing cisplatin chemotherapy. As results, a significant protection against cochlear toxic damage was demonstrated in patients who took the antioxidant supplement, which furthermore prevented the occurrence of hearing disorders and tinnitus. These clinical evidences were corroborated by the oxidative status of patients. After cisplatin chemotherapy, the plasma derivatives of reactive oxygen metabolites (d-ROMs) content rapidly increased in control patients, but it was maintained in those under dietary supplementation, likely because of a higher anti-ROMs potential. Indeed, an increment in rapid anti-ROMs was detected in supplemented patients, though no differences were highlighted in terms of slow anti-ROMs. In conclusion, in this preliminary report we demonstrated the feasibility of a dietary antioxidant supplementation in order to prevent the cisplatin induced hearing damage.

Intentional poisoning among elderly people-residents of a large urban agglomeration in Poland.

Poisoning is considered a significant health problem among elderly people in Poland. This report refers to patients treated for poisonings at the Toxicology Unit, Lodz, Poland, during the period 2008-2012. The data to be analyzed were obtained from medical records of elderly people. A group of 1167 patients aged 60+ was selected. The number of intentional poisonings in the group of patients was 417, which accounted for 35.7% of all poisonings among the elderly people. Patients attempting intentional poisonings included 301 (72.2%) women and 116 (27.8%) men. The most common cause of intentional poisonings were drugs-96.6% (n = 403). Benzodiazepines (46.9%) dominated among the intentional poisoning by drugs. During the analyzed 5 years, 80.3% (n = 335) were suicidal poisonings and 19.7% (n = 82) were demonstrative poisonings. Cardiovascular disease, which was diagnosed among 53.5% of the patients, was the most common physical illness. In conclusion, drugs are the most frequent type of the toxic agent responsible for poisoning cases among the elderly people. In this situation, the role of family doctors is very important: they should prescribe medicines in amounts not greater than absolutely necessary and maybe more often recommend psychiatric care for the elderly patients.

Thrombolytic therapy in a patient with inferolateral myocardial infarction after carbon monoxide poisoning.

INTRODUCTION: ST segment elevation myocardial infarction (STEMI) due to coronary artery occlusion caused by intracoronary thrombosis in the setting of acute carbon monoxide (CO) poisoning is a very rare presentation. We present a case of intracoronary large and mobile thrombus formation after CO poisoning. CASE PRESENTATION: A previously healthy 50-year-old woman was referred for CO poisoning. She had chest pain after exposure to CO. Her initial mental status was preoccupied with chest pain. Her initial CO fraction was 28.1%, and initial laboratory data showed creatine kinase-myocardial isoenzyme of 134 U/L (upper limit 25 U/L) and troponin I of >50 ng/mL (upper limit 0.06 ng/mL). Electrocardiography was carried out on admission, revealing an ST segment elevation in the inferolateral leads. After initial evaluation, coronary angiography was performed and an intracoronary large mobile thrombus was seen in the proximal left anterior descending (LAD) artery with no significant stenosis. We administered tenecteplase with heparin. After the thrombolytic therapy, ST elevation in the inferolateral leads resolved. Repeat angiography was performed after 24 h; the thrombus in LAD had resolved. The patient was discharged after 5 days, with persistent Q wave in the inferior leads and mild hypokinesia of the inferoposterior wall suggesting myocardial injury. CONCLUSION: We describe intracoronary thrombus formation induced by CO poisoning. Because intracoronary thrombus can result in myocardial infarction, its consideration following CO poisoning is important. Patients with CO poisoning who have symptoms of STEMI should be carefully evaluated with serial electrocardiograms, cardiac biomarkers, and an echocardiogram. When there is evidence of acute myocardial injury, a primer in coronary angiography can determine which patients could benefit from intervention.

Evaluation of genotoxic potential of commonly used organophosphate pesticides in peripheral blood lymphocytes of rats.

Chlorpyrifos (CPF), methyl parathion (MPT), and malathion (MLT) are among the most extensively used organophosphate (OP) pesticides in India. DNA protein cross-links (DPC) and DNA strand breaks are toxic lesions associated with the mechanism(s) of toxicity of carcinogenic compounds. In the present study, we examined the hypothesis that individual and interactive genotoxic effects of CPF, MPT, and MLT are involved in the formation of DPC and DNA strand break. The DNA strand break was measured by comet assay and expressed as DNA damage index, while DPC estimation was carried out by fluorescence emission assay. The results showed that exposure of rat lymphocytes with CPF, MPT, and MLT caused significantly marked increase in DNA damage and DPC formation in time-dependent manner. MPT caused the highest damage, and these pesticides do not potentiate the toxicity of each other.

Methylphenidate misuse in adult patients and the impact of therapeutic use.

OBJECTIVE: Methylphenidate (MPH) prescription rates for adults increase, but the extent of a parallel rise in toxic exposures and their causes and distribution between different MPH trade names are unexplored. METHOD: We retrospectively analyzed adult MPH exposures reported to the Danish Poison Information Centre from January 2006 to July 2012 and the association with MPH sales and the number of patients prescribed MPH. RESULTS: Of the 394 exposures (57% males, median age 27 years) reported, MPH status was available in 249 of whom 65.5% were prescribed MPH. Exposure was in 54% motivated by suicidal attempt and in 40% by recreational use (based on 375 cases). Exposure was dominated by one trade name and exposure incidence correlated significantly with sales ( p = 0.001) and prevalence of MPH-treated patients ( p = 0.0008). CONCLUSIONS: The increase in MPH exposures parallels the prescription rates (particularly Ritalin(®)/Ritalin(®) Uno). Most exposures were intentional and motivated by suicide attempts or recreational use.

The evolving high: new designer drugs of abuse.

Over the past decade, emerging drugs of abuse and synthetic derivatives of more traditional agents have flooded the market. While Europe was the first to experience a surge in the use of drugs such as synthetic cathinones and cannabinoids, poison centers throughout the United States have seen a dramatic rise in calls related to these new designer drugs of abuse. In the majority of cases, care is largely supportive but significant medical and traumatic complications may occur. Providers must be aware of the ever-changing trends in abuse, so that they may optimally care for poisoned patients.

Health related guide values for drinking-water since 1993 as guidance to assess presence of new analytes in drinking-water.

UNLABELLED: Regulatory toxicologists, when going into assessment of a new analyte in drinking-water, very often miss the occasion to revert to scientifically consensual virtually safe lifetime exposure reference doses and corresponding health-related guide values (HRGV) for drinking-water, be those derived either to avoid concern over "threshold effects" or concern over exceedance of an unacceptable non-threshold cancer risk level. They then need a more restrictive precautionary yet science-compatible approach to directly avoid concern over the presence (measured concentration) of a new analyte in drinking-water. Therefore, the German Environment Agency (UBA, Umweltbundesamt) decided in 2003 to extrapolate international toxicological expertise collected since 1993 from assessing "old" analytes in drinking-water on new ones in form of five HRIV=health related indication values. They indicate the reasonable lowest maximal concentration from which on tiered or stepwise human toxicological evaluation of a new analyte might be necessary and meaningful. Their regulatory-toxicological function is that of placeholders as long as a possibly higher scientific HRGV or a surrogate value based on a threshold of toxicological concern (TTC) was not broadly agreed by science. The five-step HRIV scale between 0.01 and 3.0 µg/l combines international toxicological experience gained from "old" analytes since 1993 with the concepts of safety factors (SF(D)) to assess database deficiency and science-related extrapolation factors (EF) to extrapolate experimental data on humans. Each HRIV is valid and safe for a 2 l/day drinking-water exposure scenario either counting for 10% relative source contribution (compounds with threshold effects) or for a lifetime non-threshold cancer risk of up to 10(-6) and is the higher the more positive information exists regarding possible effects at critical toxic endpoints and for length of possible exposure. Past (historical) and present evaluations of "old" analytes were available in form of hundreds of HRGVs to count in 2 liters per day and person for 10% RSC or a 10(-6) non-threshold risk. These HRGVs were calculated by the present author either from ADI-, TDI- or RfD-values derived since 1993 by six large health authorities or they were identified directly at their websites or in the literature, always looking for confirmed or assumed worldwide relevance for drinking-water (resources). 36 of these up to 200 "old" analytes were ascribed since 1993 at least once an HRGV at or below 1 µg/l for (confirmed or provisionally assumed) "high" or "very high" threshold chronic toxicity. None but one of the corresponding 113 scientific HRGVs fell distinctly short of 0.3 µg/l. Only 14 carcinogens turned out as being relevant for drinking-water due to confirmed occurrence and coincident toxicological significance there. 13 of these exhibited a structural alert for genotoxicity. Ten of these 13 were "high-potency" genotoxic carcinogens with presently calculated non-threshold 10(-6) risk minimal HRGVs between 0.06 µg/l and 0.005 µg/l (9 compounds) or possibly down to 0.0007 µg/l (1 compound). This motivated UBA to propose a precautionary range between a minimal HRIV0=0.01 and a HRIV1=0.1 µg/l to assess new analytes bearing a structural alert for genotoxicity. The HRGVs for the remaining three (from 13) carcinogens with alerts for genotoxicity were at best similar for both genotoxic and non-genotoxic effects and higher or equal to 0.3 µg/l. Therefore, a minimal HRIV of 0.01 µg/l (HRIV0) or even 0.1 µg/l (HRIV1) would have appeared too low for assessing the presence in drinking-water of new analytes with no other human toxicity data than proven absence of both genotoxicity and of structural alerts for such. Instead, UBA proposes to provisionally assess such compounds by its next higher precautionary of HRIV3=0.3 µg/l. Any value once set is open for falsification upwards to either 1.0 µg/l (HRIV4) or 3.0 µg/l (HRIV5) or even for being replaced by an HRGV>3.0 µg/l if pertinent high toxicity effect potentials different from genotoxicity are similarly ruled out by either mechanistic and TTC-based arguments or a tiered experimental (in vitro and/or in vivo) approach. CONCLUSION: Regulatory-toxicological expertise gained since 1993 with "old" analytes in drinking-water (resources) and its extrapolation by analogy on new analytes with patchy human toxicological database allows for provisional assessment of their presence in drinking-water in form of five precautionary HRIVs. Selecting a HRIV, instead referring to a TTC or a virtually safe reference dose, just asks an expert judgment on the degree of formal completeness and informational potential of a new analyte's human toxicity database. Exceedance of a HRIV indicates need for supplementary toxicological data to improve assessment, their nature and comprehensiveness depending on degree and expected length of exceedance. The regulatory function of a HRIV is that of a placeholder for a possibly higher TTC-based surrogate HRGVTTC or a highest possible science-based HRGV.

The placenta in toxicology. Part IV: Battery of toxicological test systems based on human placenta.

This review summarizes the potential and also some limitations of using human placentas, or placental cells and structures for toxicology testing. The placenta contains a wide spectrum of cell types and tissues, such as trophoblast cells, immune cells, fibroblasts, stem cells, endothelial cells, vessels, glands, membranes, and many others. It may be expected that in many cases the relevance of results obtained from human placenta will be higher than those from animal models due to species specificity of metabolism and placental structure. For practical and economical reasons, we propose to apply a battery of sequential experiments for analysis of potential toxicants. This should start with using cell lines, followed by testing placenta tissue explants and isolated placenta cells, and finally by application of single and dual side ex vivo placenta perfusion. With each of these steps, the relative workload increases while the number of feasible repeats decreases. Simultaneously, the predictive power enhances by increasing similarity with in vivo human conditions. Toxic effects may be detected by performing proliferation, vitality and cell death assays, analysis of protein and hormone expression, immunohistochemistry or testing functionality of signaling pathways, gene expression, transport mechanisms, and so on. When toxic effects appear at any step, the subsequent assays may be cancelled. Such a system may be useful to reduce costs and increase specificity in testing questionable toxicants. Nonetheless, it requires further standardization and end point definitions for better comparability of results from different toxicants and to estimate the respective in vivo translatability and predictive value.