Environmental Chemical, Physical and Biological Toxicants and Risk Assessment

P11Healthriskofnewbornfromlead exposed mother CTANGBANLUEKAL1,WLEELAKUNAKORN1,S RUANGKANCHANASETR2(1.DepartmentofPathology,2.DepartmentofPedi atrics,FacultyofMedicine,RamathibodiHospital,MahidolUniversity,Bangkok,Thailand)Lead(Pb)istheheavymetalthathasaneffect onanirreversiblementalretardationandbraindevelop mentinnewborntilltheageof2year;therefore,WorldHealthOrganizationhasestablishedamaximum allowancestandardforbloodleadinchildat10μg·dL-1.Thepresentstudywasconducte…     

Risk–benefit of antiemetics in prevention and treatment of chemotherapy-induced nausea and vomiting

The development of effective antiemetic prophylaxis is one of the most significant steps forward in the area of supportive care. Fifteen years ago, patients receiving chemotherapy had to face the fact that nausea and vomiting were inevitable adverse effects, which could only be partially prevented by treatment with antiemetics such as dopamine (DA) D2 receptor antagonists and corticosteroids. The first group of drugs specifically developed as antiemetics was the serotonin (5-hydroxytryptamine [5-HT]₃) receptor antagonists. These drugs have dramatically improved prophylaxis of chemotherapy-induced emesis, particularly when used in combination with a corticosteroid. This combination has resulted in a significant decrease in the number of patients vomiting, whereas the improvement in the prophylaxis of nausea has been less successful. Another group of antiemetics, the neurokinin (NK)₁ receptor antagonists, has recently been developed, and the first drug in this class, aprepitant, has been approved by the FDA and the EU authorities. Studies have showed that patients benefit from the use of this drug in combination with standard antiemetic therapy (5-HT₃ receptor antagonist plus a corticosteroid), both in the acute and delayed phase of nausea and vomiting induced by cisplatin-based chemotherapy. This development has not only led to improved efficacy but also to a decreased risk associated with the use of antiemetics. One of the problems with traditional antiemetics, for example, the DA D2 receptor antagonists, is the risk of unpleasant adverse effects including restlessness and dystonic reactions. To avoid these adverse effects, combination with benzodiazepines or antihistamines was necessary, often resulting in sedation. Modern research also includes pharmacogenomic investigations. This has led to speculation about the importance of drug–drug interactions involving antiemetics through competition for metabolism by the cytochrome P450 isoenzymes. The worst possible interaction would be a decrease in the effect of different cytotoxins but there is no evidence that such interactions are of importance in daily clinical practice. Guidelines are useful tools in the optimisation of antiemetic prophylaxis but, unfortunately, implementation of the evidence-based recommendations is far from successful. A prerequisite for further optimisation of antiemetic prophylaxis is updating of the guidelines, including recommendations for the use of NK₁ receptor antagonists (aprepitant), followed by implementation of these recommendations in the clinic. Future research must include ‘the difficult trials’ focusing on the remaining groups of patients with severe chemotherapy-induced nausea and vomiting, including patients with refractory and breakthrough emesis.     

New Approaches in Risk Assessment of Drug and Food

W21Safetyassuranceforthedietarysupple mentingredientsofplantorigin HoonjeongKWON(DepartmentofFoodandNutritionandResearchInsti tuteofHumanEcology,SeoulNationalUniversity,Se oul,Korea)Dietarysupplementsneedtoshowstatistically soundevidencefortheclaimedhealtheffect,andthis oftenrequireshighdoseofthematerialwhichinturn raisesthesafetyconcernregardlessofwhetherithas beentraditionallyusedornot,sinceitfrequentlyex ceedsthetraditionaluse.HFFmaterialcanbederived fromthetraditionalfoodsources,me…     

The Risk Environment of Heroin Use Initiation: Young Women,Intimate Partners,and “Drug Relationships”

This paper examines young women's initiation to heroin use in the context of an intimate relationship based on data from a small-scale ethno-epidemiology of heroin use in Ireland, 2007–2009. The epidemiological sample included 120 young people, and life history interviews were conducted with a sub-sample of 40 youth aged 16–25 years. A detailed analysis of the “risk environment” of young women's heroin initiation highlights a complex interplay between women's agency and intimate partner influence. It is argued that dichotomous representations of women as victims or emancipated consumers do not adequately capture the complexity of women's initiation journeys. The study's limitations are noted and implications for drug use prevention and harm reduction strategies are discussed.     

Risk assessment of chlortetracycline,oxytetracycline, sulfamethazine,sulfathiazole, and erythromycin in aquatic environment: are the current environmental concentrations safe?

To understand potential risks of major pharmaceutical residues in waters, we evaluated ecotoxicities of five major veterinary pharmaceuticals, i.e., chlortetracycline, oxytetracycline, sulfamethazine, sulfathiazole, and erythromycin, which have been frequently detected in freshwater environment worldwide. We conducted acute and chronic toxicity tests using two freshwater invertebrates (Daphnia magna and Moina macrocopa) and a fish (Oryzias latipes). In general, D. magna exhibited greater sensitivity than M. macrocopa, and chronic reproduction was the most sensitive endpoints for both organisms. The population growth rate was adversely influenced by exposure to chlortetracycline, sulfamethazine, or sulfathiazole in water fleas, but reduction in population size was not expected. In O. latipes, the tested pharmaceuticals affected several reproduction related endpoints including time to hatch and growth. Based on the toxicity values from the present study and literature, algae appeared to be the most sensitive organism, followed by Daphnia and fish. Hazard quotients derived from measured environmental concentrations (MECs) and predicted no effect concentrations (PNECs) for erythromycin and oxytetracycline exceeded unity, suggesting that potential ecological effects at highly contaminated sites cannot be ruled out. Long-term consequences of veterinary pharmaceutical contamination in the environment deserve further investigation.     

Risk factors and outcome of extended-spectrum β-lactamase-producing Enterobacter cloacae bloodstream infections

Enterobacter cloacae is a major nosocomial pathogen that causes serious infections, including bloodstream infections (BSIs). The clinical significance of extended-spectrum β-lactamase (ESBL) production in E. cloacae is not well established. A multicentre, retrospective, cohort study was conducted to identify clinical characteristics of patients with E. cloacae BSI. ESBL production was confirmed by genotypic methods. A total of 159 patients with E. cloacae BSI were identified at three medical centres in north-eastern USA. Amongst them, 16 patients (10.1%) harboured ESBL-producing E. cloacae. Independent risk factors for ESBL production included admission from a nursing home, the presence of a gastrostomy tube and history of transplant. For the outcome analysis, 15 consecutive patients who had ESBL-producing E. cloacae BSI prior to the study were included. Amongst the 31 patients with ESBL-producing E. cloacae, 8, 9, 4 and 2 patients received a carbapenem, cefepime, piperacillin/tazobactam and ciprofloxacin, respectively, as initial therapy. All patients who received a carbapenem (n=8) were alive at 28 days, whereas 7 (38.9%) of 18 patients who received a non-carbapenem antibiotic did not survive (P=0.06). Clinical failure at 96 h was observed in 2 (25.0%) of 8 patients who received a carbapenem and in 14 (77.8%) of 18 patients who received a non-carbapenem antibiotic (P=0.03). Pulsed-field gel electrophoresis showed little clonality amongst the study isolates. The majority of isolates produced SHV-type ESBL, whereas two isolates produced CTX-M-type ESBL. Initial therapy with a carbapenem appears to be associated with improved clinical outcome in BSI due to ESBL-producing E. cloacae.     

Carcinogenic Risk of Toluene Diisocyanate and 4,4′-Methylenediphenyl Diisocyanate: Epidemiological and Experimental Evidence

Diisocyanates are highly reactive compounds widely used, for example, in the production of polyure-thane foams, elastomers, paints, and adhesives. The high chemical reactivity of these compounds is also reflected in their toxicity: diisocyanates are one of the most important causes of occupational asthma but also other adverse effects, such as irritation and toxic reactions, have been described in exposed subjects. One of the open questions is whether occupational isocyanate exposure is a carcinogenic hazard. The few epidemiological studies available have been based on young cohorts and short follow-up and are not conclusive. Toluene diisocyanate (TDI) has been classified as carcinogenic in animals on the basis of gavage administration studies, but no conclusions are available on inhalation exposure. For 4,4′-methylene diphenyldiisocyanate (MDI) there is suggestive evidence for carcinoge-nicity in rats. The possible carcinogenic mechanism of TDI and MDI is not clear. Both chemicals have been positive in a number of short-term tests inducing gene mutations and chromosomal damage. The reactive form could be either the diisocyanate itself or may derive from the metabolic activation of the aromatic diamine derivatives formed by hydrolysis. TDI and MDI react with DNA in vivo and in vitro. However, the structure of the adducts has not been identified. Especially from the in vivo experiment it is not known if the adducts are a product from the reaction with the isocyanate or the corresponding amine. In conclusion, both TDI and MDI are highly reactive chemicals that bind to DNA and are probably genotoxic. The alleged animal carcinogenicity of TDI and MDI would suggest that occupational exposure to these compounds is a carcinogenic risk. The few epidemiological studies available have not, however, been able to clarify if TDI and MDI are occupational carcinogens.     

How Has CDER Prepared for the Nano Revolution? A Review of Risk Assessment,Regulatory Research,and Guidance Activities

The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration (FDA) was established to assess the potential impact of nanotechnology on drug products. One of the working group’s major initiatives has been to conduct a comprehensive risk management exercise regarding the potential impact of nanomaterial pharmaceutical ingredients and excipients on drug product quality, safety, and efficacy. This exercise concluded that current review practices and regulatory guidance are capable of detecting and managing the potential risks to quality, safety, and efficacy when a drug product incorporates a nanomaterial. However, three risk management areas were identified for continued focus during the review of drug products containing nanomaterials: (1) the understanding of how to perform the characterization of nanomaterial properties and the analytical methods used for this characterization, (2) the adequacy of in vitro tests to evaluate drug product performance for drug products containing nanomaterials, and (3) the understanding of properties arising from nanomaterials that may result in different toxicity and biodistribution profiles for drug products containing nanomaterials. CDER continues to actively track the incorporation of nanomaterials in drug products and the methodologies used to characterize them, in order to continuously improve the readiness of our science- and risk-based review approaches. In parallel to the risk management exercise, CDER has also been supporting regulatory research in the area of nanotechnology, specifically focused on characterization, safety, and equivalence (between reference and new product) considerations. This article provides a comprehensive summary of regulatory and research efforts supported by CDER in the area of drug products containing nanomaterials and other activities supporting the development of this emerging technology.     

Review of synthesis, assay, and prediction of β and γ-secretase inhibitors

Alzheimer's disease (AD) is characterize with several pathologies this disease, amyloid plaques, composed of the β-amyloid peptide and β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. AD is the most prevalent form of dementia, and current indications show that twenty-nine million people live with AD worldwide, a figure expected rise exponentially over the coming decades. Clearly, blocking disease progression or, in the best-case scenario, preventing AD altogether would be of benefit in both social and economic terms. However, current AD therapies are merely palliative and only temporarily slow cognitive decline, and treatments that address the underlying pathologic mechanisms of AD are completely lacking. While familial AD (FAD) is caused by autosomal dominant mutations in either amyloid precursor protein (APP) or the presenilin (PS1, PS2) genes. First, we revised Desing, synthesis, and Biological assay of β and γ-secretase inhibitors. Next, we review 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compound to find out the structural requirements. Next, we revised QSAR studies using method of Artificial Neural Network (ANN) in order to understand the essential structural requirement for binding with receptor for β and γ-secretase inhibitors.     

Perspective: Multiplicity and Subgroups in the Context of Benefit–Risk Assessment

ABSTRACT

Although control for multiplicity is recognized as a cornerstone of proper statistical inference, the topic has rarely been addressed in the specific context of benefit–risk assessment for medical products. This article raises key questions and provides opinions and recommendations. Topics include the symmetry between efficacy and safety endpoints, the proper stage to adjust for multiple endpoints, when and how to adjust for multiple subgroups, when a drug can be approved based on a favorable benefit–risk result in a subgroup, and multiplicity considerations arising from re-analysis of data.     

Young Urban Adolescents' Activity Spaces,Close Peers,and the Risk of Cannabis Use: A Social–Spatial Longitudinal Analysis

Background: An understudied, yet important area of youth development research is the examination of how place affects critical psychosocial processes such as identity formation, problem solving, emotional regulation, and in particular with adolescents, belongingness, autonomy, social competency, and behavioral health. A growing spatially informed literature indicates that youth interact with meaningful places as environmental strategies, shaping developmental trajectories related to behavioral health. Objectives: The objective is to investigate the relationship between place preference and health behavior among adolescents, with a focus on substance use behavior, specifically, cannabis use. We theorize that cannabis use is associated with place preference for urban, city types of places, and that this particular place preference interacts with close peer network behaviors. Methods: To understand the role of preferred locations, close peer relations, and mental health on cannabis use, 248 adolescents (ages 13 to 14) were studied longitudinally. Logistic regression models tested the moderating effects of peer network health (sum of close friends risk and protective behaviors) on selecting city locations (urban stress/neighborhoods) as preferred places, and subsequent cannabis use. Results: Results indicated that peer network health moderated the effects of choosing city locations as favorite, increasing the odds of cannabis use more than eight-fold at 24 months. Conclusions: Favorite places located in city environments appear to interact with peer risk behaviors influencing the cannabis use of young urban adolescents, even after controlling for the influence of baseline cannabis use, neighborhood disorder the home neighborhood, age, gender, and mental health effects.     

Risk assessment of thujone in foods and medicines containing sage and wormwood – Evidence for a need of regulatory changes?

Thujone is a natural substance found in plants commonly used in foods and beverages, such as wormwood and sage, as well as in herbal medicines. The current limits for thujone in food products are based on short-term animal studies from the 1960s, which provided evidence for a threshold-based mechanism, yet only allowed for the derivation of preliminary values for acceptable daily intakes (ADI) based on the no-observed effect level (NOEL). While the 2008 European Union Regulation on flavourings deregulated the food use of thujone, the European Medicines Agency introduced limits for the substance in 2009. The present study re-evaluates the available evidence using the benchmark dose (BMD) approach instead of NOEL, and for the first time includes data from a long-term chronic toxicity study of the National Toxicology Program (NTP). The NTP data provide similar results to the previous short-term studies. Using dose–response modelling, a BMD lower confidence limit for a benchmark response of 10% (BMDL10) was calculated as being 11 mg/kg bw/day for clonic seizures in male rats. Based on this, we propose an ADI of 0.11 mg/kg bw/day, which would not be reachable even for consumers of high-levels of thujone-containing foods (including absinthe). While fewer data are available concerning thujone exposure from medicines, we estimate that between 2 and 20 cups of wormwood or sage tea would be required to reach this ADI, and view that the short-term medicinal use of these herbs can also be regarded as safe. In conclusion, the evidence does not point to any need for changes in regulations but confirms the current limits as sufficiently protective for consumers.     

Risk assessment of toxaphene and its breakdown products: time for a change?

Technical toxaphene (TT) was last used in commerce in about 1982. Any environmental exposure to toxaphene in this century is to environmentally degraded forms of toxaphene, termed weathered toxaphene. Several hundred chlorinated bornane congeners have been identified in technical toxaphene. The degradation of technical toxaphene to weathered toxaphene can result in various congener mixtures, but the primary mode of degradation is dechlorination. The U.S. Environmental Protection Agency (EPA) presently estimates the risk of exposure to toxaphene by relying upon rat and mouse toxicology studies performed on technical toxaphene. No adjustment is made for the dechlorination of toxaphene in the environment. The European Union (EU), however, has modeled toxaphene risks from eating fish with chlorinated bornane residues through a series of studies on toxaphene degraded by either ultraviolet light, or biodegradation in fish. The EU risk assessment relies upon rat liver studies in vivo and mouse in vitro studies on the inhibition of gap junction intercellular communication (GJIC). This article reviews the current state of knowledge of technical and weathered toxaphene toxicology. We discuss the various current methods and opportunities to advance the risk assessment of weathered toxaphene beyond the existing U.S. EPA assessment of technical toxaphene.     

Risk Assessment of Toxaphene and its Breakdown Products: Time for a Change?

Technical toxaphene (TT) was last used in commerce in about 1982. Any environmental exposure to toxaphene in this century is to environmentally degraded forms of toxaphene, termed weathered toxaphene. Several hundred chlorinated bornane congeners have been identified in technical toxaphene. The degradation of technical toxaphene to weathered toxaphene can result in various congener mixtures, but the primary mode of degradation is dechlorination. The U.S. Environmental Protection Agency (EPA) presently estimates the risk of exposure to toxaphene by relying upon rat and mouse toxicology studies performed on technical toxaphene. No adjustment is made for the dechlorination of toxaphene in the environment. The European Union (EU), however, has modeled toxaphene risks from eating fish with chlorinated bornane residues through a series of studies on toxaphene degraded by either ultraviolet light, or biodegradation in fish. The EU risk assessment relies upon rat liver studies in vivo and mouse in vitro studies on the inhibition of gap junction intercellular communication (GJIC). This article reviews the current state of knowledge of technical and weathered toxaphene toxicology. We discuss the various current methods and opportunities to advance the risk assessment of weathered toxaphene beyond the existing U.S. EPA assessment of technical toxaphene.     

Naltrexone and β-funaltrexamine antagonism of the antinociceptive and response rate-decreasing effects of morphine, dezocine, and d-propoxyphene

  Rationale: Patterns of competitive and insurmountable antagonism provide important data to guide the classification and characterization of different types of opioid agonists as well as infer the mechanism of action for agonists. Objective: Experiments with the competitive antagonist, naltrexone, and the insurmountable antagonist, β-funaltrexamine (β-FNA), were conducted to determine whether the antinociceptive and rate-decreasing effects of the opioid agonists dezocine and d-propoxyphene are 1) mediated through μ opioid receptors in rats, and 2) differ from morphine with respect to relative efficacy. Methods: The rat tail-withdrawal assay was used to measure antinociception and a fixed ratio 20 (FR20) schedule of food delivery was used to measure rate suppression. Results: Naltrexone (0.01–1.0 mg/kg) was approximately equipotent as an antagonist of the antinociceptive and rate-decreasing effects of both morphine and dezocine and as an antagonist of the antinociceptive effects of d-propoxyphene. Naltrexone failed to block the rate-decreasing effects of d-propoxyphene. β-FNA (5 and 10 mg/kg) also antagonized the antinociceptive and rate-decreasing effects of morphine and dezocine as well as the antinociceptive effects of d-propoxyphene. β-FNA failed to produce a dose-dependent antagonism of the rate-decreasing effects of d-propoxyphene. Conclusions: These data suggest that the antinociceptive effects of morphine, dezocine, and d-propoxyphene and the rate-decreasing effects of morphine and dezocine are mediated through μ opioid receptors. Overall, high doses of β-FNA produced a greater degree of antagonism of the behavioral effects of dezocine than morphine or d-propoxyphene, confirming other reports that dezocine is a lower efficacy agonist than morphine. Additionally, the degree of antagonism produced by β-FNA was greater for the antinociceptive effects of all three compounds than for the rate-decreasing effects. Received: 14 August 1998 / Final version: 4 December 1998     

Hydrolysis of Carbonates,Thiocarbonates, Carbamates,and Carboxylic Esters of α-Naphthol, β-Naphthol,and p-Nitrophenol by Human,Rat, and Mouse Liver Carboxylesterases

Thirty carbonates, thiocarbonates, carbamates, and carboxylic esters of -naphthol, -naphthol, and p-nitrophenol were synthesized and tested as substrates for liver carboxylesterases from the crude microsomal fractions of human and mouse, and purified isozymes, hydrolases A and B, from rat liver microsomes. The carbonates, thiocarbonates, and carboxylic esters of -naphthol were cleaved more rapidly than the corresponding -naphthol isomers by the mammalian liver esterases. -Naphthyl esters of acetic, propionic, and butyric acids were among the best substrates tested for these enzymes. The majority of the substrates was consistently hydrolyzed at higher rates by hydrolase B compared with hydrolase A, although the Michaelis–Menten constant (K _m) values of selected substrates differed widely with these two isozymes. Malathion was a 15-fold better substrate for hydrolase B than for hydrolase A. Compared with the corresponding carboxylates, the carbonate moiety of - and -naphthol and p-nitrophenol lowered the specific activities of the enzymes by about fivefold but improved stability under basic conditions. The optimum pH of mouse liver esterase with the acetate, methylcarbonate, and ethylthiocarbonate of -naphthol was between pH 7.0 and pH 7.6. Human and mouse liver microsomal esterase activities were about five orders of magnitude lower than the esterase activities of purified rat liver hydrolase B. A relationship between the catalytic activity of the enzymes and the lipophilicity of the naphthyl substrates indicated that (i) in the - and -naphthyl carbonate series, an inverse relationship between enzyme activity and lipophilicity of the substrates was observed, whereas (ii) in the -naphthyl carboxylate series, an increase in enzyme activity with increasing lipophilicity of the substrates up to a log P value of about 4.0 was observed, after which the enzyme activity decreased.     

The Validity of Truant Youths’ Marijuana Use and Its Impact on Alcohol Use and Sexual Risk Taking

Few studies investigating the validity of marijuana use have used samples of truant youths. In the current study, self-reports of marijuana use are compared with urine test results for marijuana to identify marijuana underreporting among adolescents participating in a longitudinal brief intervention for drug-involved truant youths. It was hypothesized that marijuana underreporting would be associated with alcohol underreporting and engaging in sexual risk behaviors. The results indicated marijuana underreporting was significantly associated with self-denial of alcohol use, but not associated with sexual risk behavior. Also, there was an age effect in marijuana use underreporting such that younger truant youths were more likely to underreport marijuana use, compared to older truant youths. Implications for policy and future research are discussed.     

Dioxin Cancer Risk — Example of Hormesis?

A recent case-control study implied an inverse correlation between the measured body burden of dioxins (polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans, PCDD/F) and the risk of soft tissue sarcoma in normal population exposed to dioxins mainly via food. The surprising result could not be explained by biases or confounding. There is no a priori confounding by occupational chemicals in a random sample from general population, but exposures to other lipid soluble chemicals with similar sources might be expected to associate with that of dioxins. One such group is polychlorinated biphenyls (PCB). Therefore three most relevant dioxin-like PCB compounds PCB 77, PCB 126, and PCB 169 were now analyzed from the same patients. Cases were 110 soft-tissue sarcoma patients undergoing surgery for their disease, and referents were 227 patients operated for appendicitis. Dioxin and PCB concentrations were analyzed from subcutaneous fat samples by high-resolution gas chromatography-mass spectrometry and TCDD equivalent concentrations (WHO-TEq) were calculated by using toxicity equivalency factors of WHO. The highest risk of sarcoma was found in the septile with the lowest body burden of sum WHO-TEq, and the differences of septiles 2 and 6 from septile 1 were statistically significant. If soft sarcoma risk is true at high occupational levels of dioxins, the provocative result suggests that a possibility of a J-shaped dose-response curve should be taken into consideration and studied further. This is also supported by the similar J-shaped dose responses in animal studies.     

Effect of β-Endorphin and naloxone on acquisition,memory, and retrieval of shuttle avoidance and habituation learning in rats

Naloxone impairs acquisition of shuttle avoidance behavior (0.8 mg/kg IP) and habituation to a rearing response to a tone (1.6 mg/kg IP) in rats. -Endorphin (2 g/kg IP) has no effect on acquisition, but, when given prior to test sessions, facilitates retrieval of the two tasks. Naloxone has no effect of its own upon retrieval. In addition to these effects, the pretraining administration of -endorphin disrupts, and that of naloxone facilitates retention of the two tasks. The results are consistent with the hypothesis that these two forms of learning are state-dependent on the release of -endorphin (and, perpaps, of other opiate peptides as well), that this substance is released during training in a sufficient amount for this purpose, and that, in addition, there is a physiological amnesic mechanism mediated by opiate peptides. Furthermore, the results are also consistent with previous observations that -endorphin is released from the rat brain during training, but not during test sessions of the two tasks (Izquierdo et al., 1980b). The possibility is discussed that state-dependency and the amnesic effect comprise one single, rather than two separate mechanisms.