Toxicological resources for cumulative risk: an example with hazardous air pollutants

Cumulative risk assessment, concerned with the multiple health effects of chemical mixtures, challenges the utility of existing single-chemical regulatory references. We compare example cumulative risk assessments for 40 HAPs; one based on single-effect toxicological data from EPA, and another based on a multiple-effect toxicological database we developed. For the 40-chemical HAP subset, the multiple effect database contains information on approximately seven effects per chemical and contains a total of 290 toxicological values. Seven health effects are represented in the IRIS data. Seventeen health effects are represented in the multiple-effect data. Respiratory and neurological effects ranked first and second in both cumulative analyses, regardless of the source data. In addition to respiratory and neurological effects, gastro-intestinal/hepatic, renal/kidney, and immunologic effects were identified as effects of concern on the basis of the multiple effect data. Immunologic effects are not found in the 40-chemical IRIS dataset. Cumulative risk assessment has the potential to expand our understanding of the public health impacts of environmental exposures. Advancements in toxicological resources will improve cumulative risk assessment. Cumulative risk assessment will reduce risks to the extent that it can be integrated into prevention strategies to track and protect the public's health.     

Toxicological assessment of biological pesticides

The majority of pesticides are based on synthetic chemicals. Regulatory assessments are performed by comparing the findings in a range of routine toxicity studies, designed for testing chemicals, with estimates of exposures. Recently there have been significant moves towards developing natural/biological alternatives. Biological pesticides (those based on viable organisms) present the regulator with a different set of challenges to those raised by most chemical pesticides. The concerns associated with biological pesticides can vary greatly from one organism to another, requiring an almost case-by-case approach. The known toxicity of certain bio-molecules and the pathogenicity of certain organisms underlines the need for a risk assessment of biological pesticides. The main aspects of a health risk assessment are characterisation of the organism, infectivity, pathogenicity, sensitisation and production of toxic secondary metabolites. Obtaining information or data on these areas is not always easy as there are no widely accepted test schemes or protocols for organisms, though guidelines are being developed for the European Commission (EC). Predicting exposure following pesticidal use of an organism is made more complex if it multiplies or secretes toxic metabolites. Reliable data on effects (lack of) associated with naturally occurring (background) exposures can sometimes provide considerable reassurance. This paper describes the background to the proposed EC scheme, which has much in common with current UK practices, and presents three examples of biological pesticides which have been assessed under the existing UK procedures.     

Recent developments in regulatory requirements for developmental toxicology

A number of legislative and regulatory changes have occurred over the past 5 years to prompt the re-evaluation of the regulatory requirements for developmental toxicity testing and use of the data for risk assessment. In particular, passage of the 1996 Food Quality Protection Act (FQPA) in the United States required the USEPA to evaluate children's health risks in a more rigorous fashion, and to apply an additional 10-fold safety factor if data were inadequate or children appeared to be more sensitive than adults. A review of the testing protocols required by USEPA led to extension of the dosing period to term in the prenatal developmental toxicity study and the addition of endpoints to the 2-generation reproduction study protocol as indicators of possible neurologic, reproductive, or immune alterations. Revised testing guidelines for pesticides and toxic substances were published by USEPA in 1998, including a developmental neurotoxicity testing protocol. Further review for FQPA implementation resulted in the proposal for a core set of required toxicology studies, including routine developmental neurotoxicity, adult neurotoxicity, and adult immunotoxicity studies. In addition, development of new testing guidelines in several areas was recommended, these guidelines to be used in conjunction with or as follow-up when indicated from standard testing: developmental immunotoxicity, carcinogenesis, specialized neurotoxicity studies, endocrine disruptor studies, pharmacokinetics, and direct dosing of neonates. The impact of these efforts on the policies for toxicity testing of pesticides are discussed, and these issues are currently being reviewed on a broader scale, in particular, by evaluating the adequacy of the methods used for reference values (e.g. chronic RfD, RfC). Three major areas of focus for this review include life stages evaluated, endpoints assessed, and the duration of exposure used in various studies. A major focus of these efforts is to ensure that children's health risks are being adequately addressed in the risk assessment process.     

Toxicological barriers to providing better drugs

The unmet needs of the sick demand that toxicologic requirements do not stifle the rational search for new and better remedies. A number of conceptual problems hamper the rational use of toxicological testing. These include: a misplaced confidence in the value of animal testing, a failure to make sophisticated risk-benefit analyses, the proliferation of new tests of uncertain validity, and improperly executed retrospective case control studies.Regulatory barriers include the ever increasing bureaucratic demand for toxicological testing, the unseemly willingness of regulatory agencies to yield to hysterical or cynical consumer group pressures, the unreasonable demand for superiority of new products before the granting of registration, and the temptation to institute expensive but untested post-marketing surveillance schemes.Economic obstacles to new drug development have become formidable, and new demands for toxicologic studies in animals and humans are adding to these problems.Finally, some examples of unwise regulatory decisions involving saccharin, spray adhesives, Depo-Provera, and a new anti-metabolite are given.     

藏虫草胶囊毒理学安全性评价

目的:评价藏雪玛牌虫草胶囊的安全性。方法:依据食品安全性毒理学评价程序和方法进行急性毒理、骨髓细胞微核、精子畸形、Ames和30 d喂养实验。结果:小鼠经口最大给药量>24 g·kg-1,属实际无毒级;骨髓细胞微核、精子畸形和Ames实验结果均为阴性;30 d喂养实验中各项指标均未见异常。结论:藏雪玛牌藏虫草胶囊是较安全的。     

兰索拉唑药理与毒理研究进展

目的：明确兰索拉唑药理和毒理作用特点,为其临床用药提供参考。方法：通过对近十几年来兰索拉唑国内外相关文献进行整理、归纳与分析,综述兰索拉唑的构效特点、对消化系统的药理作用及对机体产生的毒理作用。结果：兰索拉唑具有保护胃黏膜、抑制溃疡形成、促进溃疡愈合、抗幽门螺杆菌等药理作用;毒理学研究表明兰索拉唑有潜在致癌风险。结论：应在观察上市后的兰索拉唑用药风险的基础上,进一步深入研究其毒理学特点和药物之间的相互作用,以便为临床不良反应发生做出合理解释和寻找有效解决办法,确保保证兰索拉唑临床用药的安全性、合理性和高效性。     

Toxicological evaluation of propane expanded tobacco

A tiered testing strategy has been developed to evaluate the potential for tobacco processes, ingredients, and other technological developments to increase or decrease the biological activity resulting from burning tobacco. The strategy is based on comparative chemical and biological testing. Propane expanded tobacco is an example of a processed tobacco used in the modern manufacture of cigarettes. Test cigarettes containing propane expanded tobacco were compared to control cigarettes containing tobacco expanded with a traditional expansion agent (Freon-11). The toxicological evaluation included chemistry studies using mainstream cigarette smoke (determination of selected constituent yields), in vitro studies using cigarette smoke condensate (Ames study in Salmonella typhimurium and sister chromatid exchange study in Chinese hamster ovary cells) and in vivo studies (13-week inhalation study of mainstream cigarette smoke in Sprague–Dawley rats and 30-week dermal tumor promotion study of cigarette smoke condensate in SENCAR mice). Although statistically significant differences in several smoke constituents were observed, most constituents from cigarettes containing 100% propane expanded tobacco were within market survey ranges. Furthermore, biological tests indicated that the cigarettes containing propane or Freon-11 expanded tobacco were not significantly different.     

环磷酰胺的毒副作用机制及应对措施

对临床上常用的抗肿瘤药和免疫抑制剂——环磷酰胺（cyclophosphanide）的毒副作用机制及应对措施的最新研究情况进行了介绍。目前，环磷酰胺是人们研究最多的化学致畸剂之一，而且由于需经代谢活化的特点，其也成为了前致畸原研究中的代表性药物。     

Toxicological and pharmacological concerns on oxidative stress and related diseases

Although reactive oxygen species (ROS) such as superoxide, hydrogen peroxide and hydroxyl radical are generated as the natural byproduct of normal oxygen metabolism, they can create oxidative damage via interaction with bio-molecules. The role of oxidative stress as a remarkable upstream part is frequently reported in the signaling cascade of inflammation as well as chemo attractant production. Even though hydrogen peroxide can control cell signaling and stimulate cell proliferation at low levels, in higher concentrations it can initiate apoptosis and in very high levels may create necrosis. So far, the role of ROS in cellular damage and death is well documented with implicating in a broad range of degenerative alterations e.g. carcinogenesis, aging and other oxidative stress related diseases (OSRDs). Reversely, it is cleared that antioxidants are potentially able to suppress (at least in part) the immune system and to enhance the normal cellular protective responses to tissue damage. In this review, we aimed to provide insights on diverse OSRDs, which are correlated with the concept of oxidative stress as well as its cellular effects that can be inhibited by antioxidants. Resveratrol, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statins, nebivolol and carvedilol, pentaerythritol tetranitrate, mitochondria-targeted antioxidants, and plant-derived drugs (alone or combined) are the potential medicines that can be used to control OSRD.     

Toxicological profile of carboxymethyl inulin.

Carboxymethylinulin (CMI), formed by carboxylation of a natural carbohydrate obtained from the chicory plant, is particularly effective in sequestration of hard water cations, and thus serves as a unique anti-scalant which could find uses in food processing. A series of toxicological studies has been performed to investigate its toxiciologic properties following repeated exposure, possible sensitization, and its potential to elicit genotoxic activity; all studies conformed to internationally accepted safety test guidelines currently in force. Subacute (4-week) oral toxicity was investigated in groups of rats exposed via gavage to 0, 50, 150 and 1000 mg/kg/day CMI. No treatment-related effects were observed in body weight, food consumption, mortality, hematology, clinical blood chemistry, organ weights or gross or microscopic pathology up to the highest dose (1000 mg/kg/day) tested. Motor activity, as observed in a functional observation battery, was elevated in high-dose females, and is not considered of significance toxicologically. Lack of adverse toxicity seen with CMI at this dosage is consistent with a similar lack of significant toxicity exhibited by other dietary carbohydrates (sorbitol, sucrose, glucose), oligofructoses (inulin/FOS) and carboxylated cellulose in repeated-dose rat studies at approximately the same dosage. No evidence of dermal sensitization was observed in groups of guinea pigs following CMI testing by the Magnusson-Kligman maximization test methodology. No mutagenic activity was observed when CMI was tested in four Salmonella strains-TA1535, TA1537, TA98 and TA100-or in Escherichia coli WP2uvrA bacterial point mutation assays or in an in vitro Chinese hamster ovary cell chromosomal aberration assay. The results obtained in the present study with CMI are consistent with similar data derived on numerous dietary carbohydrate fibers generally recognized as safe in the human diet.     

安梦(褪黑素)胶囊安全毒理学评价

对安梦（褪黑素）胶囊进行安全性毒理学评价。方法：用每克饲料中含８．３３、１６．６７、３３．３３ｍｇ安梦（褪黑素）胶囊内容物的低、中、高剂量组 ３０ ｄ喂养大鼠。结果：当剂量小于或等于每克饲料含 １６． ６７ ｍｇ安梦（褪黑素）胶囊内容物时，试验组的各项指标未发现异常，当剂量为３３．３３ ｍｇ时所有动物活动明显减少，常处于睡眠状态，摄食明显少于其它各组；体重和血红蛋白、红细胞压积均低于正常对照组。无作用剂量组为中剂量组。最大无作用剂量为 ２． ７６ ｇ／（ｍｍ· ｄ）。结论：一定剂量的安梦（褪黑素）胶囊安全可靠，对人体无副作用。     

The Threshold of Toxicological Concern (TTC) in risk assessment

The Threshold of Toxicological Concern (TTC) is a level of human intake or exposure that is considered to be of negligible risk, despite the absence of chemical-specific toxicity data. The TTC approach is a form of risk characterisation in which uncertainties arising from the use of data on other compounds are balanced against the low level of exposure. The approach was initially developed by the FDA for packaging migrants, and used a single threshold value of 1.5mug/day (called the threshold of regulation). Subsequent analyses of chronic toxicity data resulted in the development of TTC values for three structural classes with different potentials for toxicity (1,800, 540 and 90mug/day). These TTC values have been incorporated into the procedure that is used internationally for the evaluation of flavouring substances. Further developments included additional TTC values for certain structural alerts for genotoxicity (0.15mug/day), and for the presence of an organophosphate group (18mug/day). All of these TTC values were incorporated into an extended decision tree for chemicals, such as contaminants, which might be present in human foods. The TTC approach has been shown to have potential applications to risk assessments of cosmetic ingredients, household products and impurities in therapeutic drugs.     

Investigating the state of physiologically based kinetic modelling practices and challenges associated with gaining regulatory acceptance of model applications

Physiologically based kinetic (PBK) models are used widely throughout a number of working sectors, including academia and industry, to provide insight into the dosimetry related to observed adverse health effects in humans and other species. Use of these models has increased over the last several decades, especially in conjunction with emerging alternative methods to animal testing, such as in vitro studies and data-driven in silico quantitative-structure-activity-relationship (QSAR) predictions. Experimental information derived from these new approach methods can be used as input for model parameters and allows for increased confidence in models for chemicals that did not have in vivo data for model calibration. Despite significant advancements in good modelling practice (GMP) for model development and evaluation, there remains some reluctance among regulatory agencies to use such models during the risk assessment process. Here, the results of a survey disseminated to the modelling community are presented in order to inform the frequency of use and applications of PBK models in science and regulatory submission. Additionally, the survey was designed to identify a network of investigators involved in PBK modelling and knowledgeable of GMP so that they might be contacted in the future for peer review of PBK models, especially in regards to vetting the models to such a degree as to gain a greater acceptance for regulatory purposes.     

Aspartame: A Safety Evaluation Based on Current Use Levels,Regulations, and Toxicological and Epidemiological Studies

Aspartame is a methyl ester of a dipeptide used as a synthetic nonnutritive sweetener in over 90 countries worldwide in over 6000 products. The purpose of this investigation was to review the scientific literature on the absorption and metabolism, the current consumption levels worldwide, the toxicology, and recent epidemiological studies on aspartame. Current use levels of aspartame, even by high users in special subgroups, remains well below the U.S. Food and Drug Administration and European Food Safety Authority established acceptable daily intake levels of 50 and 40 mg/kg bw/day, respectively. Consumption of large doses of aspartame in a single bolus dose will have an effect on some biochemical parameters, including plasma amino acid levels and brain neurotransmitter levels. The rise in plasma levels of phenylalanine and aspartic acid following administration of aspartame at doses less than or equal to 50 mg/kg bw do not exceed those observed postprandially. Acute, subacute and chronic toxicity studies with aspartame, and its decomposition products, conducted in mice, rats, hamsters and dogs have consistently found no adverse effect of aspartame with doses up to at least 4000 mg/kg bw/day. Critical review of all carcinogenicity studies conducted on aspartame found no credible evidence that aspartame is carcinogenic. The data from the extensive investigations into the possibility of neurotoxic effects of aspartame, in general, do not support the hypothesis that aspartame in the human diet will affect nervous system function, learning or behavior. Epidemiological studies on aspartame include several case-control studies and one well-conducted prospective epidemiological study with a large cohort, in which the consumption of aspartame was measured. The studies provide no evidence to support an association between aspartame and cancer in any tissue. The weight of existing evidence is that aspartame is safe at current levels of consumption as a nonnutritive sweetener.     

Review of health safety aspects of nanotechnologies in food production

Due to new, previously unknown, properties attributed to engineered nanoparticles many new products are introduced in the agro-food area. Nanotechnologies cover many aspects, such as disease treatment, food security, new materials for pathogen detection, packaging materials and delivery systems. As with most new and evolving technologies, potential benefits are emphasized, while little is known on safety of the application of nanotechnologies in the agro-food sector. This review gives an overview of scientific issues that need to be addressed with priority in order to improve the risk assessment for nanoparticles in food. The following research topics are considered to contribute pivotally to risk assessment of nanotechnologies and nanoparticles in food products.

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Set a definition for NPs to facilitate regulatory discussions, prioritization of research and exchange of study results.     

Interaction profile for lead, manganese, zinc, and copper

This interaction profile discusses and evaluates the evidence for joint toxic action among lead, manganese, zinc, and copper. The interaction profile recommends how to incorporate concerns about possible interactions or additivity into public health assessments of hazardous waste sites where people might be exposed to mixtures of these chemicals. The profile recommends using endpoint-specific hazard indexes and a hazard quotient to screen for potential health effects. The qualitative weight-of-evidence (WOE) approach is then used to predict the impact of interactions on the endpoint-specific hazard indexes and hazard quotient.     

Toxicological effects of acrylamide on rat testicular gene expression profile

Toxicological effects of acrylamide on differential gene expression profile of rat testis were evaluated. Acrylamide induced morphological sperm defects, and decreased sperm concentration in cauda epididymis. Serum testosterone level and Leydig cell viability were also decreased dose-dependently, which resulted in decreased spermatogenesis. Acrylamide-induced histopathological lesions, such as formation of multinucleated giant cells and vacuolation, and numerous apoptotic cells were observed in seminiferous tubules. cDNA microarray analysis revealed that genes related to testicular-functions, apoptosis, cellular redox, cell growth, cell cycle, and nucleic acid-binding were up/down-regulated in testes isolated from acrylamide-treated group (60 mg/kg/day). Acrylamide toxicity appears to increase Leydig cell death and perturb gene expression levels, contributing to sperm defects and various abnormal histopathological lesions including apoptosis in rat testis.